Dr. Zachary Knight: The Science of Hunger & Medications to Combat Obesity
Andrew Huberman:
安德鲁·休伯曼：
Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.
欢迎来到休伯曼实验室播客，我们在这里讨论科学和基于科学的日常生活工具。
I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.
我是安德鲁·胡伯曼，斯坦福大学医学院神经生物学和眼科教授。
My guest today is Dr. Zachary Knight.
今天我的嘉宾是扎卡里·奈特博士。
Dr. Zachary Knight is a professor of physiology at the University of California, San Francisco, and an investigator with the Howard Hughes Medical Institute.
扎卡里·奈特 (Zachary Knight) 博士是旧金山加利福尼亚大学生理学教授，也是霍华德休斯医学研究所的研究员。
For those of you that don't know, Howard Hughes Medical investigators are selected from an extremely competitive pool of applicants and have to renew in order to maintain their investigatorship with the Howard Hughes Medical Institute every five years or so, placing him in the most elite of categories with respect to research scientists.
对于那些不知道的人来说，霍华德休斯医学研究所的研究人员是从竞争极其激烈的申请者中挑选出来的，并且必须每五年左右更新一次才能维持在霍华德休斯医学研究所的研究资格，这使他跻身研究科学家的最精英类别。
His laboratory focuses on homeostasis, in particular, what drives our sense of hunger, what drives our sense of thirst, and what controls thermoregulation, which is the ability to maintain body temperature within a specific safe range.
他的实验室专注于体内平衡，特别是是什么驱动我们的饥饿感、什么驱动我们的口渴感，以及什么控制体温调节，即将体温维持在特定安全范围内的能力。
Today, we mainly focus on hunger.
今天，我们主要关注饥饿问题。
Dr. Zachary Knight explains the biological mechanisms for craving food, for consuming food, and believe it or not, you have brain circuits that actually determine how much you're likely to eat even before you take your very first bite.
扎卡里·奈特博士解释了渴望食物、消耗食物的生物机制，不管你信不信，你的大脑回路实际上在你吃第一口之前就决定了你可能吃多少。
And he explains the biological mechanisms for satiety, that is, the sense that one has had enough of a particular food or food group.
他解释了饱腹感的生物机制，即人们已经吃饱了某种特定食物或食物组的感觉。
Dr. Knight also explains the role of dopamine in food craving and consumption, which I think everybody will find very surprising because it runs countercurrent to most people's understanding of what dopamine does in the context of eating and other cravings.
奈特博士还解释了多巴胺在食物渴望和消费中的作用，我认为每个人都会感到非常惊讶，因为它与大多数人对多巴胺在饮食和其他渴望中的作用的理解背道而驰。
Today's discussion also includes a deep dive into GLP-1, glucagon-like peptide, and the novel class of drugs such as Ozempic and Mounjaro and other related compounds that are now widespread in use for the reduction in body weight.
今天的讨论还包括深入探讨 GLP-1、胰高血糖素样肽以及 Ozempic 和 Mounjaro 等新型药物以及目前广泛用于减轻体重的其他相关化合物。
Dr. Knight explains how GLP-1 was first discovered and how these drugs were developed, how they work, and importantly, why they work, and how that is leading to the next generation of so-called diet drugs or drugs to treat obesity, diabetes, and related syndromes.
Knight 博士解释了 GLP-1 是如何首次发现的，这些药物是如何开发的，它们是如何起作用的，更重要的是，它们为什么起作用，以及它如何导致下一代所谓的减肥药物或治疗肥胖、糖尿病和相关综合症的药物。
We also discuss thirst and the intimate relationship between water consumption and food consumption, and we also talk about the relationship between sodium intake, water intake, and food intake.
我们还讨论了口渴以及水消耗和食物消耗之间的密切关系，我们还讨论了钠摄入量、水摄入量和食物摄入量之间的关系。
By the end of today's conversation, you will have learned a tremendous amount about the modern understanding of hunger, thirst, and salt intake, as well as this modern class of drugs such as Ozempic and related compounds, all from a truly world-class investigator in the subjects of researching hunger, thirst, and thermal regulation.
在今天的对话结束时，您将学到大量关于饥饿、口渴和盐摄入的现代理解，以及 Ozempic 和相关化合物等现代药物，所有这些都来自一位真正的世界级研究饥饿、口渴和热调节主题的研究人员。
Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.
在开始之前，我想强调一下，这个播客与我在斯坦福大学的教学和研究角色是分开的。
It is, however, part of my desire and effort to bring zero cost to consumer information about science and science-related tools to the general public.
然而，我的愿望和努力的一部分是向公众提供有关科学和科学相关工具的零成本消费者信息。
In keeping with that theme, I'd like to thank the sponsors of today's podcast.
为了与这个主题保持一致，我要感谢今天播客的赞助商。
Our first sponsor is BetterHelp.
我们的第一个赞助商是 BetterHelp。
BetterHelp offers professional therapy with a licensed therapist carried out entirely online.
BetterHelp 提供由持证治疗师完全在线进行的专业治疗。
Now, I've been doing weekly therapy for well over 30 years.
现在，我每周进行一次治疗已经有 30 多年了。
Initially, I didn't have a choice.
最初，我别无选择。
It was a condition of being allowed to stay in high school.
这是被允许留在高中的一个条件。
But quickly, I realized that therapy is an extremely important component to our overall health.
但很快，我意识到治疗对于我们的整体健康来说是极其重要的组成部分。
In fact, I consider doing regular therapy as important as getting regular cardiovascular exercise and resistance training, which of course, I also do every week.
事实上，我认为定期治疗与定期进行心血管锻炼和阻力训练一样重要，当然，我每周也会这样做。
Now, there are essentially three things that great therapy provides.
现在，伟大的治疗基本上可以提供三件事。
First of all, it requires that you have a really good rapport with the therapist, somebody that you can trust and talk to about what's really going on in your life.
首先，它要求你与治疗师有非常好的关系，一个你可以信任的人，可以与他谈论你生活中真正发生的事情。
And of course, an excellent therapist will provide you support in moving towards the things that are going to grow your life in the best ways.
当然，优秀的治疗师会为您提供支持，帮助您走向那些能够以最好的方式让您的生活成长的事情。
And third, and this is the one that people often overlook, an expert therapist is somebody who can really provide you useful insights that would not otherwise be obvious to you.
第三，这是人们经常忽视的一点，专家治疗师能够真正为您提供有用的见解，否则这些见解对您来说是不明显的。
With BetterHelp, they make it very easy to find the therapist with whom you can have those three essential and highly effective components.
借助 BetterHelp，您可以轻松找到能够获得这三个基本且高效组成部分的治疗师。
If you'd like to try BetterHelp, you can go to betterhelp.com/huberman to get 10% off your first month.
如果您想尝试 BetterHelp，可以访问 betterhelp.com/huberman，第一个月可享受 10% 的折扣。
Again, that's betterhelp.com/huberman.
再说一次，这是 betterhelp.com/huberman。
Today's episode is also brought to us by Eight Sleep.
今天的节目也是八觉给我们带来的。
Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity.
August Sleep 生产具有冷却、加热和睡眠跟踪功能的智能床垫套。
Now, I've spoken many times before on this podcast about the critical need for us to get adequate amounts of quality sleep each night.
现在，我之前已经在这个播客中多次谈到我们每晚获得充足的优质睡眠的迫切需要。
One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment.
确保一夜好眠的最佳方法之一是控制睡眠环境的温度。
And that's because in order to fall and stay deeply asleep, your body temperature actually has to drop by about one to three degrees.
这是因为为了入睡并保持深度睡眠，您的体温实际上必须下降约一到三度。
And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees.
为了醒来时感觉神清气爽、精力充沛，您的体温实际上必须升高约一到三度。
Eight Sleep makes it incredibly easy to control the temperature of your sleeping environment by allowing you to program the temperature of your mattress cover at the beginning, middle, and end of the night.
八睡眠让您可以非常轻松地控制睡眠环境的温度，您可以在晚上的开始、中间和结束时对床垫套的温度进行编程。
I've been sleeping on an Eight Sleep mattress cover for well over three years now, and it has completely transformed my sleep for the better.
我已经睡在八睡眠床垫罩上三年多了，它彻底改变了我的睡眠质量。
Eight Sleep recently launched their newest generation pod cover, the Pod 4 Ultra.
八睡眠最近推出了他们最新一代的 Pod 4 Ultra。
The Pod 4 Ultra has improved cooling and heating capacity, higher fidelity sleep tracking technology, and it also has snoring detection that remarkably will automatically lift your head a few degrees to improve your airflow and stop your snoring.
Pod 4 Ultra 具有改进的冷却和加热能力、更高保真度的睡眠跟踪技术，并且还具有打鼾检测功能，可以自动将您的头部抬起几度，以改善气流并停止打鼾。
If you'd like to try an Eight Sleep mattress cover, you can go to eightsleep.com/huberman to save $350 off their Pod 4 Ultra.
如果您想尝试八睡眠床垫套，您可以访问八睡眠.com/huberman，在 Pod 4 Ultra 上可节省 350 美元。
Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU, and Australia.
八睡眠目前运往美国、加拿大、英国、欧盟部分国家和澳大利亚。
Again, that's eightsleep.com/huberman.
再说一遍，这是八睡眠.com/huberman。
Today's episode is also brought to us by Waking Up.
今天的节目也是由Wakeing Up为我们带来的。
Waking Up is a meditation app that offers hundreds of guided meditation programs, mindfulness trainings, yoga nidra sessions, and I started practicing meditation when I was about 15 years old, and it made a profound impact on my life.
Waking Up 是一款冥想应用程序，提供数百个引导冥想计划、正念训练、瑜伽休息课程，我在 15 岁左右开始练习冥想，它对我的生活产生了深远的影响。
And by now, there are thousands of quality peer-reviewed studies that emphasize how useful mindfulness meditation can be for improving our focus, managing stress and anxiety, improving our mood, and much more.
到目前为止，已有数以千计的高质量同行评审研究强调正念冥想对于提高我们的注意力、管理压力和焦虑、改善我们的情绪等等有多么有用。
In recent years, I started using the Waking Up app for my meditations because I find it to be a terrific resource for allowing me to really be consistent with my meditation practice.
近年来，我开始使用“Waking Up”应用程序进行冥想，因为我发现它是一个很棒的资源，可以让我真正坚持我的冥想练习。
Many people start a meditation practice and experience some benefits, but many people also have challenges keeping up with that practice.
许多人开始冥想练习并体验到一些好处，但许多人也面临着跟上练习的挑战。
What I and so many other people love about the Waking Up app is that it has a lot of different meditations to choose from, and those meditations are of different durations.
我和许多其他人喜欢“醒来”应用程序的原因是它有很多不同的冥想可供选择，而且这些冥想的持续时间也不同。
So it makes it very easy to keep up with your meditation practice, both from the perspective of novelty, you never get tired of those meditations.
所以它让你很容易跟上你的冥想练习，无论是从新奇的角度来看，你永远不会厌倦这些冥想。
There's always something new to explore and to learn about yourself and about the effectiveness of meditation.
总有一些新的东西值得探索和了解你自己以及冥想的有效性。
And you can always fit meditation into your schedule, even if you only have two or three minutes per day in which to meditate.
即使您每天只有两到三分钟的时间进行冥想，您也可以随时将冥想纳入您的日程安排中。
I also really like doing Yoga Nidra or what is sometimes called non-sleep deep rest for about 10 or 20 minutes because it is a great way to restore mental and physical vigor without the tiredness that some people experience when they wake up from a conventional nap.
我也非常喜欢做瑜伽休息术，或者有时被称为非睡眠深度休息的大约 10 或 20 分钟，因为这是恢复精神和身体活力的好方法，而且不会像某些人从传统午睡中醒来时所经历的那样感到疲劳。
If you'd like to try the Waking Up app, please go to wakingup.com/huberman, where you can access a free 30-day trial.
如果您想尝试 Waking Up 应用程序，请访问 wakingup.com/huberman，在这里您可以免费试用 30 天。
Again, that's wakingup.com/huberman to access a free 30-day trial.
同样，访问 wakingup.com/huberman 即可获得 30 天免费试用。
And now for my discussion with Dr. Zachary Knight.
现在我与扎卡里·奈特博士进行了讨论。
Dr. Zachary Knight, welcome.
扎卡里·奈特博士，欢迎光临。
Dr. Zachary Knight:
扎卡里·奈特博士：
Great to be here.
很高兴来到这里。
Andrew Huberman:
安德鲁·休伯曼：
Today, we're going to talk about hunger, appetite, thirst, other motivated behaviors, the role of dopamine, the vagus nerve.
今天，我们将讨论饥饿、食欲、口渴、其他动机行为、多巴胺和迷走神经的作用。
These are terms and topics that a lot of people hear nowadays and for which there's a ton of interest.
这些是当今很多人听到并且引起很大兴趣的术语和主题。
But just to march us in sequentially, could you describe some of what's happening in the brain and/or body as we get hungry, decide what to eat, and then decide that we've had enough to eat?
但为了让我们按顺序进行，你能描述一下当我们感到饥饿、决定吃什么，然后决定我们已经吃饱时，大脑和/或身体中发生的一些事情吗？
I think most people just assume that, okay, that my stomach's full is what we say.
我想大多数人只是认为，好吧，我们说的是我的肚子饱了。
Dr. Zachary Knight:
扎卡里·奈特博士：
Right.
对。
Andrew Huberman:
安德鲁·休伯曼：
I've had enough.
我已经受够了。
Or we self-regulate it for some other reason, caloric restriction or monitoring in some cases.
或者我们出于其他原因进行自我调节，在某些情况下限制热量或进行监控。
What's happening in the brain in terms of the circuitries?
大脑中的电路发生了什么？
And what have you discovered about what that process looks like in terms of its kind of universality across people, and then maybe how it sometimes differs between people?
从人与人之间的普遍性来看，这个过程是什么样子的？也许人与人之间有时会有什么不同？
Dr. Zachary Knight:
扎卡里·奈特博士：
Okay.
好的。
There's a lot in that that I'll try to unpack.
其中有很多内容我将尝试解开。
Andrew Huberman:
安德鲁·休伯曼：
And I can remind of some of the nuance there.
我可以提醒一下其中的一些细微差别。
In other words, as a biologist, as a neuroscientist-
换句话说，作为一名生物学家，作为一名神经科学家——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
how do you think about this thing that we call hunger and feeding?
你如何看待我们所说的饥饿和喂养这件事？
Dr. Zachary Knight:
扎卡里·奈特博士：
Absolutely.
绝对的。
So, I think at a very high level, a good way to think about the regulation of food intake by the brain is that there's two systems, a short-term system and a long-term system, that are primarily localized to different parts of the brain, operate on different timescales, one on the timescale of a meal, so 10, 20 minutes, and the other on the timescale of sort of weeks to months to years, and tracks levels of body fat.
所以，我认为在一个非常高的水平上，思考大脑食物摄入调节的一个好方法是，有两个系统，一个短期系统和一个长期系统，它们主要分布在大脑的不同部分，在不同的时间尺度上运行，一个在一顿饭的时间尺度上，所以10、20分钟，另一个在几周到几个月到几年的时间尺度上，并跟踪身体脂肪水平。
And these two systems sort of interact so that these short-term behaviors we do, eating, are matched to our long-term need for energy.
这两个系统在某种程度上相互作用，因此我们所做的这些短期行为（饮食）与我们对能量的长期需求相匹配。
And so, I think one of the initial experiments that really led to this idea is this great experiment by Harvey Grill about 50 years ago.
因此，我认为真正引发这个想法的最初实验之一是 Harvey Grill 大约 50 年前的伟大实验。
It's called the decerebrate rat.
它被称为去大脑老鼠。
And so essentially what he did was he made a cut in the rat brains.
所以本质上他所做的就是在老鼠的大脑上切开一个口子。
He took these rats in the lab, made a cut so that he separated the brainstem, so the most posterior part of the brain, from the entire forebrain.
他把这些老鼠带到实验室，做了一个切口，将脑干（即大脑的最后部分）与整个前脑分开。
Basically got rid of 80% of the rat's brain.
基本上去掉了老鼠80%的大脑。
So basically creating these zombie rats, and all they have is a brainstem, and asked, "What can these rats still do?" And as you might imagine, they can't do a lot of things, because they basically have lost most of their brain.
所以基本上创造了这些僵尸老鼠，它们只有一个脑干，并问道：“这些老鼠还能做什么？”正如你可能想象的那样，他们不能做很多事情，因为他们基本上已经失去了大部分大脑。
But he discovered that one thing they can still do is regulate the size of a meal.
但他发现他们仍然可以做的一件事就是调节一顿饭的份量。
And so-
所以——
Andrew Huberman:
安德鲁·休伯曼：
A very informative experiment.
一个非常有用的实验。
Dr. Zachary Knight:
扎卡里·奈特博士：
And we have to be careful how we talk about this, because the way this meal works is you have to actually put food into their mouth, and then they'll swallow it as you put food into their mouth.
我们必须小心我们如何谈论这个，因为这顿饭的运作方式是你必须实际将食物放入他们的嘴里，然后当你将食物放入他们的嘴里时他们会吞下它。
But eventually, at some point, they'll start spitting it out.
但最终，在某个时候，他们会开始吐出来。
And that basically is an indication that in some sense, they're becoming sated, and they're just using the brainstem that they have left.
这基本上表明，从某种意义上说，他们已经感到满足了，他们只是在使用他们剩下的脑干。
They're able to sense those signals from the gut and drive the termination of a meal.
它们能够感知来自肠道的这些信号并驱动膳食的终止。
And he did other experiments showing that many of these signals that come from the gut, gastric stretch, hormones that come from your intestine in response to food intake, like CCK.
他还做了其他实验，表明许多信号来自肠道、胃伸展、肠道响应食物摄入而产生的激素，例如 CCK。
These decerebrate rats that just have a brainstem, if you inject those or manipulate the gut in those ways, it can, in an appropriate way, change how much the rat eats.
这些只有脑干的去大脑老鼠，如果你注射这些或以这些方式操纵肠道，它可以以适当的方式改变老鼠的进食量。
Now, what can't the rat do when it doesn't have a forebrain?
那么，当老鼠没有前脑时，它不能做什么呢？
The thing it can't do is it can't respond to longer-term changes in energy need, meaning if you fast the rat for a couple of days, this decerebrate rat, then start putting food in its mouth, the amount that it eats doesn't change.
它不能做的是它无法对能量需求的长期变化做出反应，这意味着如果你让老鼠禁食几天，这只去大脑的老鼠，然后开始把食物放入它的嘴里，它吃的量不会改变。
So basically, it doesn't eat a larger meal the way you would if you were fasted for several days and then re-fed.
所以基本上，它不会像禁食几天然后重新喂食那样吃更多的饭。
And that experiment, along with other evidence, has led to the idea that in the brainstem and in the most posterior part of your brain, there are neural circuits that control sort of a meal, and the timescale of 10 minutes or 20 minutes, deciding when a meal should end.
该实验与其他证据一起得出了这样的想法：在脑干和大脑的最后部分，有神经回路控制着一顿饭的种类，以及 10 分钟或 20 分钟的时间尺度，决定一顿饭应该何时结束。
And in the forebrain, primarily in the hypothalamus, there are neural circuits that then track what is my overall level of energy reserves, what is my level of body fat, things that would fluctuate on a timescale of, say, days when you're fasting.
在前脑中，主要是在下丘脑中，有一些神经回路可以跟踪我的总体能量储备水平，我的身体脂肪水平，以及在某个时间范围内（例如，禁食时的天数）波动的情况。
And those forebrain centers feedback to talk to the brainstem and modulate those brainstem circuits that are controlling the size of a meal to sort of match these two timescales.
这些前脑中心会反馈与脑干对话，并调节控制膳食量的脑干回路，以匹配这两个时间尺度。
So that's at the highest level how I think about the neural circuitry that controls feeding.
这就是我对控制进食的神经回路的最高层次的看法。
There's obviously a lot more going on underneath that.
显然，这背后还发生了很多事情。
Andrew Huberman:
安德鲁·休伯曼：
Fascinating.
令人着迷。
You mentioned body fat and that somehow the brain is tracking the amount of body fat.
您提到身体脂肪，并且大脑以某种方式跟踪身体脂肪量。
That caught my ear, because while it makes total sense, I'd like to know how that happens, if we happen to know the mechanism.
这引起了我的注意，因为虽然它完全有道理，但如果我们碰巧知道其中的机制，我想知道这是如何发生的。
And the second question is Why body fat and not body fat and muscular mass or body fat and overall body weight?
第二个问题是为什么是身体脂肪而不是身体脂肪和肌肉质量或身体脂肪和总体体重？
What is being signaled between body fat and the brain that allows the brain to track body fat, and why do you think body fat is the critical signal?
身体脂肪和大脑之间正在发出什么信号，使大脑能够追踪身体脂肪，为什么您认为身体脂肪是关键信号？
I realize it represents an energy reserve, but certainly there are other things about the bodily state that are important.
我意识到它代表能量储备，但当然，关于身体状态还有其他重要的事情。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Well, there are certainly other things about the bodily state that are important, and there are other things about physiology definitely that are regulated other than body fat.
嗯，关于身体状态当然还有其他重要的事情，而且除了身体脂肪之外，还有关于生理学的其他事情肯定是受到调节的。
But body fat is unique because it represents this energy reserve.
但身体脂肪是独一无二的，因为它代表了这种能量储备。
So the neural circuitry that regulates eating behavior is in some ways very unique because it has this reserve of energy.
因此，调节饮食行为的神经回路在某些方面非常独特，因为它具有这种能量储备。
We also study thirst in my lab and drinking, and you don't have a reserve of water in your body, right?
我们还在实验室里研究口渴和喝水，而你的身体里没有储备水，对吗？
And that's true for basically everything else.
基本上其他所有事情都是如此。
But for fat, we have this reserve of energy, and so it's very important that the brain know how much remains and then adjust behavior in accordance with that so that you know how urgent it is to get the next meal.
但对于脂肪来说，我们有这种能量储备，因此大脑知道还剩下多少能量，然后据此调整行为，这样你就知道下一顿饭有多紧急，这一点非常重要。
And so the thought is that the major signal of the level of body fat that we have is leptin.
因此我们的想法是，我们身体脂肪水平的主要信号是瘦素。
It's this hormone, it was discovered, it was cloned in 1994, actually by my postdoctoral advisor, a scientist named Jeff Friedman at Rockefeller University, although its history goes back way before 1994.
它就是这种激素，它是在 1994 年被发现的，实际上是由我的博士后导师、洛克菲勒大学的一位名叫 Jeff Friedman 的科学家克隆的，尽管它的历史可以追溯到 1994 年之前。
So the story behind leptin is that there's a facility called Jackson Labs that you, I'm sure, are familiar with in Maine that since the 1920s has been raising mice and selling them to academics, basically, who study physiology and behavior.
瘦素背后的故事是，我相信缅因州有一家名为 Jackson Labs 的机构，您对此很熟悉，该机构自 20 年代以来一直饲养小鼠并将其出售给研究生理学和行为的学者。
And so they breed thousands of mice.
因此他们繁殖了数千只老鼠。
They're sort of a nonprofit organization that distributes mice to the scientific community.
他们是一个非营利组织，向科学界分发老鼠。
And at some point in the 1950s, they spontaneously, just because they were breeding so many mice, they came across some spontaneous mutations, mutant mice that were extremely fat, like the fattest mice they had ever seen.
在20世纪50年代的某个时候，他们自发地，只是因为他们饲养了这么多老鼠，他们遇到了一些自发的突变，突变的老鼠非常胖，就像他们见过的最胖的老鼠一样。
These mice just eat constantly.
这些老鼠只是不停地吃东西。
They're just enormous, three times the size of a normal mouse.
它们非常巨大，是普通老鼠的三倍大。
And it's all body fat.
而且都是体内脂肪。
So they're just these huge fat mice.
所以它们只是这些巨大的肥老鼠。
And they came across several different mutant strains that all had the same phenotype in the sense that they were all extremely fat, all extremely hyperphagic.
他们遇到了几种不同的突变菌株，它们都具有相同的表型，即它们都非常肥胖，都非常贪食。
But they could tell even in the 1950s that these mutations were on different chromosomes.
但即使在 20 世纪 50 年代，他们也能判断出这些突变位于不同的染色体上。
They didn't know anything about how to identify the genes at that point, that was just science fiction.
那时他们对如何识别基因一无所知，那只是科幻小说。
But they knew that there were chromosomes, and they were on different chromosomes.
但他们知道染色体是存在的，而且他们位于不同的染色体上。
And so they labeled one obese, one of these mouse strains obese, and the other one diabetes, but they were basically the same.
因此，他们将一种小鼠标记为肥胖，其中一种小鼠品系为肥胖，另一种标记为糖尿病，但它们基本上是相同的。
And so people wondered for a long time, "Well, what's going on in these mice?" Then there was a scientist at Jackson Labs, Doug Coleman, who had the idea, what if we do an experiment where we connect the circulations of these two different strains of obese mice and test the hypothesis that maybe there's a circulating factor, a hormone that is produced by one of these strains, and that controls appetite.
因此人们很长一段时间都想知道：“那么，这些老鼠身上发生了什么？”然后，杰克逊实验室的一位科学家道格·科尔曼（Doug Coleman）提出了一个想法，如果我们做一个实验，将这两种不同品系的肥胖小鼠的循环连接起来，并测试一个假设，即可能存在一种循环因子，即由其中一种菌株产生的激素，可以控制食欲。
Because at that point, insulin was known, glucagon was known.
因为那时，胰岛素是已知的，胰高血糖素是已知的。
There were some hormones that were known that were involved in metabolism.
已知一些激素与新陈代谢有关。
So it was logical that there could be a hormone that perhaps regulates body fat levels.
因此，可能有一种激素可以调节身体脂肪水平，这是合乎逻辑的。
And what they found, which was remarkable, when you attach the ob strain to the db strain, so you basically connect their circulation, so hormones are transmitted between the two.
他们的发现是值得注意的，当你将 ob 菌株连接到 db 菌株时，基本上就连接了它们的循环，因此激素在两者之间传递。
The ob mouse, that strain dramatically loses weight.
ob小鼠，该品系的体重急剧减轻。
In fact, within a couple of weeks, it looks like a normal mouse.
事实上，几周之内，它就看起来像一只正常的老鼠了。
It just stops eating, it loses almost all of its body fat, and essentially in all aspects becomes a normal mouse.
它只是停止进食，几乎失去了所有的身体脂肪，基本上在各个方面都变成了一只正常的老鼠。
The db mouse, nothing really happens.
db 鼠标，什么也没发生。
It still remains obese and still remains hyperphagic.
它仍然肥胖并且仍然食量过多。
And based on just that piece of data, Doug Coleman hypothesized that what was going on is these two mutations were mutations in a hormone and a receptor.
基于该数据，道格·科尔曼假设这两种突变是激素和受体的突变。
The ob mouse had a mutation in the hormone that comes from fat, so it couldn't produce this hormone that comes from fat and signals to the brain how much fat you have.
ob小鼠体内的脂肪激素发生了突变，因此它无法产生这种来自脂肪的激素并向大脑发出信号，告诉大脑你有多少脂肪。
And the db mouse has a mutation in the receptor, so it can't sense the hormone.
而db小鼠的受体发生了突变，因此它无法感知激素。
And that was just an idea, it was a hypothesis.
那只是一个想法，一个假设。
But in the 1980s, as technology advanced, molecular biology had been invented, it became possible to clone genes.
但到了 20 世纪 80 年代，随着技术的进步，分子生物学的发明，克隆基因成为可能。
A number of people tried to identify what are the genetic mutations that are occurring in these mice that make them so obese.
许多人试图找出这些老鼠身上发生的基因突变是什么导致它们如此肥胖。
And Jeff basically cloned leptin and showed that, in fact, Doug was exactly right.
杰夫基本上克隆了瘦素，并表明道格实际上是完全正确的。
The ob mutation is a mutation in this hormone, leptin.
ob突变是瘦素这种激素的突变。
And later, Millennium Pharmaceuticals showed that the db mutation is in fact a receptor.
后来，Millennium Pharmaceuticals 证明 db 突变实际上是一种受体。
And it was an important discovery for a couple of reasons.
由于几个原因，这是一个重要的发现。
One, because this ob gene is just expressed in fat.
一，因为这个ob基因只在脂肪中表达。
It's exclusively expressed in adipose tissue.
它仅在脂肪组织中表达。
And how much it's expressed is directly proportional to how much body fat you have.
它表达的多少与你体内脂肪的多少成正比。
So as you gain weight, the expression of this hormone increases in a linear manner, and then it's secreted into the blood.
因此，当您体重增加时，这种激素的表达会以线性方式增加，然后分泌到血液中。
So the level of leptin in your blood is a direct readout of your body fat reserves.
因此，血液中的瘦素水平可以直接读出您体内的脂肪储备。
This receptor for leptin, the leptin receptor, the functional form of it is expressed almost exclusively in the brain, and it's expressed in all of the brain regions that we knew from previous work were important for appetite.
这种瘦素受体，瘦素受体，它的功能形式几乎只在大脑中表达，并且它在我们从之前的工作中知道对食欲很重要的所有大脑区域中表达。
So basically, the expression of this receptor gives you a map in the brain of the neurons that control hunger.
基本上，这种受体的表达为您提供了大脑中控制饥饿的神经元的地图。
And so what happens is, basically, when you lose weight, the levels of leptin in your blood fall because basically you've lost adipose tissue.
所以基本上，当你减肥时，你血液中的瘦素水平会下降，因为基本上你已经失去了脂肪组织。
The absence of that hormone sends a signal to all these neurons that have leptin receptors in the brain.
这种激素的缺失会向大脑中所有具有瘦素受体的神经元发送信号。
They're not getting that signal that I'm starving.
他们没有收到我快饿死的信号。
And basically, that initiates this entire homeostatic response to starvation.
基本上，这启动了对饥饿的整个稳态反应。
So a big part of that is obviously increased hunger, but it's also decreased energy expenditure, decreased body temperature, even decreased fertility, because you don't want to reproduce if you're starving.
因此，其中很大一部分显然是饥饿感增加，但它也减少了能量消耗，降低了体温，甚至降低了生育能力，因为如果你挨饿了，你就不想繁殖。
Andrew Huberman:
安德鲁·休伯曼：
Less spontaneous movement.
自发运动较少。
Dr. Zachary Knight:
扎卡里·奈特博士：
Less spontaneous movement, all of this.
自发运动减少，所有这一切。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
And so the thought is, which I think is absolutely correct, is that this hormone leptin is part of this negative feedback loop from the fat to the brain that basically tells you about your level of body fat reserves and how urgent it is to find the next meal.
因此，我认为绝对正确的想法是，这种激素瘦素是从脂肪到大脑的负反馈循环的一部分，它基本上告诉您体内脂肪储备的水平以及寻找下一顿饭的紧迫性。
Andrew Huberman:
安德鲁·休伯曼：
Fascinating.
令人着迷。
As I recall, Amgen Pharmaceuticals owned the patent for leptin in hopes that it would become the blockbuster diet drug.
我记得安进制药公司拥有瘦素的专利，希望它能成为重磅减肥药。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
The logic being that if you were to take this hormone somehow or activate this pathway, that the brain would be tricked into thinking that there was more body fat, more energy reserves than there was, and then people would basically be less hungry, eat less, and lose body fat.
逻辑是，如果你以某种方式服用这种激素或激活这个途径，大脑就会被欺骗，认为体内有更多的脂肪、更多的能量储备，然后人们基本上就会不那么饥饿，吃得更少，并减少体内脂肪。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
What happened with that?
那是怎么回事？
Do we know why it did not work?
我们知道为什么它不起作用吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
So that's a great question.
这是一个很好的问题。
So, there was a lot of excitement when leptin was cloned because it was thought, basically, we've cured obesity.
因此，当瘦素被克隆时，人们感到非常兴奋，因为人们认为基本上我们已经治愈了肥胖症。
There was an auction for the patent.
该专利进行了拍卖。
Amgen won, I think it was something like $20 million upfront payment plus royalties, which at the time, it still is a lot of money, but even more money.
安进赢了，我想大概是 2000 万美元的预付款加上特许权使用费，这在当时来说仍然是一大笔钱，甚至更多。
Andrew Huberman:
安德鲁·休伯曼：
But nowadays it would be a drop in the ocean compared to what companies will invest-
但如今，与公司的投资相比，这只是沧海一粟——
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly
正是如此
Andrew Huberman:
安德鲁·休伯曼：
...
...
into potential diet drugs.
成为潜在的减肥药。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
But at the time, and still a lot of money today.
但在当时，和今天还是很多钱。
And they did a clinical trial, gave obese people leptin, subcutaneous injections of this hormone, and they didn't lose a lot of weight.
他们做了一个临床试验，给肥胖的人注射瘦素，皮下注射这种激素，他们的体重并没有减轻很多。
And the question was why.
问题是为什么。
And so what was subsequently revealed is that the challenge with leptin is that individuals who are obese do not have low levels of leptin for the most part.
因此随后发现，瘦素面临的挑战是肥胖者的瘦素水平在大多数情况下并不低。
They actually have high levels of leptin.
他们实际上含有高水平的瘦素。
And so what they have is a state of leptin resistance.
所以他们所面临的是瘦素抵抗状态。
So it's analogous to someone who has type 2 diabetes.
这类似于患有 2 型糖尿病的人。
It's not because they lack insulin, it's because they actually have, over time, a high level of insulin, and so target tissues stop responding to insulin.
这并不是因为它们缺乏胰岛素，而是因为随着时间的推移，它们实际上具有高水平的胰岛素，因此目标组织停止对胰岛素做出反应。
And the thought is that it's the same way in obesity and leptin.
人们认为肥胖和瘦素的情况是一样的。
Now, subsequently, they went back and did a reanalysis of that clinical trial and asked, what if you take all of these people and stratify them according to their starting leptin level?
现在，随后，他们回去对该临床试验进行了重新分析，并问道，如果你对所有这些人根据他们的起始瘦素水平进行分层会怎样？
So some people have relatively low levels of leptin, some have higher, some have really high levels of leptin.
因此，有些人的瘦素水平相对较低，有些人的瘦素水平较高，有些人的瘦素水平非常高。
And then ask, if we reanalyze the data, how effective is leptin?
然后问，如果我们重新分析数据，瘦素的效果如何？
And as you might expect, the people with the lowest levels of leptin, they lost the most weight when you gave them this drug, and the people with the highest levels of leptin lost the least weight.
正如您所预料的那样，瘦素水平最低的人在服用这种药物时体重减轻最多，而瘦素水平最高的人体重减轻最少。
So there is a rationale there for a scenario in which leptin could work, either among the subset of people who just have, for some reason, lower levels of leptin.
因此，瘦素可以发挥作用是有道理的，无论是在那些由于某种原因瘦素水平较低的人中。
These aren't people with mutations like the obese mouse.
这些人不像肥胖老鼠那样有突变。
They have some leptin, they just don't have unusually high levels.
他们有一些瘦素，只是含量没有异常高。
Or alternatively, after weight loss.
或者，减肥后。
So after you've lost a lot of weight, your leptin levels plummet.
因此，当你减掉很多体重后，你的瘦素水平就会直线下降。
They become very low, and a big part of the reason it's so difficult to keep weight off is because those leptin levels are so low.
它们变得非常低，而减肥如此困难的一个重要原因是瘦素水平太低了。
And so it's been thought for a long time that is a scenario where treating people with leptin could be really useful to help them keep the weight off.
因此，长期以来人们一直认为，用瘦素治疗人们可能确实有助于帮助他们减轻体重。
Why it never made it as a drug for that application, I really don't understand.
为什么它从未作为该应用的药物，我真的不明白。
It has something to do, I think, with the pharmaceutical industry, with the economics, with a bunch of other issues that aren't necessarily scientific.
我认为，这与制药业、经济以及其他一些不一定是科学的问题有关。
But I think there still, in the future, is a possibility that it could come back for that indication, especially now that we have these GLP-1 drugs and now there's just millions of people losing so much weight, and perhaps they want to transition to a different kind of drug to keep the weight off.
但我认为，在未来，它仍然有可能再次出现这种适应症，特别是现在我们有了这些 GLP-1 药物，而且现在只有数百万人体重减轻了很多，也许他们想要过渡到另一种药物来减轻体重。
Andrew Huberman:
安德鲁·休伯曼：
Well, we are definitely going to talk about GLP-1, Ozempic, and some of the related compounds in a few minutes.
好吧，我们肯定会在几分钟内讨论 GLP-1、Ozempic 和一些相关化合物。
But before we do that, I'd love to get to this issue of what's happening in the brain as we get hungry, approach a meal, decide what to eat, and decide when we've had enough.
但在此之前，我想先讨论一下当我们感到饥饿、准备吃饭、决定吃什么以及决定何时吃饱时，大脑中发生了什么。
Are there separate circuitries or at least separate neurons for each of those steps?
每个步骤是否都有单独的电路或至少单独的神经元？
And if you would, could you walk us through what that process looks like since we do it every day, most people do it every day unless they're fasting-
如果你愿意的话，你能告诉我们这个过程是什么样子的吗？因为我们每天都会这样做，大多数人每天都会这样做，除非他们在禁食——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
multiple times per day.
每天多次。
What's going on in our brain and body as we think about and approach a meal-
当我们思考和接近一顿饭时，我们的大脑和身体正在发生什么——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
consume a meal-
吃一顿饭——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
and decide enough?
并决定足够吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
So, there are different neurons that are preferentially involved in different aspects of those processes.
因此，不同的神经元优先参与这些过程的不同方面。
So, I think we often divide feeding behavior and many other kinds of motivated behaviors into appetitive and consummatory phases.
所以，我认为我们经常将进食行为和许多其他类型的动机行为分为食欲阶段和完成阶段。
So appetitive is the phase of the behavior where you're, for example, searching for food.
食欲是指你的行为阶段，例如寻找食物。
It's foraging.
它正在觅食。
It's all the actions that lead up to the actual behavior itself, which then we call the consummatory phase.
所有的行动都会导致实际行为本身，我们称之为“完成阶段”。
That's actually putting the food in your mouth and eating it.
这实际上是将食物放入嘴里并吃掉。
And the general thought is that these forebrain circuits in the hypothalamus are more important, particularly in the hypothalamus, but other parts of the forebrain as well, are more important for the appetitive phase, and the brain stem circuits are more important for the consummatory phase, the actual putting it in your mouth and licking, chewing, swallowing, and all of that.
一般认为，下丘脑中的这些前脑回路更重要，特别是在下丘脑中，但前脑的其他部分对于食欲阶段也更重要，而脑干回路对于完成阶段更重要，即实际将其放入口中并舔、咀嚼、吞咽等等。
Within the hypothalamus, there's a population of neurons called AgRP neurons.
下丘脑内有一群神经元，称为 AgRP 神经元。
So it's just an acronym, AgRP, and it stands for agouti-related peptide, but it doesn't really matter.
所以它只是一个缩写词，AgRP，代表刺豚鼠相关肽，但这并不重要。
They're absolutely critical for that appetitive phase, for the searching for food, for the desire to find food and consume it when you're hungry.
它们对于食欲阶段、寻找食物、渴望找到食物并在饥饿时食用它绝对至关重要。
Andrew Huberman:
安德鲁·休伯曼：
Sorry, just to touch on the AgRP neurons and this appetitive phase, are they known to connect to areas of the brain and body that stimulate the desire to move?
抱歉，只是想谈谈 AgRP 神经元和这个食欲阶段，它们是否已知与刺激运动欲望的大脑和身体区域相连？
Because I think about when I get hungry, if I'm at my desk or something, I need to get up and find food.
因为我想到当我饿了时，如果我在办公桌前或其他什么地方，我需要站起来寻找食物。
I need to walk to lunch or go to the refrigerator.
我需要步行去吃午饭或去冰箱。
Are they somehow linked to the circuits that promote locomotion?
它们是否与促进运动的回路有某种联系？
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, they have to promote those things.
好吧，他们必须推广这些东西。
But they're not directly linked to any of those circuits.
但它们并不直接连接到任何这些电路。
They're linked directly to other forebrain circuits involved in motivation.
它们与参与动机的其他前脑回路直接相连。
So the way we think about what these kinds of neurons, like AgRP neurons, are doing, they're not directly talking to the motor circuits to tell you to move your legs or arms to pick up the sandwich or whatever.
因此，我们思考这些类型的神经元（如 AgRP 神经元）正在做什么的方式是，它们不会直接与运动回路对话，告诉你移动你的腿或手臂来捡起三明治或其他东西。
They're rather creating this general problem that the animal has to solve, which is that, "I'm hungry.
他们宁愿创造动物必须解决的普遍问题，那就是“我饿了。
I need to get food.
我需要去买食物。
It would be really great if I could have a sandwich." And then the animal uses all of its mental capacities to solve that problem.
如果我能吃到三明治那就太好了。”然后动物利用其所有的智力来解决这个问题。
So they're just there to set the goal, not so much to direct the solution.
所以他们只是设定目标，而不是指导解决方案。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
But these AgRP neurons, there are a few thousand neurons at the base of the hypothalamus.
但是这些AgRP神经元，在下丘脑的基部有几千个神经元。
So basically the most ventral, the most bottom part of the forebrain.
所以基本上是前脑的最腹侧、最底部的部分。
So a tiny population of cells, but outsized importance for the control of feeding behavior.
虽然细胞数量极少，但对于控制摄食行为却异常重要。
So if you stimulate these cells in a mouse or a rat that's not hungry, the animal will voraciously eat like it's starving.
因此，如果你刺激不饥饿的小鼠或大鼠的这些细胞，这些动物就会像饥饿一样贪婪地吃东西。
If you silence these cells, animals will starve to death.
如果你让这些细胞沉默，动物就会饿死。
So you can basically give them food, they just won't eat it voluntarily until basically you have to euthanize them because they've lost so much weight.
所以你基本上可以给他们食物，他们只是不会自愿吃东西，直到基本上你不得不对他们实施安乐死，因为他们体重减轻了很多。
And the activity of these AgRP neurons is thought to track the body's need for energy.
这些 AgRP 神经元的活动被认为可以追踪身体对能量的需求。
One reason that's thought is that they express these receptors for leptin, this hormone that I was just talking about that comes from fat and signals the level of body fat reserves.
人们认为的一个原因是它们表达瘦素的这些受体，我刚才谈到的这种激素来自脂肪，并发出身体脂肪储备水平的信号。
And leptin inhibits AgRP neurons.
瘦素抑制 AgRP 神经元。
So as you might expect, if you have lots of body fat, then a neuron that controls hunger should be less active than if you have very little body fat.
因此，正如您所预料的那样，如果您体内脂肪较多，那么控制饥饿的神经元应该比体内脂肪很少时更不活跃。
So that's one mechanism by which leptin controls hunger.
这就是瘦素控制饥饿的一种机制。
We in my lab have investigated the role of these AgRP neurons from a slightly different perspective, which is, and this relates to your question about what happens when we approach food, when we start a meal.
我们实验室从一个稍微不同的角度研究了这些 AgRP 神经元的作用，这与你的问题有关，当我们接近食物、当我们开始吃饭时会发生什么。
And to ask, what are their activity patterns?
并询问他们的活动模式是什么？
What is the natural sort of firing of this population of neurons when an animal eats a meal?
当动物进食时，这群神经元的自然放电方式是什么？
It's a very basic question, something I think we've wanted to know for a long time.
这是一个非常基本的问题，我想我们长期以来一直想知道这个问题。
Was not really addressable until about 10 years ago because just the technology didn't exist because these are such a tiny population of cells, so deep in the brain.
直到大约 10 年前，这个问题才真正得到解决，因为当时还不存在这项技术，因为这些细胞的数量非常少，而且位于大脑深处。
So one of the very first experiments we did in my lab was to investigate that, to ask for the first time what happens to these AgRP neurons when an animal eats.
因此，我们在实验室做的第一个实验就是对此进行研究，首次询问当动物进食时这些 AgRP 神经元会发生什么。
And so, one of my first graduate students, Yiming Chen, he used a technology called fiber photometry, which allows us to put a fiber optic into the mouse's brain so then we could record fluorescence from these AgRP neurons, which we could use as a readout of their activity.
因此，我的第一批研究生陈一鸣使用了一种称为光纤光度测定的技术，该技术使我们能够将光纤放入小鼠的大脑中，这样我们就可以记录这些 AgRP 神经元的荧光，我们可以将其用作其活动的读数。
It's basically using a calcium sensor, so calcium as a surrogate for neural activity.
它基本上使用钙传感器，因此钙可以作为神经活动的替代品。
And one of the very first experiments he did, we said, let's make the animal hungry.
我们说，他做的第一个实验之一就是让动物挨饿。
These AgRP neurons will be very active because the animal's hungry, and then let's give it some food and see what happens during a meal.
这些 AgRP 神经元会非常活跃，因为动物饿了，然后我们给它一些食物，看看吃饭时会发生什么。
And our expectation was that these AgRP neurons would gradually decline in activity as the animal eats and levels of hormones in the blood start changing, feeding back to inhibit these neurons.
我们的预期是，当动物进食时，这些 AgRP 神经元的活性会逐渐下降，血液中的激素水平开始变化，反馈抑制这些神经元。
What we found was really surprising.
我们的发现确实令人惊讶。
I remember when he made this discovery, basically him running into my office and saying, "Zach, I gave the mouse the piece of food, but the weirdest thing happened.
我记得当他做出这个发现时，基本上他跑进我的办公室说：“扎克，我给了老鼠一块食物，但最奇怪的事情发生了。
The neurons shut off almost immediately." And I said, "Yiming, you've made a mistake.
神经元几乎立即关闭。”我说：“一鸣，你错了。
It's okay.
没关系。
You're just starting off in graduate school.
你刚刚开始读研究生。
This happens.
会发生这种情况。
Go back and repeat the experiment, and then we'll discuss it." But he did it several times.
回去重复一下实验，然后我们再讨论。”但他这样做了好几次。
He said, "You know, Zach, every single time I do it, this happens.
他说：“你知道，扎克，每次我这样做时，都会发生这种情况。
I give a hungry mouse food and the AgRP neurons within just a few seconds, their activity has greatly diminished back to the level it would be in a fed mouse, even before they take the first bite of food." And so Yiming then went to do a series of experiments to try to understand what was going on.
我给一只饥饿的小鼠喂食，AgRP 神经元在短短几秒钟内，它们的活性就大大减弱，回到了进食小鼠的水平，甚至在它们吃第一口食物之前。”于是一鸣就去做了一系列的实验，试图了解到底发生了什么。
And what he basically showed by changing the kind of food he gave them or the accessibility of the food or how hungry the mouse was and measuring the response of these AgRP neurons, was that what the neurons were doing was predicting.
他通过改变给它们的食物种类、食物的可及性或小鼠的饥饿程度，并测量这些 AgRP 神经元的反应，基本上表明，神经元正在做的事情是预测。
The mouse looks at the food, it looks at how palatable it is, it matches how hungry the mouse is, how accessible it is, and then within a few seconds these neurons predict how much food the mouse is going to eat in the forthcoming meal.
老鼠看着食物，它会看它的可口性，它与老鼠的饥饿程度，食物的可及性相匹配，然后在几秒钟内，这些神经元预测老鼠在即将到来的一餐中会吃多少食物。
And so essentially these neurons know how much the mouse is going to eat before the mouse even takes the first bite.
因此，基本上，这些神经元在老鼠吃第一口之前就知道老鼠要吃多少东西。
And you can show this by a very simple analysis in which you give the mouse different foods and you look at how much these AgRP neurons drop when the mouse sees and smells the food.
你可以通过一个非常简单的分析来展示这一点，在该分析中，你给老鼠提供不同的食物，然后观察当老鼠看到和闻到食物时，这些 AgRP 神经元下降了多少。
And then you plot that against, this drop happens in three seconds, four seconds, something like that.
然后你将其绘制出来，这种下降发生在三秒、四秒之内，类似的事情。
Then you look at how much does the mouse go on to eat in the next 30 minutes.
然后你看看老鼠在接下来的 30 分钟内吃了多少。
You can just draw a straight line.
你可以只画一条直线。
So this was one of the first results from my lab and it was really surprising to all of us, and I think everyone.
这是我实验室的第一个结果，它让我们所有人（我想每个人）都感到惊讶。
But it illustrated a theme that we've now seen again and again, which is that these circuits that control internal state, control things like hunger and thirst, what they're constantly doing is predicting the future.
但它说明了一个我们现在一次又一次看到的主题，那就是这些控制内部状态、控制饥饿和口渴等事物的电路，它们不断做的就是预测未来。
They can sense these signals from the body that tell you about what's happened, but those signals are slow, and you don't want to wait 20 minutes from the food that you ingested to reach your stomach and then slowly start entering your intestine to figure out what was the nutrient content of the meal.
它们可以感觉到身体发出的这些信号，告诉您发生了什么，但这些信号很慢，您不想在摄入的食物到达胃部 20 分钟后才慢慢开始进入肠道来了解膳食的营养成分。
You want to try to figure that out as soon as you can.
你想尽快弄清楚这一点。
Right?
正确的？
And so the animals learn, presumably through just experience, that okay something that smells like this and looks like this, it has about this many calories and I know I'm this hungry so I'm going to eat about this much.
所以动物们大概是通过经验了解到，好吧，闻起来像这样、看起来像这样的东西，它含有这么多卡路里，我知道我很饿，所以我要吃这么多。
And then that information is all transmitted to these circuits to start the process of satiation before the meal begins.
然后这些信息全部传输到这些电路，在进餐前开始饱足过程。
Andrew Huberman:
安德鲁·休伯曼：
Is it satiation or it's ceasing of foraging so that-
是吃饱了还是停止觅食以至于——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
the animal or if I translate to a person, decides, "Okay, now I'm going to consume this sandwich, this package of food."
动物，或者如果我翻译成人，决定，“好吧，现在我要吃这个三明治，这包食物。”
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
That's a great question.
这是一个很好的问题。
So, we don't fully know the answer.
所以，我们并不完全知道答案。
So one interpretation of the data I just showed you is exactly what you said, is that what these neurons do is they control foraging alone, they don't control eating.
因此，对我刚才向您展示的数据的一种解释正是您所说的，这些神经元所做的只是它们单独控制觅食，而不是控制进食。
And so this is perfect.
所以这是完美的。
You see the food, you know it's got enough calories, the neurons shut off and then you stay there and eat it.
你看到食物，就知道它含有足够的卡路里，神经元关闭，然后你就呆在那里吃它。
You transition from this appetitive to this consummatory phase.
你从这个食欲阶段过渡到这个完成阶段。
But that doesn't seem to be the whole explanation because if you artificially stimulate these neurons, so prevent that drop from ever happening, just stimulate them continually, the mouse will just sit there and eat.
但这似乎并不是全部的解释，因为如果你人为地刺激这些神经元，防止这种下降的发生，只要不断地刺激它们，老鼠就会坐在那里吃东西。
So you can't fully separate, although we like to make this distinction between appetitive and consummatory, and we know that in different parts of the brain they're more important for one versus the other.
所以你不能完全分开，尽管我们喜欢区分欲望和完美，而且我们知道在大脑的不同部分，它们对一个比另一个更重要。
The reality is that the entire behavior is linked and you can't fully separate them.
现实情况是，整个行为都是相互关联的，你无法将它们完全分开。
So there's a number of ideas about what this means.
因此，关于这意味着什么，有很多想法。
So one idea that I just mentioned is that starting the process of satiety before the meal begins.
所以我刚才提到的一个想法是，在进餐之前就开始饱腹感的过程。
Another idea which you mentioned, which could be part of the answer is that it is reducing this appetitive drive and allowing the transition to consummatory behavior.
您提到的另一个想法（可能是答案的一部分）是，它正在减少这种食欲驱动力并允许过渡到完美行为。
Another idea is that, and I call these ideas because we don't really fully know the answer yet for exactly what the purpose is, and in biology it's always hard to answer why something happens.
另一个想法是，我之所以这么称呼这些想法，是因为我们还没有真正完全知道其目的是什么，而在生物学中，总是很难回答为什么会发生某些事情。
You can figure out what happens, but the reason why it evolved that way is challenging.
你可以弄清楚会发生什么，但它为何如此演变的原因却具有挑战性。
Another idea is it's involved in these what we call cephalic phase responses that are necessary to prepare you for a meal.
另一个想法是，它参与了我们所说的头期反应，这是准备吃饭所必需的。
Right?
正确的？
So the famous example of this is Pavlov, right?
那么著名的例子就是巴甫洛夫，对吗？
Basically, trains the dog to associate the ring of the bell with the presentation of food and then eventually the ring of the bell alone causes the dog to salivate in the absence of any food.
基本上，训练狗将铃声与食物的呈现联系起来，然后最终仅铃声一响就会导致狗在没有任何食物的情况下流口水。
And Salivation is one example of a cephalic phase response.
流涎是头相反应的一个例子。
The purpose of that is to have enzymes in your mouth that basically are going to digest the food and get them there right before you need them.
其目的是让您的口腔中含有酶，这些酶基本上可以消化食物，并在您需要它们之前将它们送到那里。
But there's all sorts of other things, like basically the secretion of insulin occurs in response to food cues, changes in gastric acid, gut motility.
但还有各种各样的其他因素，比如胰岛素的分泌基本上是根据食物信号、胃酸的变化、肠道蠕动而发生的。
All these things are getting ready for the meal to happen.
所有这些事情都在为用餐做好准备。
And so another idea is it could be part of that, but it probably is doing all of these things.
所以另一个想法是它可能是其中的一部分，但它可能正在做所有这些事情。
Andrew Huberman:
安德鲁·休伯曼：
As many of you know, I've been taking AG1 for more than 10 years now, so I'm delighted that they're sponsoring this podcast.
你们很多人都知道，我服用 AG1 已有 10 多年了，所以我很高兴他们赞助这个播客。
To be clear, I don't take AG1 because they're a sponsor.
需要明确的是，我选择 AG1 并不是因为他们是赞助商。
Rather, they are a sponsor because I take AG1.
相反，他们是赞助商，因为我选择了 AG1。
In fact, I take AG1 once and often twice every single day, and I've done that since starting way back in 2012.
事实上，我每天服用一次 AG1，经常服用两次，早在 2012 年我就开始这样做了。
There is so much conflicting information out there nowadays about what proper nutrition is, but here's what there seems to be a general consensus on.
关于什么是适当的营养，现在有很多相互矛盾的信息，但以下是似乎达成的普遍共识。
Whether you're an omnivore, a carnivore, a vegetarian, or a vegan, I think it's generally agreed that you should get most of your food from unprocessed or minimally processed sources, which allows you to eat enough but not overeat, get plenty of vitamins and minerals, probiotics, and micronutrients that we all need for physical and mental health.
无论你是杂食动物、肉食动物、素食主义者还是纯素食主义者，我认为人们普遍认为你应该从未经加工或最低限度加工的来源获取大部分食物，这样你就可以吃得足够但不过量，获得充足的维生素和矿物质、益生菌和微量营养素，这些都是我们身心健康所需的。
Now, I personally am an omnivore, and I strive to get most of my food from unprocessed or minimally processed sources.
现在，我个人是杂食动物，我努力从未加工或最低限度加工的来源获取大部分食物。
But the reason I still take AG1 once and often twice every day is that it ensures I get all of those vitamins, minerals, probiotics, etc., but it also has adaptogens to help me cope with stress.
但我仍然每天服用一次 AG1（通常是两次）的原因是它可以确保我获得所有维生素、矿物质、益生菌等，而且它还含有适应原来帮助我应对压力。
It's basically a nutritional insurance policy meant to augment, not replace, quality food.
它基本上是一项营养保险政策，旨在增强而不是取代优质食品。
So by drinking a serving of AG1 in the morning and again in the afternoon or evening, I cover all of my foundational nutritional needs.
因此，通过早上喝一份 AG1，然后在下午或晚上再喝一次，我就可以满足我所有的基本营养需求。
And I, like so many other people that take AG1, report feeling much better in a number of important ways, such as energy levels, digestion, sleep, and more.
和许多其他服用 AG1 的人一样，我报告在许多重要方面感觉好多了，例如能量水平、消化、睡眠等。
So while many supplements out there are really directed towards obtaining one specific outcome, AG1 is foundational nutrition designed to support all aspects of well-being related to mental health and physical health.
因此，虽然许多补充剂实际上是为了获得一种特定的结果，但 AG1 是基础营养，旨在支持与心理健康和身体健康相关的各个方面的福祉。
If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer.
如果您想尝试 AG1，可以访问 Drinkag1.com/huberman 申请特别优惠。
They'll give you five free travel packs with your order, plus a year's supply of vitamin D3 K2.
您订购后，他们将赠送 5 个免费旅行套装，以及一年的维生素 D3 K2。
Again, that's drinkag1.com/huberman.
再说一遍，这是 Drinkag1.com/huberman。
It's so interesting.
太有趣了。
I have a number of questions, but I think the one that I'll put at the top of the list is the other night we were out to dinner in New York, and I was very hungry.
我有很多问题，但我想我首先要问的是我们在纽约出去吃饭的那天晚上，我非常饿。
I hadn't eaten much that day, and I was looking forward to a nice steak.
那天我没吃多少东西，我期待着一顿美味的牛排。
They brought out bread, French bread.
他们带来了面包，法式面包。
It was a French restaurant.
那是一家法国餐厅。
I took one bite.
我咬了一口。
I realized it was absolutely delicious French bread.
我意识到这绝对是美味的法式面包。
The butter was fantastic, and so I had some bread and butter, which I love.
黄油很棒，所以我吃了一些我喜欢的面包和黄油。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Then they brought more, and then they started bringing out, I don't know who ordered them because I didn't, appetizers, and I realized that this was going to be a much more extensive, calorically dense meal, and suddenly my appetite for the appetizers went down because I knew there was more food coming, right?
然后他们带来了更多，然后他们开始拿出，我不知道谁点了它们，因为我没有，开胃菜，我意识到这将是一顿更丰富、热量更密集的饭菜，突然我对开胃菜的胃口下降了，因为我知道还有更多的食物，对吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Had I not known that there was more food coming-
如果我不知道还有更多食物来-
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes
是的
Andrew Huberman:
安德鲁·休伯曼：
...
...
I think I would have consumed more of the appetizers, which also looked great.
我想我会吃更多的开胃菜，看起来也很棒。
So clearly, there's something going on with these AgRP neurons at the moment.
很明显，这些 AgRP 神经元目前正在发生一些事情。
Dr. Zachary Knight:
扎卡里·奈特博士：
Right.
对。
Andrew Huberman:
安德鲁·休伯曼：
You're sort of integrating based on new information.
您正在根据新信息进行整合。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
On the other end of the spectrum, I did a solo episode about eating disorders and anorexia nervosa in particular, and one of the things that I learned from experts in that field, the psychiatrists who work on this and the scientists who work on this, is that people with anorexia are unbelievably tuned to the caloric content of food.
另一方面，我做了一个关于饮食失调和神经性厌食症的独奏节目，我从该领域的专家、从事这方面工作的精神病学家和从事这方面工作的科学家那里学到的一件事是，厌食症患者对食物的热量含量有着令人难以置信的适应。
Dr. Zachary Knight:
扎卡里·奈特博士：
Huh.
呵呵。
Andrew Huberman:
安德鲁·休伯曼：
That their visual system and presumably other systems have become almost hyper-accurate calculators of the amount of calories in food.
他们的视觉系统以及可能的其他系统几乎已经成为食物中卡路里含量的超精确计算器。
They've devoted a lot of cognition to it.
他们为此投入了大量的认知。
It sometimes can-
有时它可以——
Dr. Zachary Knight:
扎卡里·奈特博士：
Interesting
有趣
Andrew Huberman:
安德鲁·休伯曼：
...
...
border on or be placed within the obsessive realm, but that they see food and they can tell you a tremendous amount about the caloric amounts with these foods, even food combinations to-
接近或被置于痴迷领域，但他们看到食物，他们可以告诉你大量关于这些食物的热量含量，甚至是食物组合——
Dr. Zachary Knight:
扎卡里·奈特博士：
Right
右
Andrew Huberman:
安德鲁·休伯曼：
...
...
with a very small margin of error.
误差范围非常小。
Dr. Zachary Knight:
扎卡里·奈特博士：
Okay.
好的。
Andrew Huberman:
安德鲁·休伯曼：
And that drives, in that condition, obviously, food avoidance.
在这种情况下，这显然会导致人们回避食物。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
So I have to assume that these AgRP neurons are involved in this kind of thing.
所以我必须假设这些 AgRP 神经元参与了这种事情。
One represents a regulation in the case of the example I gave, and in the other case, let's just call it what it is, because anorexia nervosa is the most deadly of the psychiatric conditions, sadly.
在我给出的例子中，一个代表了一种规定，而在另一种情况下，我们就这么称呼它吧，因为可悲的是，神经性厌食症是最致命的精神疾病。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
A pathologic dysregulation, a maladaptive dysregulation.
病理性失调，适应不良失调。
So what is known about these AgRP neurons in humans?
那么，我们对人类这些 AgRP 神经元了解多少呢？
Meaning, do they exist in humans?
意思是，它们存在于人类中吗？
Presumably, they express the leptin receptor.
据推测，它们表达瘦素受体。
It sounds like they are able to integrate information, both cognitive, based on immediate experience, visual, olfactory, but also a lot of prior experience.
听起来他们能够整合信息，既有认知的、基于直接经验、视觉、嗅觉的信息，也有大量先前的经验。
A hamburger patty, I can't tell you how many calories it has.
一个汉堡肉饼，我无法告诉你它有多少卡路里。
All I know is that it's mostly protein and some fat.
我只知道它主要是蛋白质和一些脂肪。
What are these neurons doing?
这些神经元在做什么？
What do they have access to?
他们可以访问什么？
Anytime I hear about hypothalamus, I think very basic drives, but you're talking about a pretty sophisticated analysis of a real-time event-
每当我听到下丘脑时，我都会认为这是非常基本的驱动力，但你谈论的是对实时事件的相当复杂的分析 -
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
that is driving fairly nuanced behavioral decisions and updating that.
这正在推动相当微妙的行为决策并更新。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Which is a big deal.
这是一件大事。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
We're both neuroscientists, but for everyone listening and watching, this is a big deal.
我们都是神经科学家，但对于每个聆听和观看的人来说，这都是一件大事。
This is as nuanced as deciding whether or not somebody is friend or foe, or deciding whether or not you like a movie or you don't.
这就像决定某人是朋友还是敌人，或者决定你是否喜欢一部电影一样微妙。
This is some pretty sophisticated processing.
这是一些相当复杂的处理。
This isn't eat, don't eat, or eat less, eat more.
这不是吃、不吃，也不是少吃、多吃。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
These aren't switches.
这些不是开关。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
These are dials.
这些是表盘。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Yeah.
是的。
So there's a lot there.
所以那里有很多东西。
I'll try to unpack that.
我会尝试解开它。
So the first thing I'd say is they are present in humans, and humans have AgRP neurons.
所以我首先要说的是它们存在于人类体内，而人类也有 AgRP 神经元。
Human AgRP neurons express the leptin receptor, and we think the functions are very similar.
人类 AgRP 神经元表达瘦素受体，我们认为功能非常相似。
It's one of the nice things, actually, about studying these kinds of things, like basic mechanisms of hunger, thirst Because these things are so important for survival, they've been under really strong selection.
事实上，研究这些东西是一件好事，比如饥饿、口渴的基本机制，因为这些东西对于生存如此重要，所以它们一直处于非常强烈的选择之下。
And so many of the components of these systems are genetically hardwired, meaning these are cell types that have a single purpose, in this case, to control hunger.
这些系统的许多组成部分都是基因固定的，这意味着这些细胞类型只有一个目的，在这种情况下，就是控制饥饿。
They're labeled by specific genes, and those are conserved through evolution.
它们被特定的基因标记，并且通过进化得以保留。
We also know that this pathway, this AgRP neuron pathway, is important in humans due to human genetics.
我们还知道，由于人类遗传学的原因，这条 AgRP 神经元通路在人类中很重要。
So, just to add a little bit more information here, there's a companion set of neurons called POMC neurons that promote satiety.
因此，在这里添加更多信息，有一组神经元称为 POMC 神经元，可以促进饱腹感。
So they're sort of the yin and yang of hunger.
所以它们有点像饥饿的阴和阳。
AgRP neurons promote hunger, POMC neurons promote satiety.
AgRP 神经元促进饥饿，POMC 神经元促进饱腹感。
They're intermingled in the same part of the hypothalamus.
它们混合在下丘脑的同一部分。
Their axons that project to the exact same downstream brain regions, and then it's thought that these two neurons compete with each other to control appetite.
它们的轴突投射到完全相同的下游大脑区域，然后人们认为这两个神经元相互竞争来控制食欲。
And that competition occurs through neuropeptides that they release, one of which is an agonist for a downstream receptor, and the other one of which is an antagonist.
这种竞争是通过它们释放的神经肽发生的，其中一种是下游受体的激动剂，另一种是拮抗剂。
We know from human genetics that amongst severely obese people, mutations in this pathway, AgRP, POMC neurons, and their direct downstream targets, are quite common.
我们从人类遗传学中得知，在严重肥胖的人群中，AgRP、POMC 神经元及其直接下游靶标通路的突变非常常见。
Andrew Huberman:
安德鲁·休伯曼：
Really?
真的吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
So, and the way that-
所以，以及这样的方式——
Andrew Huberman:
安德鲁·休伯曼：
So is it fair to say that some amount of obesity is genetic in nature at the level of neuronal firing or circuitry?
那么，可以公平地说，一定程度的肥胖在神经元放电或电路水平上本质上是遗传性的吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
I think a lot of body weight regulation is genetic.
我认为很多体重调节都是遗传的。
It's highly heritable.
这是高度可遗传的。
There's a question of how much of it is due to single genes.
问题是其中有多少是由单基因造成的。
And the number of people quote, and this is among people who are severely obese, so not just people who you've seen someone who's overweight, but people have sort of syndromes where they're very obese from a very young age.
引用的人数，这是在严重肥胖的人中，所以不仅仅是那些你见过的超重的人，而是人们患有某种从很小的时候就非常肥胖的综合症。
Among those people, something on the order of 10% have mutations in this pathway, and it can either be this hormone, POMC, or an enzyme within those cells that processes POMC into the right form, or, and this is the most common mutation, in the downstream receptor for POMC, it's called the melanocortin 4 receptor.
在这些人中，大约 10% 的人在这条通路中发生突变，它可能是这种激素、POMC，也可能是细胞内将 POMC 加工成正确形式的酶，或者，这是最常见的突变，发生在 POMC 下游受体中，称为黑皮质素 4 受体。
And so among the severely obese people who have sort of genetically inherited severe obesity from childhood, something on the order of 10% have mutations in this pathway.
因此，在从童年起就患有严重肥胖症的严重肥胖者中，约有 10% 的人在该途径中存在突变。
So it's very clear that this pathway is involved in body weight regulation in humans.
因此很明显，这条途径与人类的体重调节有关。
Most obesity, although there is a very strong genetic component, is not associated with single gene mutations like this.
大多数肥胖虽然有很强的遗传因素，但与这样的单基因突变无关。
It's associated with the effects of many mutations.
它与许多突变的影响有关。
But we know that even in the sort of polygenic obesity that has many different genetic causes, that the brain is important.
但我们知道，即使是有许多不同遗传原因的多基因肥胖，大脑也很重要。
And one of the reasons we know that is if you look at the genes through genetic association studies that have been associated with body weight, and there's been lots of genetic association studies trying to find mutations that are associated with whether you're lean or obese.
我们知道这一点的原因之一是，如果你通过与体重相关的基因关联研究来观察基因，并且已经有很多基因关联研究试图找到与你是瘦还是肥胖相关的突变。
Something on the order of 1,000 genes have been linked to body weight regulation, and the vast majority of those are expressed in the brain.
大约有 1,000 个基因与体重调节有关，其中绝大多数在大脑中表达。
They're highly enriched for brain processes, which makes sense because body weight is controlled by food intake, right?
它们对大脑过程非常丰富，这是有道理的，因为体重是由食物摄入量控制的，对吗？
And the brain controls behavior, and also the brain controls energy expenditure.
大脑控制行为，大脑也控制能量消耗。
So maybe it's not so surprising, but it's clear that mutations in genes in the brain are important for body weight, which is consistent with the results of twin studies.
因此，也许这并不令人惊讶，但很明显，大脑中的基因突变对体重很重要，这与双胞胎研究的结果一致。
So if you look at monozygotic versus dizygotic twins, the estimates for the heritability of body weight is something on the order of 80%.
因此，如果你观察同卵双胞胎和异卵双胞胎，体重遗传率的估计约为 80%。
Andrew Huberman:
安德鲁·休伯曼：
We should explain monozygotic, dizygotic.
我们应该解释一下同卵，双卵。
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
Andrew Huberman:
安德鲁·休伯曼：
Which I've talked about before on the podcast, just to brush people up.
我之前在播客上谈到过这一点，只是为了让人们振作起来。
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
Just identical versus fraternal twins, basically.
基本上就是同卵双胞胎与异卵双胞胎。
And by comparing their body weight when they become adults, you can get a sense for how much of this is genetic versus environmental.
通过比较他们成年后的体重，你可以了解遗传因素和环境因素的影响有多大。
And something on the order of 80% of the variation between individuals is thought to have a genetic component.
人们认为，个体之间大约 80% 的变异都与遗传因素有关。
Andrew Huberman:
安德鲁·休伯曼：
Wow.
哇。
Dr. Zachary Knight:
扎卡里·奈特博士：
So-
所以——
Andrew Huberman:
安德鲁·休伯曼：
I don't think most people appreciate that.
我认为大多数人并不欣赏这一点。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
It's-
这是——
Andrew Huberman:
安德鲁·休伯曼：
And a lot of the debate we hear nowadays is because there are things that people can do to lose body fat, exercise, eat differently, et cetera, maybe embrace pharmacology-
我们现在听到的很多争论是因为人们可以采取一些措施来减肥、锻炼、饮食不同等等，也许还可以采用药理学——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
if that's appropriate.
如果合适的话。
There seems to be this, to me, silly debate as to whether or not people should be eating better and exercising or assuming that all of the obesity they might have arises through genetic causes, and therefore take a prescription drug.
在我看来，似乎有这样一个愚蠢的争论：人们是否应该更好地饮食和锻炼，或者假设他们可能患有的所有肥胖都是由遗传原因引起的，因此服用处方药。
Why wouldn't it be a combination of things?
为什么它不是事物的组合呢？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
To me, it just seems like why wouldn't people embrace some or all of the tools that they could afford and that are safe for them?
对我来说，人们为什么不接受他们买得起且安全的部分或全部工具呢？
So I just want to get that out there.
所以我只是想把它说出来。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Because the moment this comes up, people start thinking, oh, well, the moment we assign a genetic source to something, we're removing personal responsibility.
因为当这个问题出现的那一刻，人们开始思考，哦，好吧，当我们为某件事指定遗传来源的那一刻，我们就消除了个人责任。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
But of course, there are people, I know people, who have struggled with their weight their entire lives, for whom some of these new pharmaceuticals-
但当然，有些人，我认识的人，一生都在与体重作斗争，对他们来说，这些新药物中的一些——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
like Ozempic, have provided them the opportunity to finally be able to lose weight and feel better and exercise safely.
像 Ozempic 一样，为他们提供了最终能够减肥、感觉更好并安全锻炼的机会。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
For instance.
例如。
Dr. Zachary Knight:
扎卡里·奈特博士：
I completely agree with that.
我完全同意这一点。
I think there is a misconception out there about this, about what it means for something to be genetically heritable, and I think this gets to the root of why so many people find this sort of hard to believe, that there's such a strong genetic component to body weight.
我认为人们对这一点存在误解，对于某些东西具有遗传性意味着什么，我认为这就是为什么这么多人觉得很难相信体重有如此强大的遗传成分的根源。
And that's the idea that if you look at people, say, 75 years ago, they were much leaner.
这就是说，如果你看看 75 年前的人们，你会发现他们要瘦得多。
And you look at people today, and starting sometime around the 1970s, there was this explosion in body weight and increase in obesity.
你看看今天的人们，从 20 世纪 70 年代左右开始，体重出现爆炸式增长，肥胖率也随之增加。
Andrew Huberman:
安德鲁·休伯曼：
Is that when it started, mid-70s?
是从70年代中期开始的吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
Sort of the 1970s is around when a lot of us start-
差不多到了 20 世纪 70 年代，我们很多人开始——
Andrew Huberman:
安德鲁·休伯曼：
And with snack food, snacking.
并配以零食、零食。
Dr. Zachary Knight:
扎卡里·奈特博士：
So there's lots of explanations.
所以有很多解释。
Andrew Huberman:
安德鲁·休伯曼：
Seed oils, snacking.
种子油，零食。
By the way, I don't think that's the reason, folks.
顺便说一句，我不认为这是原因，伙计们。
I think there are a lot of reasons, but the theories that abound right now on social media-
我认为原因有很多，但目前社交媒体上充斥着的理论——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
I have a list of the theories as to why the obesity is increasing.
我有一份关于肥胖为何增加的理论清单。
You get everything from seed oils to snacking to smartphones to conspiracies to-- It's wild.
你可以获得从种子油到零食到智能手机到阴谋的一切——这太疯狂了。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
It's wild.
它很狂野。
The range of hypotheses is wild.
假设的范围很广。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
The challenge is some of them could be true, but it's just very hard to test those things experimentally-
挑战在于其中一些可能是真的，但很难通过实验来测试这些东西 -
Andrew Huberman:
安德鲁·休伯曼：
Sure
当然可以
Dr. Zachary Knight:
扎卡里·奈特博士：
...
...
because they're happening in the whole population, right?
因为它们正在全体人群中发生，对吧？
Andrew Huberman:
安德鲁·休伯曼：
Yep.
是的。
Dr. Zachary Knight:
扎卡里·奈特博士：
So I think the thing that people find hard to wrap their heads around, because it is a little bit of a confusing idea, is that how can it be that in, say, 50 or 75 years, there's been this explosion in obesity?
所以我认为人们很难理解这一点，因为这是一个有点令人困惑的想法，那就是，为什么在 50 或 75 年内，肥胖率会出现爆炸式增长？
Which is the environment has changed, but human genetics has not changed in that amount of time.
也就是说，环境发生了变化，但人类基因在这段时间内没有发生变化。
It's just not fast enough for people to evolve, so it can't be due to mutations in humans.
只是人类进化的速度不够快，所以不可能是由于人类的突变造成的。
Andrew Huberman:
安德鲁·休伯曼：
What about devolve?
那移交呢？
My understanding is that within a species, evolving new traits is very slow.
我的理解是，在一个物种内，进化新特征的速度非常缓慢。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
But mutations arise, like the OB mutation, and then you can get very fat versions of an animal very quickly, right?
但是突变会出现，比如 OB 突变，然后你就可以很快获得非常肥胖的动物版本，对吗？
All you need is a-
你所需要的只是——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
if it's a recessive allele, you need two copies, and the next thing you know, you've got a mouse that's four times larger than a typical mouse-
如果它是隐性等位基因，你需要两个副本，接下来你知道的，你就得到了一只比典型老鼠大四倍的老鼠——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
and it's all explained by increased body weight.
这一切都可以用体重增加来解释。
So that can happen very quickly-
所以这会很快发生——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
within a species.
一个物种内。
What's rare to find is an entire new branch of a species-
罕见的是一个物种的全新分支——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
that has a very new adaptive function.
它有一个非常新的自适应功能。
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
Andrew Huberman:
安德鲁·休伯曼：
That seems more rare.
那个好像比较少见。
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, so that's true.
嗯，确实如此。
So definitely there's some things that take longer to evolve than others.
所以肯定有一些东西比其他东西需要更长的时间才能进化。
But with humans, we're talking about just two generations.
但对于人类来说，我们谈论的只是两代人。
There just isn't enough time for any evolution of any significance to happen.
没有足够的时间来发生任何有意义的演变。
Andrew Huberman:
安德鲁·休伯曼：
Yeah.
是的。
We went baby boomers, right?
我们是婴儿潮一代，对吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
Generation X.
X一代。
Andrew Huberman:
安德鲁·休伯曼：
Gen X.
X世代。
That's me, right?
那是我，对吧？
And then whatever is Y, Z, millennial-
然后无论 Y、Z、千禧一代是什么——
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly
正是如此
Andrew Huberman:
安德鲁·休伯曼：
...
...
or what have you.
或者你有什么。
I lose track after that.
之后我就失去了踪迹。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
So, I think the thing that people find hard to wrap their heads around is how can it be that that increase in body weight is clearly environmental, right?
所以，我认为人们很难理解的是，体重的增加怎么可能明显是环境因素，对吧？
Because that's all that's changed is the environment.
因为改变的只是环境。
Nothing has changed genetically.
基因上没有任何改变。
Yet, it's also true what I said, that body weight is extremely heritable.
然而，我所说的也是正确的，体重是极其可遗传的。
It's one of the most heritable features, and something on the order of 80%.
这是最可遗传的特征之一，约占 80%。
One of the only things we know about that's actually more heritable than body weight is height.
我们所知道的唯一比体重更具有遗传性的东西之一就是身高。
Right?
正确的？
Most diseases are not as heritable as body weight.
大多数疾病不像体重那样具有遗传性。
How can you explain that?
你怎么解释呢？
And the idea is this.
这个想法是这样的。
There's a distribution of body weights among people.
人们之间存在体重分布。
So in any given society, at any point in time, some people are going to be leaner, some people are going to be more obese.
因此，在任何特定社会、任何时间点，有些人会变得更瘦，有些人会变得更肥胖。
That distribution, where you lie on that distribution, is determined primarily by genetics.
该分布，即您所处的分布，主要由遗传决定。
So you may be the person who has the thrifty genes that basically cause you to save energy, and so you would be more on the obese side.
所以你可能是一个拥有节俭基因的人，这基本上会让你节省能量，所以你会更容易肥胖。
Or you may be a person who has different genes that cause you to be a little bit less hungry, so you would be on the leaner side.
或者你可能有不同的基因，导致你不那么饥饿，所以你会更瘦。
What environment does is then it shifts that whole distribution, so that basically the mean shifts so that everyone becomes, or most people become heavier.
环境的作用是改变整个分布，因此基本上均值发生变化，使每个人或大多数人变得更重。
And so sort of a phrase that people sometimes use is that genetics loads the gun and environment pulls the trigger.
人们有时会用这样的一句话：基因给枪上膛，环境扣动扳机。
So basically, genetics sets your propensity, and then environment can basically unmask that.
所以基本上，遗传决定了你的倾向，然后环境基本上可以揭露这一点。
And so as we've had this change in environment where there's all of this, and we don't know exactly what the things are that have changed that are important, but there's all this ultra-processed food, highly palatable food, just various other things that you mentioned, seed oils, who knows if that's important.
因此，当我们的环境发生变化时，我们不知道到底发生了什么变化是重要的，但有所有这些超加工食品、高度适口的食品，还有你提到的各种其他东西，种子油，谁知道这是否重要。
Certain people had these latent mutations that made them, say, very sensitive to palatable food.
某些人具有这些潜在的突变，使他们对美味的食物非常敏感。
And in an earlier time, they may have been lean, but now because they have that latent capacity to be sensitive to ultra-processed food, they now gain tons of weight in the environment that we're in.
在早些时候，它们可能很瘦，但现在因为它们具有对超加工食品敏感的潜在能力，所以它们现在在我们所处的环境中体重增加了很多。
It's still because of genetics, but it also requires the environmental component.
这仍然是因为遗传，但也需要环境因素。
I mean, just take a step back, right?
我的意思是，退后一步，对吧？
You can make anyone lean by just putting them in prison and just only feeding them 1,500 calories.
只要把任何人关进监狱，只给他们喂食 1,500 卡路里，你就可以让他们变瘦。
I mean, we've done those kinds of experiments.
我的意思是，我们已经做过这类实验。
There's this famous experiment, the Minnesota Starvation Experiment, right?
有一个著名的实验，明尼苏达饥饿实验，对吗？
They put people in prison, but this is in World War II.
他们把人关进监狱，但这是在第二次世界大战。
They took a bunch of healthy volunteers, fed them 1,600 calories a day, and just asked what would happen if you basically semi-starve people.
他们找了一群健康的志愿者，每天给他们喂食 1,600 卡路里，然后问如果让人们基本上处于半饥饿状态会发生什么。
And unsurprisingly, they lose an incredible amount of weight.
毫不奇怪，他们的体重减轻得令人难以置信。
All they think about is food.
他们只想到食物。
Basically, their body temperature goes down, their heart rate goes down.
基本上，他们的体温下降，心率下降。
They just become obsessed with food.
他们只是对食物着迷。
And you could always do that for anyone, right?
你总是可以为任何人这样做，对吧？
But in a given environment where you're not in that kind of situation, then your propensity to gain weight will be determined by genetics.
但在特定的环境中，如果你不处于这种情况，那么你的体重增加倾向将由遗传决定。
So that's the idea.
这就是我们的想法。
Andrew Huberman:
安德鲁·休伯曼：
I very much appreciate that description, and I know a great number of other people will as well because the explanation for the increase in obesity has not been described with that level of accuracy and detail with respect to the interactions between genetics and the environment.
我非常欣赏这种描述，而且我知道很多其他人也会这么认为，因为关于遗传与环境之间的相互作用，肥胖增加的解释尚未得到如此准确和详细的描述。
Is it fair to say that what's changed in our environment is the free availability of food?
公平地说，我们的环境发生的变化是食物的免费供应吗？
I was walking through an airport yesterday, and every 20 meters or so, there's a vending machine or a restaurant.
昨天我走过机场，每隔 20 米左右就有一个自动售货机或一家餐厅。
The cost of calories-
卡路里的成本——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
is fairly low, right?
相当低，对吧？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Getting high-quality, nutritious food that tastes great is expensive-
获得高品质、营养丰富、味道鲜美的食物是昂贵的——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
I would argue.
我会争辩。
But getting calories is fairly inexpensive.
但获取卡路里的成本相当低廉。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
I think that's a plausible hypothesis.
我认为这是一个合理的假设。
It's one of several plausible hypotheses, and it would be surprising to me if it didn't contribute.
这是几个看似合理的假设之一，如果它没有贡献，我会感到惊讶。
But the reality is these population-level questions, it's just so hard to actually know because you can't do an experiment, right?
但现实是这些人口层面的问题，很难真正知道，因为你无法做实验，对吧？
We can't create a parallel society where we manipulate one of these variables and see if the people become obese.
我们无法创建一个平行的社会，我们可以操纵其中一个变量来观察人们是否变得肥胖。
So I think probably the availability of food, of the free availability, the low cost is one part of it.
所以我认为食物的供应、免费供应和低成本可能是其中的一部分。
Another part of it is probably, although again, it's not proven, is that these ultra-processed foods have a number of features that make people prone to gain weight.
另一部分可能是，尽管尚未得到证实，这些超加工食品具有许多使人们容易发胖的特征。
And this really beautiful work, I don't know if you know about this, from Kevin Hall at the NIH, who's investigated this.
这项非常漂亮的工作，我不知道你是否知道，来自美国国立卫生研究院 (NIH) 的凯文·霍尔 (Kevin Hall)，他对此进行了调查。
So he's really, in my opinion, the best person doing this kind of human obesity research today, and he does these experiments where he takes people into the NIH, into the hospital, hospitalizes them for several weeks, so he can exactly control what they eat.
所以，在我看来，他确实是当今进行此类人类肥胖研究的最佳人选，他进行这些实验时，他将人们带到美国国立卫生研究院、医院，让他们住院几周，这样他就可以精确控制他们的饮食。
And he did this beautiful experiment where basically he had chefs prepare two kinds of food, one ultra-processed and the other not ultra-processed, sort of more whole foods, more healthier foods.
他做了这个漂亮的实验，基本上他让厨师准备两种食物，一种是超加工的，另一种是非超加工的，有点更天然的食物，更健康的食物。
But had them take a lot of care so that when they gave the foods to independent raters, to people to taste, they would say, "This is about equally palatable.
但如果他们非常小心，那么当他们将食物交给独立评估者、人们品尝时，他们会说：“这几乎同样美味。
So I like this ultra-processed dish as much as this non-ultra-processed dish."
所以我喜欢这种超加工的菜肴，就像这种非超加工的菜肴一样。”
Andrew Huberman:
安德鲁·休伯曼：
What's an example of an ultra-processed dish?
超加工菜肴的例子是什么？
Like an out-of-package macaroni and cheese-
就像包装外的通心粉和奶酪一样——
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
That kind of stuff
那种东西
Andrew Huberman:
安德鲁·休伯曼：
...
...
with bacon kind of thing?
培根之类的东西？
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
Versus some pasta sitting next to a vegetable and some-
与一些放在蔬菜旁边的面食和一些-
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly
正是如此
Andrew Huberman:
安德鲁·休伯曼：
...
...
a nice piece of salmon or something.
一块美味的鲑鱼什么的。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
Okay.
好的。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
And took people into the hospital, basically allowed them to eat just as much as they would like, first of the ultra-processed meals, so they had the selection of ultra-processed meals for a couple of weeks, and then switched them to the non-ultra-processed meals, and then also did it in the reverse order, so the other half of the people, they got the regular food first, then they got the ultra-processed food.
带人去医院，基本上让他们想吃多少就吃多少，首先是超加工食品，所以他们选择超加工食品几个星期，然后换成非超加工食品，然后也按照相反的顺序做，所以另一半人，他们先吃普通食品，然后再吃超加工食品。
And what he found is that even though people rated the foods as equally palatable, they ate much more of the ultra-processed food, and they actually gained weight during that two-week period when they were being given the ultra-processed foods.
他发现，尽管人们认为这些食物同样美味，但他们吃的超加工食品要多得多，而且在食用超加工食品的两周内，他们的体重实际上增加了。
And then when you switch them, they lost weight.
然后当你更换它们时，它们的重量就会减轻。
So the idea being that you can have two sets of food that you have equal preferences for, but something about the ultra-processed food is making you eat more of it when you actually consume it.
因此，我们的想法是，你可以拥有两套你有相同偏好的食物，但超加工食品的某些成分会让你在实际食用时吃得更多。
And there's a number of ideas about why that could be.
关于为什么会出现这种情况，有很多想法。
So one idea is that these ultra-processed foods have been optimized to have the right percentage of fat and sugar and protein to sort of promote more consumption once you start eating it.
因此，一个想法是，这些超加工食品经过优化，含有适当比例的脂肪、糖和蛋白质，以便在您开始食用后促进更多消费。
So that could be part of it.
所以这可能是其中的一部分。
Another idea is that, a big thing about whole foods is that they take more energy to digest, and they have more volume.
另一个想法是，天然食品的一大特点是它们需要更多的能量来消化，而且体积更大。
So one of the striking things from that study is if you just look at the pictures of the meals, they're the same number of calories, but there's so much more food seemingly on the non-processed food versus the ultra-processed food.
因此，这项研究的一个引人注目的事情是，如果你只看膳食的图片，它们的卡路里含量是相同的，但非加工食品中的食物似乎比超加工食品中的食物多得多。
And that's just because whole foods are bigger, because they're not so energy-dense.
这只是因为天然食品更大，因为它们的能量密度不那么高。
So, and we know that, for example, volume is a major signal in the short term for regulating food intake.
因此，我们知道，例如，量是短期内调节食物摄入量的主要信号。
So if you just eat more volume, that could be valuable.
因此，如果你吃更多的量，那可能是有价值的。
And so there's lots of things like that.
诸如此类的事情还有很多。
So I think that that's another plausible hypothesis, but the truth is we don't really know.
所以我认为这是另一个看似合理的假设，但事实是我们并不真正知道。
Andrew Huberman:
安德鲁·休伯曼：
I have a hypothesis, and I don't want to force you into speculation, but given that you've studied and discovered that the neurons and circuits involved in appetitive and consummatory behaviors can learn based on experience and expectation, I think it's fair game to at least ask your thoughts on this.
我有一个假设，我不想强迫你进行猜测，但考虑到你已经研究并发现参与欲望和完成行为的神经元和回路可以根据经验和期望进行学习，我认为至少询问你对此的想法是公平的游戏。
So I've been paying a lot of attention to the landscape of what the general public think about, let's call them elimination diets, where people will just eat meat-
所以我一直非常关注公众的想法，我们称之为消除饮食，人们只吃肉——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes
是的
Andrew Huberman:
安德鲁·休伯曼：
...
...
or will go onto a vegan diet, or do some time-restricted feeding, or do any number of different things that have been shown to promote weight loss, provided people obey the laws of thermodynamics and consume fewer calories than they burn.
或者会采取纯素饮食，或者进行一些有时间限制的喂食，或者做一些已被证明可以促进减肥的不同事情，前提是人们遵守热力学定律并且消耗的热量少于燃烧的热量。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Right.
对。
I do believe in calories in, calories out.
我确实相信卡路里摄入和卡路里消耗。
And there are a number of different routes to get there, and some are more painful, some are less painful, and it depends on the individual lifestyle, exercise, and on and on.
有许多不同的路线可以到达那里，有些更痛苦，有些不那么痛苦，这取决于个人的生活方式、锻炼等等。
But let's just suppose for a moment, based on Kevin's work on highly processed foods versus whole foods, that there's a learning that takes place when we eat.
但让我们暂时假设一下，根据凯文关于高度加工食品与天然食品的研究，我们在吃东西时会发生一种学习。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
And that this learning takes place over time, such that our brain and appetite start to link the variables of taste, macronutrients, proteins, fats, and carbohydrates, sort of knowledge about macronutrients.
这种学习是随着时间的推移而发生的，这样我们的大脑和食欲就开始将味道、常量营养素、蛋白质、脂肪和碳水化合物等变量联系起来，这些变量是有关常量营养素的知识。
A piece of fish is mostly protein, has some fat.
一块鱼主要是蛋白质，还有一些脂肪。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
A bowl of rice is mostly carbohydrate, has some protein.
一碗米饭主要是碳水化合物，还有一些蛋白质。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Put a pat of butter on it, has some fat also, right?
抹上一点黄油，也有一些脂肪吧？
It's sort of obvious.
这很明显。
But taste, macronutrient content, calories, which we already know people with anorexia are exquisitely good at counting with their eyes.
但味道、常量营养素含量、卡路里，我们已经知道厌食症患者非常擅长用眼睛来计算。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
So it's possible they represent, again, a pathologic extreme of this.
因此，它们可能再次代表了这种病态的极端。
And micronutrient content, maybe even amino acid content, like how much leucine is there.
还有微量营养素含量，甚至可能是氨基酸含量，例如亮氨酸的含量。
Now, most people aren't thinking about how much leucine is in a meal, but we know that leucine is important for certain aspects of muscle metabolism.
现在，大多数人并没有考虑一顿饭中含有多少亮氨酸，但我们知道亮氨酸对于肌肉代谢的某些方面很重要。
It's present in certain proteins and not others.
它存在于某些蛋白质中，而不存在于其他蛋白质中。
You're going to find less of it in a vegetable, typically, than you would in a piece of chicken, and so on.
通常，蔬菜中的维生素E含量比鸡肉等中的维生素E含量要少。
And that when people eat mostly non-processed or minimally processed foods, and not in combination, so we're not talking about stewing all this together or blending all of it together, which sounds disgusting, right?
当人们主要吃未加工或最低限度加工的食物，而不是混合食用时，所以我们不是在谈论将所有这些食物炖在一起或将它们混合在一起，这听起来很恶心，对吗？
Broccoli, rice, and a chicken breast blended together just sounds horrible.
西兰花、米饭和鸡胸肉混合在一起听起来很糟糕。
But eating them separately, if there's some olive oil and a little pat of butter involved, that sounds pretty good.
但分开吃，如果有一些橄榄油和一点黄油，听起来不错。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
But a highly processed food, in some ways, is a blending together of macronutrients, micronutrients, if there are any, and other features of the food that neurons in the brain seem to pay attention to, and then giving it a unified taste.
但在某种程度上，高度加工的食品是将大量营养素、微量营养素（如果有的话）以及大脑神经元似乎关注的食物的其他特征混合在一起，然后赋予其统一的味道。
A Dorito, right?
多力多力多力托，对吧？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
A candy bar that we attach to the product, we attach to the name of the processed food, to the packaging.
我们将糖果贴在产品上，将其贴在加工食品的名称和包装上。
But I could imagine, and here's the hypothesis, that that is quote unquote confusing to our neural circuits in a way that doesn't match up well with our thermodynamic requirements of how much we're burning versus how much we need to eat.
但我可以想象，这是一个假设，这对我们的神经回路造成了混乱，与我们燃烧多少与需要吃多少的热力学要求不太相符。
Whereas when I eat a piece of steak and a vegetable, I actually want less carbohydrate afterwards.
然而当我吃一块牛排和一份蔬菜时，我实际上想要更少的碳水化合物。
If I eat the carbohydrate first, for me, it's difficult because I love the taste of carbohydrates-
如果我先吃碳水化合物，对我来说，很难，因为我喜欢碳水化合物的味道——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
especially when they're combined with fat.
尤其是当它们与脂肪结合时。
But there seems to be an easier time regulating food intake when people step back and say, "I'm going to consume minimally processed whole foods." And I'm guessing it's not just because they're trying to be healthier.
但当人们退后一步说“我将食用经过最低限度加工的天然食品”时，似乎更容易调节食物摄入量。我猜这不仅仅是因为他们想变得更健康。
That might be what stimulates the shift, but that the brain starts to learn the relationship between food volume, smell, taste, what these things look like, and satiation at the level of, oh, that's enough amino acids because I had a piece of fish.
这可能是刺激这种转变的原因，但大脑开始学习食物量、气味、味道、这些东西的样子和饱腹感之间的关系，哦，因为我吃了一块鱼，氨基酸就足够了。
So maybe I don't need to consume as much of some other things.
所以也许我不需要消耗太多其他东西。
Or the vegetables provide volume and fiber, and often vegetables can taste really delicious too.
或者蔬菜提供体积和纤维，而且蔬菜通常味道也非常美味。
So that there's a linking of nutrients, calories, and taste in a way that's more appropriately matched to the energetic demands of the organism-
这样，营养物质、卡路里和味道就会以一种更适合有机体能量需求的方式联系起来——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
in this case, us, humans, that highly processed foods bypass.
在这种情况下，我们人类就被高度加工的食品绕过了。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Okay, now I realize that was long-winded, and forgive me, but my audience is used to that.
好吧，现在我意识到这很啰嗦，请原谅我，但我的观众已经习惯了。
Whenever I'm trying to table something for, no pun intended, for discussion that I would like to think can at least stimulate some additional thinking about a landscape, in this case, nutrition and feeding behavior, that for a lot of people is just really confusing.
每当我试图提出一些东西（没有双关语）进行讨论时，我想至少可以激发对景观的一些额外思考，在这种情况下，营养和喂养行为，这对很多人来说真的很令人困惑。
And here's why, and this is the last thing I'll say.
这就是原因，这是我要说的最后一件事。
I have several friends who have been very overweight their entire lives-
我有几个朋友一生都超重——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
for whom the following diet has worked exceptionally well I'm not a diet coach, I'm not a nutritionist, I don't pretend to be one.
对于以下饮食效果特别好的人来说，我不是饮食教练，我不是营养师，我不会假装自己是营养师。
I say eat proteins like meat, fish, eggs, vegetables, and fruit, and do that for a couple of months, and then add back in starches as you see fit based on your food intake.
我说吃肉、鱼、蛋、蔬菜和水果等蛋白质，坚持几个月，然后根据你的食物摄入量添加你认为合适的淀粉。
And without fail, they all lose a ton of weight.
毫无疑问，他们都减掉了很多体重。
They're very happy with that.
他们对此非常满意。
They add back in a minimum of starches, they keep the weight off, and they're also exercising, but not more than they were before in most cases.
他们补充最少的淀粉，保持体重，并且也进行锻炼，但在大多数情况下不会比以前更多。
And I don't think that it's meat or fish or vegetables per se, I think it's that they finally develop an appreciation for what different foods have in terms of what they actually need.
我不认为这本身就是肉、鱼或蔬菜，我认为这是他们最终对不同食物所具有的他们实际需要的东西产生了欣赏。
And without fail, they all say, "Oh, I went to this party and I had a piece of cake, and it didn't taste good to me after three or four bites." So that's interesting too.
他们无一例外地都会说：“哦，我参加了这个聚会，我吃了一块蛋糕，但我咬了三四口之后，味道就不太好了。”所以这也很有趣。
So I just would like your thoughts on this.
所以我想知道你对此的想法。
We're not defining any new diets.
我们没有定义任何新的饮食习惯。
I don't sell any diets.
我不卖任何饮食。
I don't do any of that.
我什么都不做。
But I find it amazing that when people start eating minimally processed whole foods, I have to assume that their brain changes as it relates to appetite, craving, and just kind of an unconscious understanding about what food is providing them or not, and that highly processed foods basically bypass all of this and just get you to consume more.
但我发现令人惊讶的是，当人们开始吃最低限度加工的天然食品时，我不得不假设他们的大脑发生了变化，因为它与食欲、渴望有关，并且只是一种无意识地了解食物为他们提供或不提供什么，而高度加工的食品基本上绕过了所有这些，只会让你消耗更多。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Perhaps in hopes of getting something that you probably aren't getting at all, or that you need to consume a lot of this food in order to get.
也许是希望得到一些你可能根本得不到的东西，或者你需要消耗大量这种食物才能得到。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
There's several interesting ideas there.
其中有几个有趣的想法。
So there's two that come to mind, just thinking about what you just said.
只要想想你刚才所说的，我就会想到两个。
So the one is the idea of what's going on when these people consume simpler diets, more of whole foods.
因此，一个问题是，当这些人食用更简单的饮食、更多的天然食品时会发生什么。
And one thing I think that's very likely going on is this phenomenon of sensory specific satiety as being engaged.
我认为很可能发生的一件事就是这种在参与时产生特定感官饱腹感的现象。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
And so, sensory specific satiety is just the idea that as you expose yourself repeatedly to a certain flavor or taste, you basically lose appetite for that.
因此，感官特定的饱腹感就是当你反复接触某种风味或味道时，你基本上会失去食欲。
You get specific loss of appetite for that flavor or taste.
您会对该味道或味道产生特定的食欲丧失。
This is why, as you said, basically, if you start off eating the protein, after a while, you're, "I don't want any more salmon, but I would like some carbohydrates now," because you have this sensory specific satiety.
这就是为什么，正如你所说，基本上，如果你开始吃蛋白质，过了一段时间，你就会“我不再想要鲑鱼，但我现在想要一些碳水化合物”，因为你有这种感官特定的饱腹感。
And so, it's well-known actually that if you simplify your diet, make your diet really simple so there's just a few things, the sensory specific satiety alone can cause you to eat less.
所以，众所周知，如果你简化你的饮食，让你的饮食非常简单，那么只有几件事，仅感官特定的饱腹感就可以让你吃得更少。
Basically because there's just less variety in your diet, and you don't want to eat more of that same thing.
基本上是因为你的饮食种类较少，而且你不想吃更多同样的东西。
And so I think a lot of diets actually, it's not about the specific macronutrient or the specific food, it's just that they're reducing the variety in the diet.
所以我认为实际上很多饮食并不是关于特定的常量营养素或特定的食物，而是他们减少了饮食的多样性。
Eventually you just get sick of eating the same thing.
最终你会厌倦吃同样的东西。
And the thought behind that idea is that it's important evolutionarily so that you eat a diverse diet.
这个想法背后的想法是，从进化的角度来看，多样化的饮食很重要。
It's the reason probably that you want sweets after you've eaten a savory meal and so on.
这可能是您在吃过美味佳肴后想要吃甜食等的原因。
A second idea though that comes to mind is just as you mentioned, this idea of learning, and so much about our preferences for food are not innate, they're driven by learning.
不过，正如你提到的，我想到的第二个想法是，这种学习的想法以及我们对食物的偏好都不是天生的，而是由学习驱动的。
Right?
正确的？
And so there are some things that are innate.
所以有些东西是与生俱来的。
So if you put sugar on a baby's tongue, it'll smile indicating that it likes it, and if you put something bitter, it'll frown, and a rat will do the same thing, a neonate rat.
因此，如果你把糖放在婴儿的舌头上，它会微笑，表明它喜欢它，如果你放苦的东西，它会皱起眉头，而老鼠也会做同样的事情，一只新生的老鼠。
But most of flavor and the perception of food is not just sweet or bitter.
但大多数味道和对食物的感知不仅仅是甜或苦。
It's this much more complex sensation that involves smells, it involves tastes, and then it involves how those tastes and smells interact with the post-ingestive effects of the nutrients.
这是一种更复杂的感觉，涉及气味、味道，然后涉及这些味道和气味如何与营养物质的摄入后效应相互作用。
So the sensing of those nutrients in your stomach and in your intestine, primarily in your intestine, are thought to then feed back and then change your preference for these foods.
因此，人们认为，胃和肠道（主要是肠道）对这些营养物质的感知会反馈并改变您对这些食物的偏好。
And so there's lots of examples of this that you can just imagine from everyday experience.
因此，有很多这样的例子，你可以从日常经验中想象出来。
Most people, the first time they had a beer or the first time they had a glass of coffee, found it repulsive, right, because it's extremely bitter.
大多数人，第一次喝啤酒或者第一次喝咖啡，都会觉得恶心，对吧，因为它非常苦。
But then we come to crave these things because we know what they do to our body.
但后来我们开始渴望这些东西，因为我们知道它们对我们的身体有什么影响。
We like what they do to our body, and that doesn't just make us take them like they're medicine.
我们喜欢它们对我们身体的作用，这不仅仅让我们把它们当作药物来服用。
We actually somehow change our very perception of how that flavor is.
实际上，我们以某种方式改变了我们对这种味道的看法。
We actually come to savor that flavor we previously found disgusting.
我们实际上是来品尝以前觉得恶心的味道的。
And it's because our sensation of whether something's good or bad depends on our internal state.
这是因为我们对事物好坏的感觉取决于我们的内部状态。
And so it's an interesting idea, perhaps if these ultra-processed foods that have so many different ingredients and such an unnatural combination, perhaps this process of learning about the nutrient content of different foods and flavors becomes impaired because it's just the brain is not used to it.
所以这是一个有趣的想法，也许如果这些超加工食品有这么多不同的成分和如此不自然的组合，也许这个了解不同食物和口味的营养成分的过程会受到损害，因为只是大脑不习惯它。
The brain's used to saying, "This is a piece of chicken, and this is primarily protein, and so I can connect this flavor to an amino acid content," but something that's so diverse, it might be harder to do.
大脑习惯于说，“这是一块鸡肉，主要是蛋白质，所以我可以将这种味道与氨基酸含量联系起来”，但事情如此多样化，可能更难做到。
Andrew Huberman:
安德鲁·休伯曼：
And isn't it the case that the neurons in the gut and the hormones that are produced by the gut as we digest food, and that the neurons in the brain that control appetite and feeding have to be tuned to macronutrient content because those are the primary colors of nutrients, and nutrients are the way in which we can persist on a day-to-day basis.
肠道中的神经元和我们消化食物时肠道产生的激素，以及大脑中控制食欲和进食的神经元，都必须根据大量营养素的含量进行调整，因为这些是营养素的原色，而营养素是我们每天能够坚持下去的方式。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Right?
对吗？
I mean, I'm not trying to sound more sophisticated where simpler terms would suffice.
我的意思是，我并不是试图用更简单的术语来听起来更复杂。
What I'm basically saying is that the neurons in our brains that control these behaviors, both eating and cessation of eating an ingredient or an entire meal, can't be tuned to a particular food product or to chicken or to an egg or to a steak or to lentils, but rather to amino acid content, essential amino acid content in particular, essential fatty acids, and in the case of carbohydrate, whatever is going to replace whatever glycogen we might have depleted.
我基本上想说的是，我们大脑中控制这些行为的神经元，无论是进食还是停止进食某种成分或整顿饭，都不能调整为特定的食品、鸡肉、鸡蛋、牛排或扁豆，而是调整为氨基酸含量，特别是必需氨基酸含量，必需脂肪酸，以及碳水化合物的情况，无论是取代我们可能耗尽的糖原的任何东西。
Right?
正确的？
If we really break it down into biology, eating is for a purpose, and my understanding is that the purpose of eating is to replace those things as needed.
如果我们真的把它分解到生物学上，吃东西是有目的的，而我的理解是，吃东西的目的是根据需要替换那些东西。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Rather than to taste savory or taste-
而不是品尝咸味或味道-
Dr. Zachary Knight:
扎卡里·奈特博士：
Absolutely.
绝对的。
Absolutely.
绝对地。
Those sensory cues are just markers that tell the brain what might be in that substance.
这些感官线索只是告诉大脑该物质中可能含有什么成分的标记。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
I think if you look broadly at this difference between calories and macronutrients and micronutrients, I would say what you see is that most of the circuits that are controlling hunger are primarily calorie specific.
我认为，如果你广泛地观察卡路里、常量营养素和微量营养素之间的差异，我会说你看到的是，大多数控制饥饿的回路主要是卡路里特定的。
So for example, an AgRP neuron I can put sugar, fat, or protein into the stomach of a mouse and to an equal extent inhibit an AgRP neuron, as long as they have equal calories.
例如，AgRP 神经元可以将糖、脂肪或蛋白质放入小鼠的胃中，并在同等程度上抑制 AgRP 神经元，只要它们具有相同的卡路里。
Andrew Huberman:
安德鲁·休伯曼：
Really?
真的吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
So a little drop of olive oil into the belly of an animal that has, let's say 120 calories of olive oil is equipotent to 120 calories of chicken breast?
那么，在动物的肚子里滴一点橄榄油，比方说，120 卡路里的橄榄油相当于 120 卡路里的鸡胸肉吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
At the level of these AgRP neurons, it is.
在这些 AgRP 神经元的水平上，确实如此。
Andrew Huberman:
安德鲁·休伯曼：
So they don't care about the macronutrient.
所以他们不关心常量营养素。
Dr. Zachary Knight:
扎卡里·奈特博士：
They don't care about the mac-- No. They're really concerned about energy.
他们不关心苹果电脑——不。他们真正关心的是能源。
Andrew Huberman:
安德鲁·休伯曼：
Okay.
好的。
So I'm probably wrong in my earlier hypothesis.
所以我之前的假设可能是错误的。
Dr. Zachary Knight:
扎卡里·奈特博士：
They're really concerned about energy.
他们确实关心能源。
Andrew Huberman:
安德鲁·休伯曼：
Uh-huh.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
There are circuitries that are more concerned with macronutrients individually, although I don't think we know nearly as much about how that works.
有些电路更关注单独的常量营养素，尽管我认为我们对其工作原理了解得还不够多。
And I think the evidence is clear that the strongest defended macronutrient by far is protein.
我认为证据很清楚，迄今为止最受保护的常量营养素是蛋白质。
So protein, I don't think really sugar and fat intake are strongly defended in the sense that you're fine if you go without eating sugar.
所以蛋白质，我不认为真正的糖和脂肪摄入量受到强烈保护，因为如果你不吃糖就没事。
Basically, you can synthesize sugar from amino acids, for example.
例如，基本上，您可以从氨基酸合成糖。
And you don't develop a specific sugar appetite in the same way you do, for example, if you deprive yourself of hunger and you develop a protein hunger.
而且你不会像你那样产生特定的糖食欲，例如，如果你剥夺自己的饥饿感，你就会产生蛋白质饥饿。
I think the difference is that proteins consist of essential amino acids.
我认为区别在于蛋白质由必需氨基酸组成。
There's this, I forget if it's nine, I think, amino acids that your body cannot synthesize.
有这个，我忘了它是否是九种，我想，你的身体无法合成的氨基酸。
You absolutely need them or you will die.
你绝对需要它们，否则你就会死。
Whereas sugar and fat can be interchanged with other macronutrients.
而糖和脂肪可以与其他常量营养素互换。
And there's other things also that you absolutely need to ingest, like sodium chloride.
还有其他一些你绝对需要摄入的东西，比如氯化钠。
So sodium.
所以钠。
So, if you deprive an animal of sodium, they'll develop this salt appetite that's incredible, basically, and that's completely innate.
因此，如果你剥夺动物的钠摄入量，它们就会产生这种令人难以置信的盐食欲，基本上，这是完全与生俱来的。
But I think salt appetite and protein appetite are the things that are probably the most strongly regulated at the level of the macro and micronutrients.
但我认为盐食欲和蛋白质食欲可能是在宏观和微量营养素水平上受到最严格调节的事物。
Andrew Huberman:
安德鲁·休伯曼：
I'd like to take a brief break and acknowledge one of our sponsors, LMNT.
我想稍微休息一下并感谢我们的赞助商之一 LMNT。
LMNT is an electrolyte drink that has everything you need.
LMNT 是一种电解质饮料，拥有您所需的一切。
That means the electrolytes sodium, magnesium, and potassium in the correct amounts and ratios, and nothing you don't, which means no sugar.
这意味着电解质的钠、镁和钾的含量和比例正确，没有任何不合适的东西，这意味着没有糖。
Now, I and others on this podcast have talked about the critical importance of hydration for proper brain and body functioning.
现在，我和这个播客中的其他人讨论了水合作用对于大脑和身体正常功能的至关重要性。
Even a slight degree of dehydration can diminish cognitive and physical performance.
即使是轻微程度的脱水也会降低认知和身体表现。
It's also important that you get adequate electrolytes.
获得充足的电解质也很重要。
The electrolytes sodium, magnesium, and potassium are critical for the functioning of all the cells in your body, especially your neurons, your nerve cells.
电解质钠、镁和钾对于体内所有细胞的功能至关重要，尤其是神经元、神经细胞。
Drinking LMNT dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes.
饮用溶解在水中的 LMNT 可以很容易地确保您获得足够的水分和电解质。
To make sure I'm getting proper amounts of hydration and electrolytes, I dissolve one packet of LMNT in about 16 to 32 ounces of water when I wake up in the morning, and I drink that basically first thing in the morning.
为了确保我获得适量的水合作用和电解质，当我早上醒来时，我将一包 LMNT 溶解在大约 16 至 32 盎司的水中，并且我基本上早上第一件事就是喝它。
I'll also drink LMNT dissolved in water during any kind of physical exercise I'm doing, especially on hot days when I'm sweating a lot, losing water and electrolytes.
我还会在进行任何体育锻炼时饮用溶解在水中的 LMNT，尤其是在炎热的日子里，当我大量出汗、失去水分和电解质时。
They have a bunch of different great-tasting flavors of LMNT.
他们有多种不同口味的 LMNT。
My favorite is the watermelon, although I confess I also like the raspberry and the citrus.
我最喜欢的是西瓜，尽管我承认我也喜欢覆盆子和柑橘。
Basically, I like all the flavors.
基本上所有的口味我都喜欢。
And LMNT has also just released a new line of canned sparkling LMNT.
LMNT 还刚刚推出了新系列的罐装起泡 LMNT。
So these aren't the packets you dissolve in water, these are cans of LMNT that you crack open like any other canned drink, like a soda, but you're getting your hydration and your electrolytes with no sugar.
所以这些不是你溶解在水中的小包，这些是 LMNT 罐头，你可以像任何其他罐装饮料（如苏打水）一样打开它们，但你会得到水分和电解质，但不含糖。
If you'd like to try LMNT, you can go to drinklmnt, spelled L-M-N-T .com/huberman to claim a free LMNT sample pack with the purchase of any LMNT drink mix.
如果您想尝试 LMNT，可以前往 Drinklmnt（拼写为 L-M-N-T .com/huberman），购买任意 LMNT 混合饮料即可获得免费 LMNT 样品包。
Again, that's drinklmnt.com/huberman to claim a free sample pack.
再次强调，请访问 Drinklmnt.com/huberman 索取免费样品包。
If we could talk about body weight homeostasis for a moment, I think that would be useful.
如果我们能谈谈体重稳态，我认为那会很有用。
So, let's say somebody decides they want to lose some weight.
那么，假设有人决定要减肥。
They caloric restrict slightly, either by exercising more or eating less, or both.
他们通过增加锻炼或减少饮食，或两者兼而有之，稍微限制热量。
Their body weight drops by a bit.
他们的体重有所下降。
Let's say they lose 10 pounds, 8 of which are body fat.
假设他们减掉了 10 磅，其中 8 磅是体内脂肪。
They lose a little bit of lean mass also.
他们也失去了一点瘦体重。
They're now at a new lower body weight.
他们现在的体重达到了新的较低水平。
Are the AgRP neurons motivated to have them seek out more food?
AgRP 神经元是否有动力让它们寻找更多食物？
In other words, are they hungrier and more motivated to find and eat food, or do these AgRP neurons learn, "Hey, body weight is lower, and I don't need to push to find so much food so often"?
换句话说，它们是否更饥饿，更有动力去寻找和吃食物，或者这些 AgRP 神经元是否学习到，“嘿，体重较低，我不需要那么频繁地寻找这么多食物”？
Dr. Zachary Knight:
扎卡里·奈特博士：
No, the idea is that the AgRP neurons are more active when you lose weight, and that chronic activation of those neurons, in part because leptin levels are lower in the blood because you've lost weight, is that drive, that counterregulatory drive that drives you to then consume more food.
不，我们的想法是，当你减肥时，AgRP 神经元会更加活跃，而这些神经元的慢性激活，部分原因是因为你体重减轻了，血液中的瘦素水平较低，这是一种驱动力，一种反调节驱动力，驱使你消耗更多的食物。
Andrew Huberman:
安德鲁·休伯曼：
But then how do people ever keep weight off?
但人们如何才能减肥呢？
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, so part of the answer is they don't.
嗯，部分答案是他们不这样做。
Andrew Huberman:
安德鲁·休伯曼：
Really?
真的吗？
Because I would argue, I have these friends who were very heavy.
因为我会争辩说，我有这些非常沉重的朋友。
Most of the excess weight was body fat for a long time.
长期以来，多余的体重大部分是体内脂肪。
They seem to be doing great-
他们似乎做得很好——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
eating the way that I described before.
按照我之前描述的方式吃。
And by the way, I'm not a proponent of any one particular diet.
顺便说一句，我不支持任何一种特定的饮食习惯。
I have vegan friends, carnivore friends, et cetera.
我有素食朋友、肉食朋友等等。
But that pattern of eating I described before has been enormously successful for them.
但我之前描述的这种饮食模式对他们来说非常成功。
I haven't run a randomized control trial.
我还没有进行随机对照试验。
It's not my job to do that in the realm of nutrition, but they're doing great.
在营养领域做到这一点不是我的工作，但他们做得很好。
They claim to be sated.
他们声称已经满足了。
They are so happy with the way things are going, and I don't hear that they're constantly hungry.
他们对事情的进展非常满意，而且我没有听说他们经常挨饿。
I hear that they're constantly sated.
我听说他们总是很满足。
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, so I would say that there have been efforts for a long time to develop diets that would help people consistently lose weight, and it has been very unsuccessful.
嗯，所以我想说，长期以来，人们一直在努力开发可以帮助人们持续减肥的饮食，但非常不成功。
There are some people who, for various reasons, can successfully lose weight and keep it off, and I don't know that I have a good answer for what's going on in those individual cases, how they are the exceptions to the rule.
有些人由于各种原因可以成功减肥并保持体重，但我不知道我对这些个别案例中发生的事情以及他们如何成为规则的例外有一个很好的答案。
What about them is different that makes them successful?
他们有什么不同之处使得他们成功？
Andrew Huberman:
安德鲁·休伯曼：
Some also quit drinking alcohol.
有些人还戒酒。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
So there's other things.
所以还有其他事情。
Andrew Huberman:
安德鲁·休伯曼：
Right.
对。
Dr. Zachary Knight:
扎卡里·奈特博士：
So, I think if you-
所以，我想如果你——
Andrew Huberman:
安德鲁·休伯曼：
So behavioral regulation is better when you're sober as opposed to inebriated.
因此，与醉酒相比，清醒时的行为调节效果更好。
Dr. Zachary Knight:
扎卡里·奈特博士：
You can change your environment.
你可以改变你的环境。
But so what this is sort of getting at is what is the counterregulatory response to weight loss?
但这的目的是想了解减肥的反监管反应是什么？
And so this has been studied.
因此我们对此进行了研究。
It was first studied in the context of energy expenditure.
它首先是在能量消耗的背景下进行研究的。
And, because energy expenditure is actually surprisingly easier to measure in humans than food intake because people don't tell you accurately what food they eat.
而且，因为人类的能量消耗实际上比食物摄入更容易测量，因为人们不会准确地告诉你他们吃什么食物。
If they're free-living humans, they have to fill out a questionnaire.
如果他们是自由生活的人，他们必须填写一份调查问卷。
And the idea is that for every kilogram of weight you lose, so it's about 2.2 pounds, I think, your energy expenditure decreases by about 30 kilocalories a day.
这个想法是，我认为，你每减掉一公斤体重，大约是 2.2 磅，你每天的能量消耗就会减少大约 30 卡路里。
Now, so not a ton, but that is significant, 30 calories.
现在，虽然不是一吨，但也很重要了，30 卡路里。
And then if you lose, as you said, 10 pounds, then that's 150 calories, and that adds up over time.
然后，如您所说，如果您减掉了 10 磅，那么热量就是 150 卡路里，随着时间的推移，热量会不断增加。
One interesting thing about that is that if you take people who were obese and then they've lost a ton of weight, so there's a study by Rudy Leibel about 25 years ago that did this.
一件有趣的事情是，如果你拿肥胖的人来说，他们的体重就会减轻很多，鲁迪·莱贝尔 (Rudy Leibel) 大约 25 年前的一项研究就做到了这一点。
Take people who lost 100 pounds, and then take a control group that has the same height, weight, basically the same body composition as those people who've now lost 100 pounds.
以减掉 100 磅的人为例，然后选择与现在减掉 100 磅的人具有相同身高、体重、基本相同身体成分的对照组。
Compare their energy expenditure.
比较他们的能量消耗。
The energy expenditure in the people that lost all the weight is about 25% lower than the people who never were obese.
体重全部减轻的人的能量消耗比从未肥胖的人低约 25%。
And so those people who lost the weight, we call them the reduced obese.
因此，那些体重减轻的人，我们称他们为减重肥胖者。
So that's what they were called in those studies.
这就是这些研究中对它们的称呼。
And the idea is that there's now this chronic deficit.
这个想法是现在存在这种长期赤字。
They have to eat 25% less than someone who looks the same as them, is the same height as them, same weight as them, in order to maintain that body weight.
为了保持体重，他们必须比那些看起来和他们一样、身高和体重相同的人少吃25%。
What's unclear is whether that's because those people simply always had a slower metabolism, they were always destined to be obese, and then you just basically you're comparing two different groups, or whether something about the process of gaining weight and being at a higher weight for a longer period of time changes the brain, so that then once you lose the weight, it's irreversible.
目前尚不清楚的是，这是否是因为这些人的新陈代谢总是较慢，他们总是注定会肥胖，然后你基本上只是在比较两个不同的群体，或者体重增加和长时间保持较高体重的过程是否会改变大脑，所以一旦你减肥，它是不可逆转的。
But there have been studies looking at at least a year, and it doesn't seem to come back within a year, that difference in energy expenditure.
但有研究至少观察了一年，但似乎一年内并没有发现能量消耗的差异。
Now the question is, is that really the big effect?
现在的问题是，这真的有那么大的影响吗？
Is that why it's so hard to lose weight, energy expenditure?
这就是减肥如此困难、能量消耗如此之大的原因吗？
Or is it because you're hungrier?
还是因为你更饿了？
And that's actually much harder to measure.
这实际上更难衡量。
But there was another really nice study, again by Kevin Hall, investigating this.
但凯文·霍尔（Kevin Hall）又进行了另一项非常好的研究，对此进行了调查。
He used a really clever approach, this drug.
他用了一个非常聪明的方法，就是这种药物。
So basically what he wanted to do was, he reasoned that you can measure people's body weight, and you can measure people's energy expenditure.
所以基本上他想做的是，他推断你可以测量人们的体重，你可以测量人们的能量消耗。
And because calories in, calories out, if we can measure body weight and energy expenditure accurately, we can then back-calculate how much that person was actually eating.
因为卡路里摄入量，卡路里消耗量，如果我们能够准确测量体重和能量消耗，我们就可以反算出这个人实际吃了多少。
So let's see what happens when you have people lose weight, how does their food intake change?
那么让我们看看当人们减肥时会发生什么，他们的食物摄入量会如何变化？
But the trick to this is you need to do it in such a way that you don't just tell them to go run on a treadmill, because if you tell someone to go run on a treadmill and lose weight, then basically they're thinking about the fact that they're doing this.
但这样做的诀窍是，你需要以这样的方式来做，你不只是告诉他们去跑步机上跑步，因为如果你告诉某人去跑步机上跑步并减肥，那么基本上他们会想到他们正在这样做的事实。
So you need to do it in some way covertly, so that you increase their energy expenditure, cause them to lose weight, but without them realizing that's what's happening.
所以你需要以某种方式秘密地做到这一点，这样你就可以增加他们的能量消耗，让他们减肥，但他们却没有意识到正在发生的事情。
So they gave them these drugs, these SGLT2 inhibitors, and it's a pill you can take.
所以他们给了他们这些药物，这些 SGLT2 抑制剂，这是一种你可以服用的药丸。
They're used for diabetes.
它们用于治疗糖尿病。
They block this protein, SGLT2 in the kidney, that is necessary for glucose to be reabsorbed into the blood.
它们阻断肾脏中的 SGLT2 蛋白，这是葡萄糖重新吸收到血液中所必需的。
And so basically what happens, you pee out about 90 grams of glucose a day, but you don't know that you're doing that.
基本上，您每天会排出大约 90 克葡萄糖，但您不知道自己正在这样做。
And that causes you to lose energy, and so these people would lose some weight.
这会导致你失去能量，所以这些人会减轻一些体重。
And then measure how their food intake changes.
然后测量他们的食物摄入量如何变化。
And what that showed is that for every two pounds or so of weight you lose, your hunger goes up by 100 calories per day.
结果表明，你每减掉两磅左右的体重，你每天的饥饿感就会增加 100 卡路里。
So basically you've got a 30-kilocalorie decrease in energy expenditure, 100-kilocalorie decrease in appetite for every two pounds you lose, on average.
所以基本上，平均每减掉两磅，你的能量消耗会减少 30 卡路里，食欲会减少 100 卡路里。
Some people will be exceptions, and they won't experience that at all for aspects of their physiology we don't understand.
有些人会是例外，他们根本不会经历这种情况，因为他们的生理学方面我们不了解。
And so the increased hunger seems to be the main reason people find it so difficult to keep weight off.
因此，饥饿感的增加似乎是人们发现减肥如此困难的主要原因。
Andrew Huberman:
安德鲁·休伯曼：
That seems the perfect segue to talk about GLP-1, glucagon-like peptide 1, Ozempic, Mounjaro, and similar drugs.
这似乎是谈论 GLP-1、胰高血糖素样肽 1、Ozempic、Mounjaro 和类似药物的完美延续。
My understanding of the back history on these is that a biologist obsessed with Gila monsters, a reptile that doesn't need to eat very often, discovered a peptide within their bloodstream called extendin-
我对这些历史的理解是，一位痴迷于希拉毒蜥（一种不需要经常进食的爬行动物）的生物学家，在它们的血液中发现了一种肽，称为延伸素-
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
that allowed them to eat very seldom.
这使得他们吃得很少。
It curbed appetite in the Gila monster, of all things.
它抑制了吉拉毒蜥的食欲。
And it has an analog homolog, we don't know.
它有一个类似的同系物，我们不知道。
I don't know the sequence homology exactly, but there's a similar peptide made in mice and in humans that suppresses appetite.
我不知道确切的序列同源性，但在小鼠和人类中产生了一种类似的肽，可以抑制食欲。
If you would, could you tell us what is known about how GLP-1 works to suppress appetite, where in the body and/or brain?
如果愿意，您能否告诉我们 GLP-1 在身体和/或大脑的哪个部位如何发挥抑制食欲的作用？
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
Andrew Huberman:
安德鲁·休伯曼：
And your read of these drugs and what's happening there.
还有你对这些药物的了解以及那里发生的事情。
Good, bad, exciting-
好的、坏的、令人兴奋的——
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure
当然可以
Andrew Huberman:
安德鲁·休伯曼：
...
...
ugly.
丑陋的。
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
I'm happy to.
我很高兴。
Andrew Huberman:
安德鲁·休伯曼：
Anything else.
还有什么。
Dr. Zachary Knight:
扎卡里·奈特博士：
So the story of GLP-1, so the Gila monster is an important turn, and I'll talk about that.
所以 GLP-1 的故事，所以希拉毒蜥的故事是一个重要的转折，我会谈论这个。
It actually goes back before that quite a ways.
它实际上可以追溯到很久以前。
So I should take a step back and say, these were developed as drugs for diabetes.
所以我应该退一步说，这些是作为糖尿病药物而开发的。
And diabetes is a condition where basically you have elevated blood glucose, either because you don't produce enough insulin or because your insulin is not effective.
糖尿病基本上是一种血糖升高的疾病，要么是因为您无法产生足够的胰岛素，要么是因为您的胰岛素无效。
And so back in the 1920s, right around the time insulin was discovered, there was this phenomenon discovered known as the incretin effect.
早在 20 世纪 20 年代，就在胰岛素被发现的时候，出现了一种被称为肠促胰岛素效应的现象。
And what it was-
那是什么——
Andrew Huberman:
安德鲁·休伯曼：
Incretin?
肠促胰岛素？
Dr. Zachary Knight:
扎卡里·奈特博士：
Incretin, yeah.
肠促胰岛素，是的。
Andrew Huberman:
安德鲁·休伯曼：
Not the cretin effect.
不是白痴效应。
Dr. Zachary Knight:
扎卡里·奈特博士：
Not the cretin effect.
不是白痴效应。
Andrew Huberman:
安德鲁·休伯曼：
You can observe the cretin effect in numerous places in daily life and online.
您可以在日常生活和网络的许多地方观察到白痴效应。
Just kidding.
只是在开玩笑。
Dr. Zachary Knight:
扎卡里·奈特博士：
So it's called the incretin effect.
因此称为肠促胰素效应。
You can think of it as increase insulin, because that's what the effect is.
您可以将其视为增加胰岛素，因为这就是效果。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
And the idea was that if you take glucose by mouth, if you consume glucose orally, versus if you have the same amount of glucose injected intravenously, more insulin is produced when you take the glucose orally versus if it's delivered intravenously.
这个想法是，如果你口服葡萄糖，如果你口服葡萄糖，与静脉注射相同量的葡萄糖相比，口服葡萄糖时会产生更多的胰岛素，而静脉注射葡萄糖时会产生更多的胰岛素。
Suggesting something about the process of ingesting the glucose causes more insulin to be released and causes you to lower your body sugar more accurately and more strongly.
对摄入葡萄糖的过程提出一些建议会导致更多的胰岛素释放，并使您更准确、更强烈地降低体内血糖。
Andrew Huberman:
安德鲁·休伯曼：
Interesting.
有趣。
Dr. Zachary Knight:
扎卡里·奈特博士：
Which is a little bit counterintuitive because in the pancreas, so insulin is released from the pancreas, from the beta cell, the pancreas senses the glucose concentration in the blood directly.
这有点违反直觉，因为在胰腺中，胰岛素是从胰腺、β细胞中释放出来的，胰腺直接感知血液中的葡萄糖浓度。
And so it suggests that insulin is being released not just in response to changes in blood glucose, but in response to a second factor.
因此，这表明胰岛素的释放不仅是对血糖变化的反应，也是对第二个因素的反应。
And so they called that an incretin.
所以他们称之为肠促胰岛素。
And through various experiments, it was shown that this incretin effect comes from the intestine, that there's some substance being produced by the intestine that when you eat a meal If sugar goes through your intestine, that boosts this insulin response to glucose in the blood.
通过各种实验，结果表明，这种肠促胰岛素的作用来自肠道，当你吃饭时，肠道会产生一些物质，如果糖通过你的肠道，就会增强胰岛素对血液中葡萄糖的反应。
And people immediately realized this could potentially be very valuable.
人们立即意识到这可能非常有价值。
And the reason is that you can treat diabetes with insulin injections, but insulin is dangerous, right?
原因是注射胰岛素可以治疗糖尿病，但胰岛素很危险，对吗？
Because if you inject too much insulin, you can kill yourself by making yourself hypoglycemic, right?
因为如果你注射过多的胰岛素，你就会因为低血糖而自杀，对吗？
So you have to be very careful.
所以你必须非常小心。
But the thing about the incretin effect is it's not causing insulin release directly, but it's rather boosting the natural insulin release that comes when your glucose is higher in your blood.
但肠促胰素效应的问题在于，它不会直接导致胰岛素释放，而是会促进血液中葡萄糖较高时自然释放的胰岛素。
So it's sort of an amplifier on the natural insulin release.
所以它是自然胰岛素释放的放大器。
So basically, in the years that followed, whenever someone would find a new hormone, they would test it, is it this incretin?
所以基本上，在接下来的几年里，每当有人发现一种新的激素时，他们都会测试它，是肠促胰素吗？
And there was lots of failures.
并且有很多失败。
They weren't the incretin.
它们不是肠促胰岛素。
So there's this other hormone that comes from the pancreas called glucagon.
还有另一种来自胰腺的激素，称为胰高血糖素。
And so glucagon, which was also discovered in the 1920s, glucagon is kind of the anti-insulin.
胰高血糖素也是在 20 世纪 20 年代发现的，它是一种抗胰岛素药物。
So when blood sugar goes low, glucagon is released in order to cause your liver to release glucose into the blood.
因此，当血糖降低时，胰高血糖素就会被释放，从而使肝脏将葡萄糖释放到血液中。
So glucagon and insulin are these two opposing hormones.
所以胰高血糖素和胰岛素是这两种相反的激素。
Glucagon was known for a long time, but people discovered in the 1980s that the glucagon gene is expressed in other tissues other than the pancreas, and it's differentially processed.
胰高血糖素早已为人所知，但人们在20世纪80年代发现胰高血糖素基因在胰腺以外的其他组织中表达，并且经过差异化加工。
The protein is differentially processed to produce different hormones, hormones other than glucagon.
该蛋白质经过差异化处理，产生不同的激素，即胰高血糖素以外的激素。
And they discovered there was one in the intestine, and so they called it glucagon-like peptide because it comes from the same gene, but it's just slightly different.
他们发现肠道里有一种肽，所以他们把它称为胰高血糖素样肽，因为它来自相同的基因，但只是略有不同。
It's cut up slightly differently.
它的切割方式略有不同。
And this hormone was an incretin.
这种激素是肠促胰岛素。
So basically, if you put it on beta cells, you get this increased response of insulin in response to glucose.
所以基本上，如果你把它放在β细胞上，你就会得到胰岛素对葡萄糖的反应增强。
And so there was the idea, okay, this could be a great diabetes drug, right?
所以就有了这个想法，好吧，这可能是一种很棒的糖尿病药物，对吧？
And I should say there was one other incretin that's been found.
我应该说还发现了另一种肠促胰岛素。
It's called GIP, G-I-P, and that will be important in talking about some of these other drugs.
它被称为 GIP，G-I-P，这在谈论其他一些药物时很重要。
Also, a hormone that comes from the intestine.
此外，还有一种来自肠道的激素。
And so, the challenge with making GLP-1 into a drug is that it has an extremely short half-life.
因此，将 GLP-1 制成药物的挑战在于它的半衰期极短。
So it has a half-life of about two minutes in the blood.
因此它在血液中的半衰期约为两分钟。
And so even if you inject people with GLP-1, it won't really be useful for anything.
因此，即使你给人们注射 GLP-1，它也不会真正有任何用处。
You don't decrease appetite, you don't affect blood sugar because it's just degraded too fast.
你不会降低食欲，也不会影响血糖，因为它只是降解得太快了。
And the reason it's degraded is because there's an enzyme, DPP-4 is what it's called, that degrades GLP-1.
它被降解的原因是因为有一种酶，即所谓的 DPP-4，可以降解 GLP-1。
So the first thing people tried was let's make inhibitors of that enzyme so we can boost this natural GLP-1 signal, and those are approved diabetes drugs.
因此，人们尝试的第一件事就是制造该酶的抑制剂，这样我们就可以增强这种天然的 GLP-1 信号，而这些都是批准的糖尿病药物。
They're called gliptins.
它们被称为格列汀。
You've probably heard about them.
您可能听说过它们。
Januvia is the most common one.
Januvia 是最常见的一种。
And those boost the level of GLP-1, the natural GLP-1 produced from the intestine by about threefold, and they're effective in treating diabetes.
这些药物可将 GLP-1（肠道产生的天然 GLP-1）水平提高约三倍，并且可有效治疗糖尿病。
Andrew Huberman:
安德鲁·休伯曼：
Do people lose weight?
人们减肥吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
People do not lose weight.
人们并没有减肥。
Andrew Huberman:
安德鲁·休伯曼：
Interesting.
有趣。
Dr. Zachary Knight:
扎卡里·奈特博士：
And that's one of the key reasons that we know that the natural function of GLP-1 is not really to control body weight, because you can boost the level threefold with these DPP-4 drugs.
这是我们知道 GLP-1 的天然功能并不是真正控制体重的关键原因之一，因为使用这些 DPP-4 药物可以将其水平提高三倍。
Millions of people have taken them.
数百万人已经拿走了它们。
They do not lose weight.
他们不减肥。
That's a great question.
这是一个很好的问题。
But a threefold is great, but you'd like to increase it even more, right?
但三倍已经很好了，但您还想增加更多，对吧？
And to do that, you can't block this enzyme.
为此，您无法阻止这种酶。
You have to actually produce a GLP-1 that is more stable in the blood.
您必须真正产生在血液中更稳定的 GLP-1。
And that's where this lizard that you mentioned comes into play.
这就是你提到的这只蜥蜴发挥作用的地方。
It produces a stabilized form of GLP-1 in its venom.
它在毒液中产生稳定形式的 GLP-1。
No one knows why.
没有人知道为什么。
One hypothesis is that it's something to do with the lizard, as you said, basically having this long time period between meals, and it needs to regulate its blood glucose.
一种假设是，这与蜥蜴有关，正如你所说，基本上两餐之间的时间间隔很长，它需要调节血糖。
Who knows if that is true?
谁知道这是不是真的？
But it turned out to be fortuitous because then this GLP-1 from this lizard, it has a half-life of two hours.
但事实证明这是偶然的，因为来自这种蜥蜴的 GLP-1 的半衰期为两个小时。
And so the first GLP-1 drug that was approved was just this molecule from this lizard, basically.
因此，第一个获得批准的 GLP-1 药物基本上就是来自这种蜥蜴的这种分子。
And it's called exenatide and it was approved in 2005.
它叫艾塞那肽，于 2005 年获得批准。
Works well for diabetes, has a half-life of two hours.
对糖尿病有效，半衰期为两小时。
You inject it and it doesn't cause a ton of weight loss.
你注射它并不会导致体重大幅减轻。
But two hours is good, but it's not so great.
两个小时虽好，但也不是那么好。
So then the pharmaceutical industry tried to say, "Can we basically improve this even further?" And so they started engineering this hormone, making mutations, attaching lipid tails to make it bind to proteins in the blood that would stabilize it.
因此，制药行业试图说：“我们基本上可以进一步改进这一点吗？”因此，他们开始设计这种激素，进行突变，附加脂质尾部，使其与血液中的蛋白质结合，从而稳定它。
Andrew Huberman:
安德鲁·休伯曼：
Chemistry jockey stuff.
化学骑师的东西。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah, exactly.
是的，完全正确。
And I think the next big advance was this compound, liraglutide.
我认为下一个重大进展是这种化合物，利拉鲁肽。
And liraglutide was approved for diabetes in 2010 and then for weight loss in 2014.
利拉鲁肽于 2010 年被批准用于治疗糖尿病，随后于 2014 年被批准用于减肥。
And so liraglutide has a half-life of about 13 hours in the blood.
因此利拉鲁肽在血液中的半衰期约为 13 小时。
Now you're getting up to something serious.
现在你正在做一些严肃的事情。
We've gone from two minutes, two hours, 13 hours.
我们已经从两分钟、两小时、十三小时过去了。
And you get better effects on aspects of blood glucose and diabetes control, and they started to see that some people were losing weight.
在血糖和糖尿病控制方面你会得到更好的效果，他们开始看到有些人体重减轻了。
Very variable responses.
反应非常多变。
Not everyone loses weight on liraglutide.
并不是每个人都可以通过利拉鲁肽减肥。
And one of the things they noticed that I think is a fascinating example of how drug discovery works in the real world, a lot of these people who take liraglutide, now it has this longer half-life, they start to get nauseous, and that would limit how much of the liraglutide they could take.
他们注意到的一件事我认为是药物发现在现实世界中如何运作的一个有趣的例子，很多服用利拉鲁肽的人，现在它的半衰期更长，他们开始感到恶心，这将限制他们可以服用的利拉鲁肽的量。
And it's a known side effect of these GLP-1 drugs.
这是这些 GLP-1 药物的已知副作用。
It causes nausea and this gastrointestinal distress.
它会引起恶心和胃肠道不适。
But they noticed that over time, the nausea would just sort of go away.
但他们注意到，随着时间的推移，恶心感会逐渐消失。
And so they would start dose escalating, sort of raising the dose that the person would take.
因此他们会开始增加剂量，某种程度上提高了患者服用的剂量。
So you would go a month at this dose and then a month at a slightly higher dose, and then a month at a slightly higher dose, and you could work your way up, and these side effects would reappear, but then they'd go away.
所以你会用这个剂量一个月，然后用稍高的剂量一个月，然后用稍高的剂量一个月，你可以逐步增加，这些副作用会再次出现，但随后就会消失。
And then once you got up to the highest doses, then people really started losing weight.
一旦达到最高剂量，人们就真正开始减肥。
And so there's a couple things there.
所以有一些事情。
Pharmaceutical industry realized, wow, these are potentially really effective weight loss drugs.
制药行业意识到，哇，这些可能是真正有效的减肥药。
And also this nausea, which we thought was a killer, people are able to just get used to it, and then it just goes away.
还有这种恶心，我们认为这是一个杀手，人们能够习惯它，然后它就会消失。
It undergoes, the word is tachyphylaxis.
它经历了，这个词就是快速耐受。
So the idea is that the receptor in the gut that's causing these effects, it undergoes some sort of downregulation with chronic exposure.
因此，我们的想法是，肠道中引起这些影响的受体会随着长期暴露而经历某种下调。
So liraglutide, it's been on the market for 14 years now, was used, but still you're only getting sort of seven to 10% weight loss, which is good, but not amazing.
因此，利拉鲁肽已经上市 14 年了，人们使用了它，但仍然只能减轻 7% 到 10% 的体重，这很好，但并不令人惊奇。
Impressive.
感人的。
But then semaglutide came along, and that was approved for diabetes in 2017.
但后来索马鲁肽出现了，并于 2017 年被批准用于治疗糖尿病。
And semaglutide is Ozempic or also marketed as Wegovy for weight loss.
索马鲁肽是 Ozempic，也以 Wegovy 的名称销售，用于减肥。
And semaglutide now has a half-life of seven days.
索马鲁肽现在的半衰期为 7 天。
So now we've gone from two minutes, two hours, 13 hours, seven days.
现在我们已经从两分钟、两小时、13 小时、7 天过去了。
And you can really jack up the concentration with a seven-day half-life.
7 天的半衰期确实可以提高浓度。
And then they saw people start really losing weight.
然后他们看到人们开始真正减肥。
And so, in some of those trials, people lost 16% of their body weight, which previously had been unattainable.
因此，在其中一些试验中，人们的体重减轻了 16%，这在以前是无法实现的。
Andrew Huberman:
安德鲁·休伯曼：
In what time frame?
在什么时间范围内？
Dr. Zachary Knight:
扎卡里·奈特博士：
It typically takes about a year.
通常需要一年左右的时间。
Andrew Huberman:
安德鲁·休伯曼：
Okay.
好的。
And most of the loss in body weight is from body fat or from other compartments?
体重的大部分减轻是来自体内脂肪还是来自其他部位？
Dr. Zachary Knight:
扎卡里·奈特博士：
The typical number is that if you lose weight, either through dieting or through taking one of these drugs, and you don't do anything like eat a high-protein diet or do resistance training, somewhere between 25% and 33% of what you lose is going to be muscle.
典型的数字是，如果你通过节食或服用其中一种药物来减肥，并且你不做任何事情，比如吃高蛋白饮食或进行阻力训练，那么你失去的 25% 到 33% 之间将是肌肉。
The rest is going to be fat.
剩下的都会变胖。
Andrew Huberman:
安德鲁·休伯曼：
But as you said, some of that could be offset by resistance training and/or consuming a higher protein diet.
但正如你所说，其中一些可以通过阻力训练和/或摄入更高蛋白质的饮食来抵消。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah, you can almost completely eliminate that if you eat enough protein and do serious weightlifting.
是的，如果你摄入足够的蛋白质并认真进行举重，你几乎可以完全消除这种情况。
Obviously, not the whole population is interested in doing that.
显然，并非所有人都有兴趣这样做。
And there's been a lot of discussion of how serious a side effect this is.
关于这种副作用有多严重已经有很多讨论。
Among elderly people, you don't want to be losing muscle mass because you're already losing so much muscle mass.
对于老年人来说，你不想失去肌肉质量，因为你已经失去了太多的肌肉质量。
On the other hand, the counterargument that has been made, which I think is also kind of convincing, is that, true, you're losing some muscle, but you're also losing all this fat, and you no longer need as much muscle when you're not carrying around as much body fat.
另一方面，我认为也很有说服力的反驳是，确实，你失去了一些肌肉，但你也失去了所有这些脂肪，当你不再携带那么多的身体脂肪时，你就不再需要那么多的肌肉。
So people who are heavier naturally have more muscle because they need to, to move their body, right?
所以体重较重的人自然有更多的肌肉，因为他们需要移动身体，对吗？
And so-
所以——
Andrew Huberman:
安德鲁·休伯曼：
Yeah, the calves on very obese people are often enormous.
是的，非常肥胖的人的小腿通常很大。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
And then they lose weight and-
然后他们减肥并且——
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly
正是如此
Andrew Huberman:
安德鲁·休伯曼：
...
...
and I mention the calves in particular because they're carrying a lot of the body load.
我特别提到小腿，因为它们承受着很大的身体负荷。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
So, it's still an open question as to how serious a problem this lean muscle mass loss is.
因此，这种瘦肌肉质量损失的问题有多严重仍然是一个悬而未决的问题。
Although, the pharmaceutical industry is all in now on making drugs that basically are going to prevent that.
尽管如此，制药行业现在正在全力生产基本上可以防止这种情况发生的药物。
So that's something that will be happening probably in the future.
所以这可能是未来会发生的事情。
Andrew Huberman:
安德鲁·休伯曼：
Sorry to interrupt, but is the weight loss on these drugs the consequence of reduced appetite or some other aspect of metabolism?
抱歉打断一下，这些药物导致的体重减轻是食欲下降还是新陈代谢的其他方面的结果吗？
And if it's the consequence of reduced appetite, is that occurring at the level of the brain and gut, or a combination?
如果这是食欲下降的结果，那么这是发生在大脑和肠道层面，还是两者的结合？
Dr. Zachary Knight:
扎卡里·奈特博士：
So it's almost entirely reduced appetite, and it's almost entirely occurring at the level of the brain.
所以它几乎完全降低了食欲，而且几乎完全发生在大脑层面。
Andrew Huberman:
安德鲁·休伯曼：
Which neurons?
哪些神经元？
Dr. Zachary Knight:
扎卡里·奈特博士：
It's thought that the key targets of these drugs are neurons in these two regions.
人们认为这些药物的关键靶点是这两个区域的神经元。
One's called the nucleus of the solitary tract, and the other one's called the area postrema.
一个称为孤束核，另一个称为后区。
Andrew Huberman:
安德鲁·休伯曼：
So we're back in the brain stem.
所以我们又回到了脑干。
Dr. Zachary Knight:
扎卡里·奈特博士：
Back in the brain stem.
回到脑干。
So these are actually the neurons in that decerebrate rat story I was telling earlier.
所以这些实际上是我之前讲的去大脑老鼠故事中的神经元。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
These are the brain regions that are preserved in the decerebrate rat.
这些是去大脑大鼠中保留的大脑区域。
The decerebrate rat still has these very caudal brain stem structures.
去大脑大鼠仍然具有这些非常尾部的脑干结构。
They're two very special brain regions because they get direct input from the vagus nerve.
它们是两个非常特殊的大脑区域，因为它们从迷走神经获得直接输入。
So the vagus nerve is the nerve that innervates your stomach and intestines and heart and lungs, and is sort of the major pathway from gut to brain, and provides most of the neural input from gut to brain, telling you about things like your stomach distension, how many nutrients are in your intestine, breathing, all that stuff.
因此，迷走神经是支配胃、肠、心脏和肺的神经，是从肠道到大脑的主要通路，提供从肠道到大脑的大部分神经输入，告诉你诸如胃胀、肠道中有多少营养物质、呼吸等信息。
And almost all of those vagal nerves terminate on these two structures in the brain stem.
几乎所有迷走神经都终止于脑干的这两个结构。
Andrew Huberman:
安德鲁·休伯曼：
When I hear postrema, I think about nausea.
当我听到Postrema时，我想到了恶心。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yep.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Because I was taught that postrema contains neurons that can stimulate vomiting.
因为我被告知，postrema 含有可以刺激呕吐的神经元。
And this seems to link up well, at least in the logical sense, with the idea that stimulating, activating receptors in these neurons within postrema might explain part of the transient nausea side effect-
这似乎有很好的联系，至少在逻辑意义上，刺激、激活后区这些神经元中的受体可能解释部分短暂的恶心副作用——
Dr. Zachary Knight:
扎卡里·奈特博士：
It does
确实如此
Andrew Huberman:
安德鲁·休伯曼：
...
...
of Ozempic and related drugs.
臭氧及相关药物。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
So the current thought is that a lot of the nausea is coming from activating the neurons of the area postrema, and that a lot of the physiologic satiety is coming from activating the neurons in the nucleus of the solitary tract.
因此，目前的想法是，很多恶心感来自激活后区的神经元，而很多生理饱腹感则来自激活孤束核中的神经元。
Now, the whole brain is connected to each other, and so if you really turn on these neurons in the NTS and the AP, they're going to talk to the hypothalamus and all these other brain regions, it's going to change the whole brain.
现在，整个大脑是相互连接的，所以如果你真的打开 NTS 和 AP 中的这些神经元，它们将与下丘脑和所有其他大脑区域对话，这将改变整个大脑。
So it's not just those regions, but these drugs don't have great access to the brain.
因此，不仅仅是这些区域，这些药物也无法很好地进入大脑。
They can penetrate a little bit into the brain, but they don't penetrate into the whole brain.
它们可以渗透到大脑的一小部分，但不会渗透到整个大脑。
And it's thought that if you take fluorescently labeled versions of these drugs and see, so you can visualize where do they actually go, they're enriched in these structures in the brain stem.
人们认为，如果你服用这些药物的荧光标记版本并观察，这样你就可以想象它们实际上去了哪里，它们在脑干的这些结构中丰富了。
So that's why people think that this is probably where they're acting.
所以这就是为什么人们认为这可能就是他们行动的地方。
Andrew Huberman:
安德鲁·休伯曼：
And is that because there's an abundance of the receptors for these compounds in postrema and NTS, or is it because the blood-brain barrier is somehow weaker at that location?
这是因为后部和 NTS 中存在大量这些化合物的受体，还是因为该位置的血脑屏障在某种程度上较弱？
Dr. Zachary Knight:
扎卡里·奈特博士：
It's because the blood-brain barrier is weaker.
这是因为血脑屏障较弱。
So basically, it's a region, what's known as a circumventricular organ, meaning it's one of these rare places in the brain where the blood-brain barrier is weakened, and so substances can come from the outside into the brain.
所以基本上，它是一个区域，被称为脑室周围器官，这意味着它是大脑中血脑屏障被削弱的罕见区域之一，因此物质可以从外部进入大脑。
And that's important for these big peptides, because these are not small molecules, these are big peptides with lipid chains on them and other things.
这对于这些大肽很重要，因为它们不是小分子，而是带有脂质链和其他物质的大肽。
And so they can really only get into areas of the brain where the blood-brain barrier is weakened.
因此，它们实际上只能进入血脑屏障减弱的大脑区域。
Andrew Huberman:
安德鲁·休伯曼：
I really appreciate that you mentioned the half-life issue with GLP-1 and the fact that these DPP4 antagonists did not lead to weight loss despite increasing circulating GLP by threefold.
我非常感谢您提到 GLP-1 的半衰期问题，以及尽管循环 GLP 增加三倍，但这些 DPP4 拮抗剂并未导致体重减轻的事实。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
This is relevant to a number of different claims that people make, that a given food or a given drink increases GLP-1.
这与人们提出的许多不同说法相关，即特定食物或特定饮料会增加 GLP-1。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
I've actually said before, I'm a big consumer of yerba mate.
事实上我之前就说过，我是马黛茶的忠实消费者。
My father's side is Argentine, and it's a known appetite suppressant, but it contains caffeine and other stimulants that might explain some of that.
我父亲的方是阿根廷的，它是一种众所周知的食欲抑制剂，但它含有咖啡因和其他兴奋剂，这可能可以解释其中的一些原因。
And it's not a robust appetite suppressant to the point where most people would rely on it as a weight loss compound.
而且它并不是一种强大的食欲抑制剂，以至于大多数人都会依赖它作为减肥化合物。
But anyway, it's my preferred source of caffeine, but I've said before there's some evidence that it can increase GLP-1.
但无论如何，它是我首选的咖啡因来源，但我之前说过有一些证据表明它可以增加 GLP-1。
But based on what you've said, the increases in GLP-1 that it creates are very unlikely to produce the kind of appetite suppressive effect that would lead to any significant weight loss in somebody that's obese, presumably that are separate from any caffeine stimulatory effect.
但根据你所说的，它产生的 GLP-1 增加不太可能产生那种会导致肥胖者体重显着减轻的食欲抑制作用，大概与任何咖啡因刺激作用无关。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly, yeah.
没错，是的。
Andrew Huberman:
安德鲁·休伯曼：
So you can't separate it because it's a complex compound-
所以你无法分离它，因为它是一种复杂的化合物-
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
this yerba mate thing.
这个马黛茶的事。
It's got lots of things in it.
里面有很多东西。
But also, I've observed you being vocal on social media when people have said, "Hey, this thing increases GLP-1." You Quite appropriately, I think, said, wait, Ozempic and drugs like that increase GLP-1 thousandfold.
而且，我还观察到，当人们说“嘿，这个东西会增加 GLP-1”时，您会在社交媒体上大声疾呼。我想，你说得非常恰当，等等，Ozempic 和类似的药物可以使 GLP-1 增加千倍。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
When you talk about a food or drink, or maybe a supplement increasing GLP-1, it's very unlikely that it increases GLP-1 to that level.
当您谈论食物或饮料，或者可能增加 GLP-1 的补充剂时，它不太可能将 GLP-1 增加到该水平。
Meaning, unless you're getting into the hundredfold or thousandfold increases, probably not right to talk about GLP-1 being the source of any appetite suppressive effect.
这意味着，除非您要增加数百倍或数千倍，否则谈论 GLP-1 是任何食欲抑制作用的来源可能是不正确的。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
That's all correct.
这都是正确的。
So, I think it's important sometimes to distinguish between pharmacologic and physiologic effects.
因此，我认为有时区分药理作用和生理作用很重要。
So physiologic is what the hormone naturally does in your body and what can be modulated by natural things like eating a different food.
因此，生理性是指激素在您体内自然发挥的作用，以及可以通过自然事物（例如吃不同的食物）进行调节的作用。
And you might get a twofold change in your GLP-1 by eating a different food, one food versus the other.
通过吃不同的食物（一种食物与另一种食物），您的 GLP-1 可能会发生双重变化。
But as we know from those DPP-4 inhibitors, it's not going to really change your appetite because the drugs increase it threefold.
但正如我们从 DPP-4 抑制剂中了解到的那样，它不会真正改变您的食欲，因为这些药物会使您的食欲增加三倍。
These GLP-1 agonists are really a pharmacologic effect, an effect that only happens with drugs.
这些GLP-1激动剂确实是一种药理作用，一种只有药物才会发生的作用。
So you get 1,000 to 10,000-fold higher concentrations of these drugs in your blood than the natural hormone.
因此，您血液中这些药物的浓度比天然激素高 1,000 至 10,000 倍。
And so there's no diet that's ever going to give you that.
所以没有任何饮食可以给你带来这些。
Andrew Huberman:
安德鲁·休伯曼：
And there's no precedent for it either.
而且这也是没有先例的。
So should we be at all concerned about that?
那么我们应该担心这一点吗？
They've run clinical trials and addressed safety, but when you're talking about a thousandfold increase in essentially a peptide hormone-
他们已经进行了临床试验并解决了安全问题，但是当你谈论本质上是肽激素的千倍增加时-
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
if we were talking about a different peptide hormone, pick one, oxytocin or estrogen, testosterone-
如果我们谈论另一种肽激素，请选择一种，催产素或雌激素、睾酮-
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
they're not really, broadly speaking, most people would be concerned about thousandfold dosing-
从广义上讲，大多数人并不真正担心千倍剂量——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
of something like that.
类似的东西。
And obviously, there are clinical indications where that's important.
显然，有一些临床迹象表明这一点很重要。
However, my observation of the ever-expanding literature on GLP-1 agonists is that there seems to be improvements in reduction in alcohol consumption.
然而，根据我对不断扩大的 GLP-1 激动剂文献的观察，饮酒量似乎在减少方面有所改善。
And by the way, why would increasing GLP-1 reduce craving for alcohol?
顺便问一下，为什么增加 GLP-1 会减少对酒精的渴望？
It seems like there's an ever-expanding list of things that GLP-1 agonism is good for.
GLP-1 激动剂的益处似乎在不断扩大。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
But we are talking about super physiological levels-
但我们谈论的是超生理层面——
Dr. Zachary Knight:
扎卡里·奈特博士：
Absolutely
绝对
Andrew Huberman:
安德鲁·休伯曼：
...
...
when one takes it.
当一个人拿走它的时候。
And again, I'm not against it-
再说一遍，我并不反对——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
more for it, I'm just paying attention to the literature.
更重要的是，我只是关注文献。
Dr. Zachary Knight:
扎卡里·奈特博士：
So I would say that that's absolutely right.
所以我想说这是绝对正确的。
When you're increasing the level of a hormone a thousandfold, you need to be careful and see what's happening.
当你将激素水平增加一千倍时，你需要小心并看看会发生什么。
But at the end, it's an empirical question.
但归根结底，这是一个经验问题。
What does it actually do to a person?
它实际上对一个人有什么作用？
And it can only be answered through experiments.
而这只能通过实验来回答。
And I think the nice thing about these GLP-1 drugs that a lot of people don't realize is they've been around and approved since 2005, the earliest ones.
我认为这些 GLP-1 药物的好处是很多人没有意识到它们自 2005 年以来就已经存在并获得批准，是最早的药物。
And even something like Ozempic, which maybe only entered the public consciousness in the last year or two, it's been around for seven-ish years, I think.
甚至像 Ozempic 这样的东西，可能只是在过去一两年才进入公众意识，我认为它已经存在了七年左右。
And big clinical trials with these drugs.
以及这些药物的大型临床试验。
And the evidence so far is that they seem to be incredibly safe, and as you said, not just incredibly safe, but they seem to have all these unexpected health benefits that seems to be, in some cases, even unrelated to weight loss.
到目前为止的证据表明，它们似乎非常安全，正如你所说，不仅非常安全，而且它们似乎具有所有这些意想不到的健康益处，在某些情况下，这些益处甚至与减肥无关。
And so because of the reasons you mentioned, one of the things the FDA requires from these pharmaceutical companies for diabetes drugs is these large cardiac outcome trials.
因此，由于您提到的原因，FDA 对这些糖尿病药物制药公司的要求之一就是进行大型心脏结果试验。
So basically, where you measure stroke and where you measure heart attacks and death from any cardiac cause.
基本上，您可以在其中测量中风，也可以在其中测量心脏病发作和任何心脏原因导致的死亡。
Big trials, like 20,000 people, four years, costs like a billion dollars to run.
大型试验，如 20,000 人、四年时间，运行成本约为 10 亿美元。
And the data from the semaglutide, the Ozempic trial, came out last year, and as expected, reduced the rate of heart attacks, strokes, all-cause mortality for cardiac reasons.
索马鲁肽（Ozempic 试验）的数据于去年公布，正如预期的那样，它降低了心脏病发作、中风和心脏病引起的全因死亡率。
But what's really surprising was a lot of that seemed to happen before the people even lost weight.
但真正令人惊讶的是，很多事情似乎发生在人们减肥之前。
So there was already a difference between the placebo group and the semaglutide group before the people on the drug had lost a significant amount of weight.
因此，在服用该药物的人体重大幅减轻之前，安慰剂组和索马鲁肽组之间就已经存在差异。
And there was no correlation between the amount of weight they lost and how well they were protected from heart disease.
而且他们减轻的体重与他们预防心脏病的程度之间没有相关性。
And that's led many people to think that some of these effects actually could be due to other things that GLP-1s are doing that we didn't expect.
这让许多人认为其中一些影响实际上可能是由于 GLP-1 所做的其他我们没有预料到的事情造成的。
And so one thing is there's an idea emerging that they are anti-inflammatory.
因此，有一种观点认为它们具有抗炎作用。
So these brain regions, the area postrema and the NTS, are also really important for this reflex known as the inflammatory reflex that basically acts, starts with the vagus nerve, goes to these brain regions in the brain stem, and then goes back down to the body to basically prevent out-of-control inflammation.
因此，这些大脑区域，即后区和 NTS，对于这种被称为炎症反射的反射也非常重要，炎症反射的作用是从迷走神经开始，到达脑干中的这些大脑区域，然后返回到身体，以基本上防止失控的炎症。
And so it's thought that these drugs perhaps have an anti-inflammatory effect that explains some of that.
因此，人们认为这些药物可能具有抗炎作用，这可以解释其中的一些原因。
Andrew Huberman:
安德鲁·休伯曼：
Sounds like the patent on these drugs just got extended by another 100 years.
听起来这些药物的专利又被延长了 100 年。
That's a biopharma joke.
这是一个生物制药笑话。
Just to put context on it, drugs can be patented and sold as a commercial version and not as generic versions until the patent runs out.
简单来说，在专利到期之前，药物可以申请专利并以商业版本而非仿制药的形式出售。
Unless companies are able to find another approved clinical use, in which case it can be remarketed only as a brand name, not generic version.
除非公司能够找到另一种批准的临床用途，在这种情况下，它只能作为品牌名称而不是通用版本重新销售。
So a lot of companies, once they do the safety testing and given everything they put into the R&D, into the research and development, there's a very big incentive to not necessarily finding new drugs, but finding new uses for the same drugs-
因此，很多公司，一旦他们进行了安全性测试，并投入了研发中的一切，就会有很大的动力，不一定是寻找新药，而是寻找相同药物的新用途——
Dr. Zachary Knight:
扎卡里·奈特博士：
Absolutely
绝对
Andrew Huberman:
安德鲁·休伯曼：
...
...
and not allowing generic versions into the picture.
并且不允许通用版本进入图片。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Absolutely.
绝对地。
Andrew Huberman:
安德鲁·休伯曼：
And that's why it's likely to be, based on what sounds like additional uses of Ozempic-related compounds, a long time before there's generic Ozempic available.
这就是为什么，基于听起来像是与 Ozempic 相关的化合物的额外用途，很可能在通用 Ozempic 出现之前很长一段时间。
Dr. Zachary Knight:
扎卡里·奈特博士：
I think it will be a while.
我想还需要一段时间。
I don't know the exact status of the patents, but I'm guessing it's going to be a while before there are generic versions, but there's a lot of competition coming.
我不知道专利的确切状态，但我猜测通用版本还需要一段时间才能出现，但会有很多竞争到来。
So every major pharmaceutical company, or almost every major pharmaceutical company now has a GLP-1 program.
因此，每个主要制药公司，或者几乎每个主要制药公司现在都有 GLP-1 计划。
Andrew Huberman:
安德鲁·休伯曼：
Really?
真的吗？
Dr. Zachary Knight:
扎卡里·奈特博士：
And some of them are really exciting, actually.
事实上，其中一些确实令人兴奋。
The general trend in this area is what people call GLP-1+, which means you take the GLP-1 agonist, which is already giving you 15% weight loss or so, and then you add additional things to that to give it additional properties So one compound is from Eli Lilly, which makes this other drug on the market that we haven't talked about, but tirzepatide, which is known as Mounjaro for diabetes and Zepbound for obesity, which is even better, really in almost every respect, a better drug than Ozempic.
这一领域的总体趋势是人们所说的 GLP-1+，这意味着你服用 GLP-1 激动剂，它已经能让你减轻 15% 左右的体重，然后你添加额外的东西来赋予它额外的特性。所以一种化合物来自礼来公司，这使得市场上的另一种药物我们还没有讨论过，但是替西帕肽，它被称为治疗糖尿病的 Mounjaro 和治疗肥胖的 Zepbound，它甚至更好，实际上在几乎所有方面，比 Ozempic 更好的药物。
So people lose more weight.
所以人们减肥更多。
So it's about 21% weight loss at a year.
所以一年大约减重21%。
Fewer side effects, at least at comparable doses.
副作用更少，至少在相当的剂量下是这样。
That seems to be because this other drug, tirzepatide, it has two targets, not one.
这似乎是因为另一种药物，替西帕肽，它有两个目标，而不是一个。
So whereas Ozempic is just a GLP-1 receptor agonist, tirzepatide is a dual agonist of GLP-1 and this other incretin that we talked about, GIP, G-I-P.
因此，Ozempic 只是一种 GLP-1 受体激动剂，而替泽帕肽是 GLP-1 和我们谈到的另一种肠促胰岛素 GIP、G-I-P 的双重激动剂。
And it seems like having that GIP agonism actually acts as an anti-nausea effect that sort of counteracts some of the nausea caused by the GLP-1 in the area postrema.
GIP 激动似乎实际上具有抗恶心作用，可以抵消后区 GLP-1 引起的一些恶心。
There are GIP receptor neurons in the area postrema, this nausea center.
后区（即恶心中心）有 GIP 受体神经元。
It allows you to crank up the dose of the GLP-1 agonism even further while you're suppressing the nausea and just get even more weight loss.
它可以让您在抑制恶心的同时进一步提高 GLP-1 激动剂的剂量，从而进一步减轻体重。
So now talking about the future, things that aren't available yet, but will be in the next couple of years.
现在谈论未来，那些目前还无法实现但将在未来几年内实现的事情。
So Eli Lilly, the company that makes this drug, tirzepatide/Mounjaro, they have a triple agonist that's in phase three clinical trials now.
礼来公司（Eli Lilly）生产这种药物，tirzepatide/Mounjaro，他们有一种三重激动剂，目前正处于第三阶段临床试验。
So this is now three hormones in one.
所以现在这是三种激素合二为一。
It's the GLP-1, which all these drugs have, the GIP, which is the anti-nausea component, and then glucagon itself.
所有这些药物都含有 GLP-1、抗恶心成分 GIP，然后是胰高血糖素本身。
And so these three hormones all combined in one pill.
因此，这三种激素全部结合在一颗药丸中。
And what the glucagon does is it increases energy expenditure.
胰高血糖素的作用是增加能量消耗。
This is a well-known effect of glucagon.
这是胰高血糖素的众所周知的作用。
And so you're basically eating less, your nausea isn't as bad, and now you're just burning more calories at baseline.
所以你基本上吃得更少了，你的恶心也没有那么严重了，现在你只是在基线上燃烧了更多的卡路里。
And the results from this drug are incredible.
这种药物的效果令人难以置信。
So basically, there's been one phase two trial published, and people lost 25% of their body weight at the end of the, I think it was 48-week period, and they were still losing weight.
所以基本上，已经发表了一项第二阶段试验，人们在试验结束时体重减轻了 25%，我认为这是 48 周的时间，而且他们仍在减肥。
So we don't know where the end point, we don't know what the maximum is.
所以我们不知道终点在哪里，也不知道最大值是多少。
So there are bigger, longer trials going on now to figure that out.
因此，现在正在进行更大、更长的试验来解决这个问题。
But at that point, when you get beyond 25% body weight, you're talking about basically bariatric surgery, which is currently the best thing we have, like these surgeries people do to-
但到那时，当你的体重超过 25% 时，你基本上就在谈论减肥手术，这是目前我们拥有的最好的手术，就像人们所做的这些手术一样——
Andrew Huberman:
安德鲁·休伯曼：
Quote-unquote stomach staple
引用-不引用胃主食
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Removing a portion of the stomach.
切除胃的一部分。
Dr. Zachary Knight:
扎卡里·奈特博士：
Removing a portion of the gut.
切除一部分内脏。
So really, it's a pharmacologic version of bariatric surgery.
事实上，这是减肥手术的药物版本。
The other one that I think is really exciting, there's this compound from Amgen.
另一种我认为非常令人兴奋的化合物是安进公司的这种化合物。
Right now it's just a code.
现在它只是一个代码。
It's AMG 133.
这是 AMG 133。
But it's like tirzepatide in the sense that it targets both GLP-1 and GIP, so it's dual targeted.
但从某种意义上说，它类似于替西帕肽，它同时针对 GLP-1 和 GIP，因此它是双重靶向的。
But unlike tirzepatide, which activates the GIP receptor, this Amgen compound inhibits it.
但与激活 GIP 受体的替泽帕肽不同，安进的这种化合物会抑制它。
And for reasons that people don't understand, either activating or inhibiting this receptor causes you to lose weight.
由于人们不明白的原因，激活或抑制这种受体都会导致体重减轻。
So, still a mystery, but a lot of debate about what's going on there.
所以，这仍然是一个谜，但关于那里发生的事情有很多争论。
But the way this Amgen compound inhibits the GIP receptor is that it's an antibody.
但安进公司的这种化合物抑制 GIP 受体的方式是它是一种抗体。
So all these other things were peptides, but this is a much bigger, it's actual protein.
所以所有其他的东西都是肽，但这是一个更大的、真正的蛋白质。
This is an antibody.
这是一种抗体。
And because it's an antibody, it has a much longer lifetime, even than something like semaglutide, which is seven days, so it lasts like a month in the blood or something.
而且因为它是一种抗体，所以它的寿命要长得多，甚至比索马鲁肽之类的东西要长得多，它的寿命是 7 天，所以它在血液中可以持续一个月之类的。
And so you give people monthly injections of this, and they lose dramatic amounts of weight.
因此，你每月给人们注射这种药物，他们的体重就会大幅减轻。
And then, at least in this initial trial, at the end of this, they stopped, and people maintained the weight loss for six months.
然后，至少在最初的试验中，在试验结束时，他们停止了，人们将减肥维持了六个月。
Andrew Huberman:
安德鲁·休伯曼：
That's impressive.
这令人印象深刻。
Dr. Zachary Knight:
扎卡里·奈特博士：
Potentially because of the long-lasting effects of this antibody, or potentially because of other things that we don't understand.
可能是因为这种抗体的长期作用，或者可能是因为我们不了解的其他事情。
So, and those are just two.
所以，这些只是两个。
There are all sorts of other crazy things happening.
还有各种各样其他疯狂的事情正在发生。
So really, I think it's just created this explosion of interest in pharma.
所以说真的，我认为这才引起了人们对制药业兴趣的爆炸性增长。
Basically, it's one of these things, once you see that something can be done, all of a sudden, that changes everyone's perspective.
基本上，这是其中之一，一旦你看到某件事可以做，突然之间，就会改变每个人的观点。
And so now obesity drug discovery has gone from something that 10 years ago everyone wanted to stay away from because there were so many nightmare stories about drugs that turned out to be not safe, till now everybody's all in on this.
因此，现在肥胖药物的发现已经不再是 10 年前每个人都想远离的事情，因为有很多关于药物的噩梦故事最终证明是不安全的，直到现在每个人都全力以赴。
Andrew Huberman:
安德鲁·休伯曼：
Yeah, I remember in college the fen-phen debacle where a diet drug was released and people had cardiac issues, started dying, so it was pulled from market, and then it was essentially a quiet field-
是的，我记得在大学里，芬芬崩溃了，一种减肥药被释放，人们有心脏问题，开始死亡，所以它被从市场上撤下来，然后它基本上是一个安静的领域 -
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
for a long time.
很长一段时间。
In part to bring us back into the brain, and in part because it's directly relevant to what we've been discussing about Ozempic and GLP-1, there are other neurons in the brain that regulate feeding, and there are other peptides involved in appetite control for which I would say niche communities have started to indulge in.
部分是为了让我们回到大脑，部分是因为它与我们一直在讨论的 Ozempic 和 GLP-1 直接相关，大脑中还有其他神经元负责调节进食，还有其他涉及食欲控制的肽，我想说，利基社区已经开始沉迷于这些肽。
And by the way, people were taking GLP-1 analogs long before they were FDA approved in niche communities.
顺便说一句，早在 GLP-1 类似物获得 FDA 批准在利基社区使用之前，人们就已经开始服用它们了。
These aren't communities I'm a part of, but every once in a while, I'll stick an ear into one of these communities and hear what people are taking.
这些不是我所属的社区，但每隔一段时间，我就会倾听其中一个社区的情况，听听人们在拿什么。
And a big thing right now in these communities is the use of other peptides that are in the melanocyte-stimulating hormone pathway.
现在这些社区中的一件大事是使用黑素细胞刺激激素途径中的其他肽。
And you mentioned melanocortin receptor-containing neurons.
你提到了含有黑皮质素受体的神经元。
Could you tell us a little bit about what these neurons do in the absence of any pharmacologic stimulation, and then why it would be that people would perhaps stimulate these pathways with these drugs?
您能否告诉我们一些关于这些神经元在没有任何药物刺激的情况下会做什么，以及为什么人们可能会用这些药物刺激这些通路？
Not that we're recommending that.
并不是说我们建议这样做。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
But I do think that given that some of these neurons are also involved in sexual behavior and are FDA approved for the treatment of hyposexual function in women, things like that, there is FDA approval for some of these compounds that they're interesting hypothalamic neurons that are starting to gain more attention and that I predict, based on their potential involvement in feeding appetite and weight control, are likely to enter the picture with more prominence in the not too distant future.
但我确实认为，鉴于其中一些神经元也与性行为有关，并且 FDA 批准用于治疗女性性功能减退，诸如此类的事情， FDA 批准了其中一些化合物，它们是有趣的下丘脑神经元，开始获得更多关注，并且我预测，基于它们在喂养食欲和体重控制方面的潜在参与，可能会在不远的将来以更加突出的方式进入画面。
Dr. Zachary Knight:
扎卡里·奈特博士：
So alpha-MSH, as scientists call it, the hormone you were just referring to, is a product of the POMC gene.
因此，α-MSH，正如科学家所说的，你刚才提到的激素，是 POMC 基因的产物。
So in the same way that we just talked about how glucagon can be processed into different things.
就像我们刚才讨论胰高血糖素如何被加工成不同的东西一样。
In some cells, it's made into the glucagon hormone.
在一些细胞中，它被制成胰高血糖素激素。
In other cells, it's made into GLP-1.
在其他细胞中，它被制成 GLP-1。
POMC, that gene can be processed to produce different hormones, and one is alpha-MSH, which is very important for feeding control.
POMC，该基因可以被加工产生不同的激素，其中之一是α-MSH，这对于摄食控制非常重要。
And so these POMC neurons that are in the arcuate nucleus of the hypothalamus, the same region where these AgRP neurons I talked about earlier are located, and they're sort of these These two sets of neurons have opposing effects on body weight regulation.
这些 POMC 神经元位于下丘脑的弓状核中，我之前谈到的这些 AgRP 神经元也位于同一区域，这两组神经元对体重调节具有相反的作用。
And so alpha-MSH inhibits food intake, and AgRP neurons promote food intake.
因此，α-MSH 抑制食物摄入，而 AgRP 神经元则促进食物摄入。
And where they converge is at this receptor, the melanocortin 4 receptor, which is important for body weight regulation.
它们汇聚的地方是黑皮质素 4 受体，它对体重调节很重要。
And so alpha-MSH is an agonist.
因此 alpha-MSH 是一种激动剂。
It turns on that receptor, and the AgRP peptide is an antagonist.
它会打开该受体，而 AgRP 肽是一种拮抗剂。
It turns it off.
它会将其关闭。
And so, there's a lot of human genetics, as I mentioned earlier, implicating this pathway in body weight regulation.
因此，正如我之前提到的，有很多人类遗传学表明这条途径与体重调节有关。
There's been a lot of efforts over many years to turn alpha-MSH into a drug, and it's been very difficult.
多年来，人们为将 α-MSH 转化为药物做出了很多努力，但过程非常困难。
There is one drug that's now approved.
有一种药物现已获得批准。
I'm going to get the name wrong.
我会把名字弄错的。
It's setmelanotide or something like this.
它是 setmelanotide 或类似的东西。
It's an MC4 receptor agonist.
它是一种 MC4 受体激动剂。
It's mainly used in relatively small populations of people that, for example, have mutations in this pathway.
它主要用于相对较小的人群，例如在该途径中发生突变的人群。
It's not used as widespread as a drug.
它不像药物那样广泛使用。
And the challenge has been really side effects.
挑战确实是副作用。
So there's an increase in blood pressure that happens sometimes with these medicines, partly because this pathway controls not only appetite but also autonomic tone and sympathetic nervous system activation.
因此，使用这些药物有时会导致血压升高，部分原因是这条通路不仅控制食欲，还控制自主神经张力和交感神经系统的激活。
So, it's just taking a step back from everything we've talked about today.
所以，这只是我们今天讨论的一切的后退一步。
I talked about this short-term system and the long-term system that controls energy balance and body weight, the short-term system in the brainstem, the long-term system in the hypothalamus, the long-term system being leptin and alpha-MSH and AgRP.
我谈到了这个短期系统和控制能量平衡和体重的长期系统，脑干中的短期系统，下丘脑中的长期系统，长期系统是瘦素和α-MSH和AgRP。
When I was coming up learning about this stuff 15 years ago, or 20 years ago, the dogma was you could only affect body weight through the long-term system, by manipulating the long-term system, because any manipulation you did of the short-term system in the brainstem, the animal would just compensate.
当我 15 年前或 20 年前开始学习这些东西时，教条是你只能通过长期系统，通过操纵长期系统来影响体重，因为你对脑干中的短期系统所做的任何操纵，动物都会补偿。
And there were these famous experiments where they would take CCK, which is a hormone just like GLP-1, inject it into rats, inject it several times a day.
还有一些著名的实验，他们将 CCK（一种类似于 GLP-1 的激素）注射到老鼠体内，每天注射几次。
And CCK is known to decrease the size of meals, and it would decrease the size of meals, but the rats would never lose any weight because they would just eat more meals to compensate, and they would just perfectly compensate by eating more meals.
众所周知，CCK 会减少膳食量，而且它会减少膳食量，但老鼠永远不会减轻任何体重，因为它们只会吃更多的食物来补偿，而且它们会通过吃更多的食物来完美地补偿。
And so the lore was, it's just impossible.
所以传说是，这是不可能的。
The animal will always compensate unless you hit this body weight set point regulating area, which is the hypothalamus, the long-term system.
动物总是会补偿，除非你达到这个体重设定点调节区域，即下丘脑，长期系统。
But then what the pharmaceutical industry discovered, which I guess maybe shouldn't be so surprising, but I guess it was to some people, is that if you just hit that receptor, the short-term system, 24 hours a day, seven days a week, and never let it stop, then you will lose weight.
但后来制药行业发现，我想也许不应该那么令人惊讶，但我想对某些人来说，如果你每周 7 天，每天 24 小时，击中那个受体，即短期系统，并且永不停止，那么你就会减肥。
Right?
正确的？
And so the short-term system alone is enough to cause body weight regulation.
因此，仅短期系统就足以引起体重调节。
On the other hand, the long-term system with alpha-MSH and AgRP neurons and POMC and all this stuff has been a challenge to pharmaceutically target.
另一方面，具有 α-MSH 和 AgRP 神经元以及 POMC 和所有这些东西的长期系统一直是药物靶向的挑战。
Because leptin, we discussed, didn't really work.
因为我们讨论过瘦素并没有真正起作用。
And so I think there's going to be, as you mentioned, a reemergence of interest in considering this other pathway now that we've seen the success of the GLP-1s.
因此，我认为，正如您所提到的，既然我们已经看到了 GLP-1 的成功，人们就会重新出现考虑其他途径的兴趣。
And I think one area where it may emerge is in considering their combination, perhaps at different stages of weight loss.
我认为可能出现的一个领域是考虑它们的组合，也许是在减肥的不同阶段。
So perhaps what would make a lot of sense scientifically, I don't know if it'll work in practice, is that you would take a GLP-1 drug to lose the weight, and then at some point, you might stop that drug and switch to a more hypothalamus-centered, leptin-based drug to keep the weight off.
因此，也许从科学上讲，我不知道它是否会在实践中发挥作用，是你会服用 GLP-1 药物来减肥，然后在某个时候，你可能会停止该药物并改用一种更以下丘脑为中心的、基于瘦素的药物来保持体重。
So basically, use the GLP-1 drug to force yourself to lose the weight, and then use the leptin hypothalamus-based drug to sort of say, "Okay, this is our new body weight set point.
所以基本上，使用 GLP-1 药物强迫自己减肥，然后使用基于瘦素下丘脑的药物说，“好吧，这是我们新的体重设定点。
Let's not resist this weight loss that's happened." Whether that will actually make sense practically is hard to say because the GLP-1 drugs have just a lot of benefits, even beyond weight loss.
我们不要抗拒已经发生的体重减轻。”很难说这实际上是否有意义，因为 GLP-1 药物有很多好处，甚至超出了减肥的好处。
So people might not want to stop taking them.
所以人们可能不想停止服用它们。
But that's one idea.
但这只是一个想法。
Andrew Huberman:
安德鲁·休伯曼：
Very interesting.
非常有趣。
I'd love to talk about dopamine.
我很想谈谈多巴胺。
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
Andrew Huberman:
安德鲁·休伯曼：
We hear so much about dopamine being involved in pleasure.
我们经常听说多巴胺与快乐有关。
I like to think I've had at least a small level of impact in convincing people that it's also involved, and perhaps mostly involved, in things like motivation, different forms of learning, and lots of other things too, folks.
我想我至少在让人们相信它也涉及，也许主要涉及诸如动机、不同形式的学习以及许多其他事情等方面产生了一定程度的影响，伙计们。
Dopamine does lots of things.
多巴胺有很多作用。
It's even expressed in the eye and controls adaptation to light, so it does lots of things.
它甚至在眼睛中表达并控制对光的适应，因此它可以做很多事情。
But it certainly is believed that dopamine is involved in our either craving for food or pleasure from food.
但人们确信多巴胺与我们对食物的渴望或从食物中获得的快乐有关。
What's the real story on dopamine as it relates to food and eating behavior?
多巴胺与食物和饮食行为相关的真实故事是什么？
You had a beautiful paper published in "Nature" entitled, and we'll put a link to this in the show note captions, "Dopamine Subsystems that Track Internal States." And I love this paper for a variety of reasons, but if you could give us the high points of your discoveries on dopamine as it relates to feeding, I know, in fact, that people would find it very illuminating.
您在《自然》杂志上发表了一篇漂亮的论文，标题为“跟踪内部状态的多巴胺子系统”，我们将在节目笔记标题中放置该论文的链接。我喜欢这篇论文的原因有很多，但如果你能给我们介绍一下你在多巴胺方面的发现的要点，因为它与喂养有关，我知道，事实上，人们会发现它非常有启发性。
Dr. Zachary Knight:
扎卡里·奈特博士：
Sure.
当然。
Fantastic.
极好的。
So, yeah, the question of what dopamine does with respect to feeding is a great question and a difficult question, I think, to answer.
所以，是的，多巴胺在喂养方面的作用是一个很好的问题，也是一个很难回答的问题。
There's a lot of misconceptions.
有很多误解。
I think the evidence is dopamine probably isn't so much involved in the pleasure of food, that taste, the hedonic experience.
我认为证据是多巴胺可能与食物的愉悦、味道和享乐体验没有太大关系。
One reason we think this is because you can make mice, Richard Palmiter did this decades ago, that don't have any dopamine, and they still show the same sort of effective responses to foods.
我们认为这是因为你可以制造出没有任何多巴胺的老鼠，理查德·帕尔米特几十年前就做过，而且它们仍然对食物表现出同样有效的反应。
You put something sweet in their mouth, they like it, right?
你把甜的东西放进他们嘴里，他们就喜欢吃，对吧？
What dopamine seems to be important for with respect to food is two things.
多巴胺对于食物的重要性似乎有两点。
One is the motivation to engage in work to get food, particularly when it's high levels of effort.
一是为了获取食物而从事工作的动机，特别是当工作需要付出很大的努力时。
So if you ask a mouse to press a lever to get a pellet of food, if it doesn't have any dopamine, it won't do it.
因此，如果你要求老鼠按下杠杆来获取食物颗粒，如果它没有多巴胺，它就不会这样做。
And if it has low levels of dopamine, it'll just work a little bit.
如果它的多巴胺水平较低，它的作用就只是一点点。
So dopamine is important for sort of energizing action and motivating you to engage in hard tasks.
因此，多巴胺对于激励行动和激励您从事艰巨的任务非常重要。
The other thing that dopamine's really important for is learning.
多巴胺真正重要的另一件事是学习。
And it's important for learning about which cues predict something useful for the body and Feeding is a central example of that.
对于了解哪些线索可以预测对身体有用的东西非常重要，喂食就是一个核心例子。
And what that paper of ours is about is the idea that this learning actually happens on two different timescales for two different kinds of cues.
我们这篇论文的思想是，这种学习实际上是在两种不同的时间尺度上针对两种不同的线索发生的。
So what we almost always talk about with dopamine and learning, which is important, is learning about how external cues in the environment predict something like food availability.
因此，我们几乎总是谈论多巴胺和学习，这很重要，是了解环境中的外部线索如何预测食物供应等因素。
So you see a McDonald's sign, and you know that means there's some tasty food in there.
所以你看到麦当劳的标志，你就知道这意味着那里有一些美味的食物。
And so dopamine is involved in that process of learning what that external cue means.
因此，多巴胺参与了学习外部提示含义的过程。
And that's a very fast timescale process.
这是一个非常快的时间过程。
So in the laboratory, for example, we will play a tone and then give an animal a sip of a solution that has calories in it, for example.
例如，在实验室中，我们会播放一个音调，然后让动物喝一口含有卡路里的溶液。
And it can learn the association between that tone and that the food is going to be available if they're separated by a few seconds, but that's all.
它可以了解该音调与如果相隔几秒钟就会有食物之间的关联，但仅此而已。
And that's a dopamine-dependent process.
这是一个依赖多巴胺的过程。
But there's a second much slower timescale learning about food, which isn't about where I go to get a hamburger, but rather about what the experience of eating the food, the oral sensory experience, its taste, its flavor, its texture, how that relates to the post-ingestive effects.
但学习食物的第二个时间尺度要慢得多，这不是关于我去哪里买汉堡，而是关于吃食物的体验，口腔感官体验，它的味道，它的风味，它的质地，以及它们与摄入后效果的关系。
Andrew Huberman:
安德鲁·休伯曼：
And I should say that this seems extremely relevant to the McDonald's example, because in your experimental situation, the tone is analogous to the golden arches of the McDonald's sign.
我应该说，这似乎与麦当劳的例子极其相关，因为在你的实验情况下，基调类似于麦当劳标志的金色拱门。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
But in my experience, and forgive me, but most of the food that I've consumed from McDonald's does not taste good relative to other really delicious hamburgers or french fries or something like that.
但根据我的经验，请原谅我，我从麦当劳吃过的大部分食物相对于其他真正美味的汉堡包或炸薯条或类似的东西来说味道并不好。
So you're saying dopamine is required to link the signal, the golden arches or the tone, to the presence of food at a particular location.
所以你是说需要多巴胺将信号、金色拱门或音调与特定位置的食物存在联系起来。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
But not to the experience of pleasure from that food.
但不是从食物中体验到快乐。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
Which squares very well with my experience with McDonald's, and I probably haven't had a bite of McDonald's in 20 plus years.
这与我在麦当劳的经历非常吻合，我可能已经有 20 多年没有吃过麦当劳了。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
I would have to be pretty hungry.
我一定会很饿。
Dr. Zachary Knight:
扎卡里·奈特博士：
I haven't either.
我也没有。
And it's funny, the golden arches thing is just something that people in neuroscience talks about dopamine use, and so now I've started subconsciously just talking about golden arches-
有趣的是，金拱门的事情只是神经科学领域的人们谈论多巴胺的使用，所以现在我开始下意识地谈论金拱门 -
Andrew Huberman:
安德鲁·休伯曼：
Yeah
是啊
Dr. Zachary Knight:
扎卡里·奈特博士：
...
...
even though I also haven't eaten at McDonald's in decades.
尽管我也有几十年没吃过麦当劳了。
Andrew Huberman:
安德鲁·休伯曼：
In-N-Out Burger, better tasting, from what I understand, probably better sourcing.
In-N-Out Burger，味道更好，据我了解，可能是采购更好。
We're not going to get into all this in detail, but everyone has their preferences.
我们不会详细讨论这一切，但每个人都有自己的偏好。
But I do think it's interesting because what we're talking about here is related, I think, to this notion of highly processed food, packaging-
但我确实认为这很有趣，因为我认为我们在这里讨论的内容与高度加工食品、包装的概念有关-
Dr. Zachary Knight:
扎卡里·奈特博士：
That's right
没错
Andrew Huberman:
安德鲁·休伯曼：
...
...
the commoditization of food, which is the idea that we are drawn to food for things other than the taste that we expect for it.
食物的商品化，即我们被食物所吸引，除了我们所期望的味道之外。
Dr. Zachary Knight:
扎卡里·奈特博士：
That's right.
没错。
Andrew Huberman:
安德鲁·休伯曼：
There's all this context.
这就是所有的背景。
Dr. Zachary Knight:
扎卡里·奈特博士：
That's right.
没错。
So I think an important distinction that people make is the distinction between wanting and liking.
所以我认为人们做出的一个重要区分是想要和喜欢之间的区别。
I don't know if you've talked about this previously on the podcast.
我不知道你之前是否在播客上谈过这个问题。
Andrew Huberman:
安德鲁·休伯曼：
Yeah, Anna Lembke, my colleague at Stanford, came on the podcast, talked about dopamine is about wanting as opposed to-
是的，我在斯坦福大学的同事安娜·伦布克 (Anna Lembke) 参加了播客，谈到多巴胺是关于想要，而不是——
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly
正是如此
Andrew Huberman:
安德鲁·休伯曼：
...
...
enjoying.
享受。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
In most cases.
大多数情况下。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
So liking is the subjective hedonic pleasure in the moment of eating it, but wanting is just what's what you want.
所以喜欢是吃东西那一刻的主观享乐，而想要就是你想要的东西。
And these can be uncoupled all the time.
而且这些可以一直解耦。
You could want things that at the end of the day, you don't actually enjoy it when you get it.
你可能想要一些东西，但最终你得到它时你并不真正喜欢它。
I feel like a lot of life is like that.
我感觉生活很多都是如此。
Andrew Huberman:
安德鲁·休伯曼：
Indeed.
确实如此。
Dr. Zachary Knight:
扎卡里·奈特博士：
And so, dopamine is very powerful at making you want something, but not to necessarily like it.
因此，多巴胺非常强大，可以让你想要某种东西，但不一定喜欢它。
So that's one element.
这就是其中一个要素。
But then there's this other element that is important but much less studied, but I find much more interesting, which is how you connect these sensory cues associated with food, its taste, its flavor, its smell, with the consequences for the body.
但还有一个很重要但研究较少的元素，但我发现更有趣，这就是如何将与食物、其味道、风味、气味相关的这些感官线索与对身体的影响联系起来。
And this is so important because so much of whether we like or dislike a particular food or drink is related to its post-ingestive effects.
这非常重要，因为我们是否喜欢或不喜欢某种特定的食物或饮料很大程度上与其摄入后的影响有关。
You come to like things, for example, that have calories.
例如，您开始喜欢含有卡路里的东西。
So this is one of the reasons that adults will eat vegetables and other savory foods that children find disgusting.
所以这就是大人会吃孩子们觉得恶心的蔬菜和其他咸味食物的原因之一。
Even though they're a little bit bitter, you learn through experience, this makes me feel good to eat this.
虽然有点苦，但是通过经验学习，吃起来感觉很好。
And even maybe at a completely subconscious level, there's also a level of learning that occurs.
甚至可能在完全潜意识的层面上，也会发生一定程度的学习。
And this, of course, happens with other things like coffee and beer and other things like that.
当然，这种情况也会发生在咖啡、啤酒等其他东西上。
And so there's been an idea that this other much slower learning occurs.
因此，有人认为这种学习速度要慢得多。
And the reason I say it's slower is because the time between when you taste the food and when it actually gets into your intestine and releases the hormones that might drive this is quite slow.
我之所以说它更慢，是因为从你品尝食物到食物真正进入你的肠道并释放可能驱动它的激素之间的时间非常慢。
It's separated by tens of minutes.
中间相隔几十分钟。
But how that works hasn't been clear.
但具体如何运作尚不清楚。
There's been an idea that dopamine might be involved, but it hadn't really received a lot of attention.
有人认为多巴胺可能参与其中，但并没有真正引起太多关注。
And so we set out to investigate what is the role of dopamine in these post-ingestive responses, and map out for the dopamine system, how does the dopamine system respond, not when you see the golden arches, which is usually the kinds of experiments that have been performed, but rather when you deliver nutrients directly to your stomach, or when you deliver water directly to your stomach if you're thirsty, and so on.
因此，我们着手研究多巴胺在这些摄入后反应中的作用，并绘制多巴胺系统，多巴胺系统如何反应，不是当你看到金色拱门时，这通常是已经进行的实验，而是当你将营养直接输送到你的胃时，或者当你口渴时，当你直接将水输送到你的胃时，等等。
And what we saw was that there are these different populations of dopamine neurons that are tuned to respond to signals from inside the body.
我们看到的是，这些不同的多巴胺神经元群体被调整来响应来自体内的信号。
And so there are some that respond when nutrients are in the stomach and intestine.
因此，当营养物质进入胃和肠道时，有些细胞会做出反应。
There are others that respond when, in a thirsty mouse, when the blood is rehydrated, when you basically satiate your thirst.
当老鼠口渴时，当血液补充水分时，当你基本上满足了口渴时，还有其他一些反应。
And we showed that the purpose, or at least a purpose of that activation, is to cause you to learn about the effects of what you just ate, basically to create this connection between the flavor of something and its post-ingestive effects.
我们表明，目的，或者至少是激活的目的，是让你了解你刚刚吃的东西的影响，基本上是在某种东西的味道和摄入后的影响之间建立这种联系。
So that delayed dopamine signal after ingested food and fluids is sort of reinforcing this connection between the flavor of what I just ate and that it was something good for me.
因此，摄入食物和液体后延迟的多巴胺信号在某种程度上强化了我刚刚吃的东西的味道和它对我有好处之间的联系。
One of the interesting things about that paper that was not the direction we initially expected to go in is that for food, I think it's kind of intuitive.
该论文的一个有趣之处在于，对于食物来说，这不是我们最初预期的方向，我认为这是一种直觉。
There are lots of flavors to food.
食物有很多种口味。
You have to learn what all these different flavors mean.
您必须了解所有这些不同口味的含义。
For thirst, people find it a little less obvious because thirst is just water.
对于口渴，人们觉得不太明显，因为口渴只是水。
Aren't you just born knowing what water is?
你不是刚出生就知道水是什么吗？
How do you have to learn anything to do with drinking a glass of water?
您如何学习与喝一杯水有关的事情？
But it actually is a learning question, in part because for many animals, probably most animals, thirst is something that's associated with eating, not drinking.
但这实际上是一个学习问题，部分原因是对于许多动物（可能是大多数动物）来说，口渴与吃有关，而不是与喝有关。
There's this study I love of rabbits in New Zealand.
我很喜欢新西兰的一项关于兔子的研究。
So there's not a lot of people studying what animals, how they get their fluids in the wild, because who cares?
所以没有很多人研究什么动物，它们如何在野外获取液体，因为谁在乎呢？
But it's kind of interesting.
但这有点有趣。
And so in New Zealand, they have this huge rabbit problem because they're an invasive pest species that was introduced in the 1800s, and they're just eating all the land.
因此，在新西兰，他们面临着巨大的兔子问题，因为它们是 1800 年代引入的入侵性害虫物种，而且它们正在吃掉所有土地。
And so there's lots of money to study rabbits, to understand their ecology.
因此有很多钱来研究兔子，了解它们的生态。
And so a group of researchers did this experiment where they made this big pen outside where they put a bunch of rabbits in this.
因此，一群研究人员做了这个实验，他们在外面做了一个大围栏，然后在里面放了一群兔子。
The rabbits couldn't escape, but they had all their natural food.
兔子无法逃脱，但它们拥有所有天然食物。
It was like an outdoor area.
这就像一个室外区域。
And they also put a trough of water, so the rabbits always had access to water, which is clean water, and they could measure how much water the rabbits drank.
他们还放了一个水槽，这样兔子就能一直喝到水，而且是干净的水，他们可以测量兔子喝了多少水。
And what they basically found is that nine months out of a year, rabbits drink zero water.
他们基本上发现，一年中有九个月，兔子喝水为零。
They drink absolutely zero, because they get all of their water from food.
他们的饮水量绝对为零，因为他们从食物中获取所有水分。
The only time they drink is during the winter when all of the greenery has sort of become shriveled, and then they can't get water from that anymore.
他们唯一喝水的时候是在冬天，那时所有的绿色植物都枯萎了，然后他们就无法再从中获取水了。
And so it's just kind of interesting aspect of how many animals are very different from the way we think about ingestive behavior.
因此，有趣的是，有多少动物与我们对摄食行为的看法截然不同。
But that fact that animals have to get water from food raises this question: how do they know which foods are rehydrating?
但动物必须从食物中获取水分这一事实提出了一个问题：它们如何知道哪些食物正在补充水分？
Presumably they have to learn that, because you can't just look at a food and say if you've never had any experience, "Oh, yeah, this is something that's very water rich, and this will rehydrate me when I'm thirsty, and this one is not."
想必他们必须了解这一点，因为如果你从未有过任何经验，你不能只看一种食物就说，“哦，是的，这是一种富含水分的东西，当我口渴时，它可以给我补充水分，而这个则不然。”
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
And so James, the graduate student who led this project, basically investigated this by giving mice different fluids and then measuring the dopamine response.
因此，领导该项目的研究生詹姆斯主要通过给小鼠提供不同的液体，然后测量多巴胺反应来研究这一问题。
And he showed there was this delayed dopamine response after the mice had drank the fluids that correlated with rehydration of the blood.
他发现，在小鼠饮用与血液补液相关的液体后，多巴胺反应会出现延迟。
So a whole bunch of dopamine neurons get strongly activated when the blood is rehydrated.
因此，当血液重新水化时，一大堆多巴胺神经元会被强烈激活。
And he hypothesized this might be a signal, this delayed activation of dopamine neurons, that allows animals in the wild to learn, "That food I just ate is rehydrating." And so he did an experiment where he basically gave them two different flavors, mimicking the flavors of two different foods, one of which was hydrating and one of which was not.
他假设这可能是一个信号，多巴胺神经元的延迟激活，可以让野生动物了解到，“我刚刚吃的食物正在补充水分。”所以他做了一个实验，基本上给了他们两种不同的味道，模仿两种不同食物的味道，其中一种是保湿的，另一种不是。
And the animals couldn't tell because he infused the water directly into their stomach.
动物们无法分辨，因为他将水直接注入它们的胃中。
And he showed that basically, these dopamine neurons are critical for them learning that association.
他表明，基本上，这些多巴胺神经元对于它们学习这种关联至关重要。
So that's the story of that.
这就是那个故事。
Andrew Huberman:
安德鲁·休伯曼：
I love it, and I'll tell you why.
我喜欢它，我会告诉你为什么。
When I was in college, for reasons that I don't recall, I decided to run an experiment on myself where I would eat one meal that was fairly low water content, like a piece of meat or something with some cheese.
当我上大学时，出于我不记得的原因，我决定对自己进行一项实验，我会吃一顿含水量相当低的饭菜，比如一块肉或加一些奶酪的东西。
What some people call a keto meal, but I wasn't ketogenic.
有些人称之为酮餐，但我不是生酮饮食。
I don't even think I knew what a ketogenic diet was at that point.
我什至认为我当时还不知道什么是生酮饮食。
And then the next meal, I would have a salad and some fruits.
然后下一顿饭，我会吃沙拉和一些水果。
And then I would switch back and forth.
然后我会来回切换。
And I generally would only eat two or three times a day anyway.
而且我一般一天只吃两到三次。
There's only so many hours in the day.
一天只有这么多个小时。
And I found it to be incredibly satiating.
我发现它令人难以置信的满足。
Dr. Zachary Knight:
扎卡里·奈特博士：
Interesting.
有趣。
Andrew Huberman:
安德鲁·休伯曼：
And I found that I felt great, and I can imagine any number of different reasons for that.
我发现我感觉很好，我可以想象出许多不同的原因。
And there are these theories that you probably recall that the diet that was being promoted in the '90s where people would either eat carbohydrates or protein separately.
您可能还记得 90 年代提倡的饮食理论，人们要么单独吃碳水化合物，要么单独吃蛋白质。
There was some wackiness out there.
那里有一些古怪的东西。
Dr. Zachary Knight:
扎卡里·奈特博士：
Okay.
好的。
Andrew Huberman:
安德鲁·休伯曼：
And as I say that, I'm sure I'll get assaulted in the comments.
当我这么说时，我确信我会在评论中受到攻击。
It's probably not wacky.
这可能并不古怪。
I'm sure there's some enzymatic basis for why that would be useful.
我确信有一些酶学基础可以解释为什么它有用。
If you enjoy it, go for it.
如果你喜欢它，那就去吧。
I don't have a feeling about it one way or the other.
我对此没有任何感觉。
But one thing I noticed was that low water content containing meals, either by virtue of the foods that they include or by virtue of the fact that they're not diluted, so to speak, it's a different taste experience to eat those foods-
但我注意到的一件事是，膳食中含水量低，要么是因为它们包含的食物，要么是因为它们没有被稀释，可以说，吃这些食物是一种不同的味觉体验——
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm
嗯嗯
Andrew Huberman:
安德鲁·休伯曼：
...
...
than it is to eat a big salad or something of that sort.
比吃一大份沙拉或类似的东西更好。
Dr. Zachary Knight:
扎卡里·奈特博士：
Right.
对。
Andrew Huberman:
安德鲁·休伯曼：
In any event, I don't do that any longer.
无论如何，我不再这样做了。
I just sort of stopped.
我只是停了下来。
But it was a fun experiment.
但这是一个有趣的实验。
And I think it was efficient because at the time, I had very little money as a student, so generally fruits and vegetables were less costly than meats and things of that sort.
我认为这是有效的，因为当时我作为学生的钱很少，所以通常水果和蔬菜比肉类和类似的东西便宜。
But in all seriousness, to what extent do you think humans overeat or undereat depending on the water content of the food?
但严肃地说，你认为人类在多大程度上会根据食物的含水量而吃得过多或过少？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
It's an interesting question.
这是一个有趣的问题。
So, there is this advice that you should, if you're hungry, first drink something, drink some water, and see if you're still hungry.
所以，有这样的建议，如果你饿了，你应该先喝点东西，喝点水，看看你是否还饿。
And the idea is that perhaps humans can't always-- Our interoceptive sense, our ability to sense what our body needs is not perfect.
这个想法是，也许人类不能总是——我们的内感受，我们感知身体需求的能力并不完美。
And sometimes we could be confused, and we could really be thirsty when we're hungry and hungry when we're thirsty.
有时我们可能会感到困惑，当我们饿的时候我们可能真的很渴，当我们渴的时候我们可能真的很饿。
And there's some evidence that could help.
有一些证据可以提供帮助。
I would say it's probably not a huge effect in most of modern-day life, but it's an interesting idea.
我想说，这对大多数现代生活来说可能不会产生巨大影响，但这是一个有趣的想法。
Andrew Huberman:
安德鲁·休伯曼：
Mm-hmm.
嗯嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
This brings us to the topic of thirst, something that-
这给我们带来了口渴的话题，一些东西——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
your laboratory's worked on extensively, and the topic of osmolarity-
你们的实验室进行了广泛的研究，渗透压主题-
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
of salt consumption and things of that sort.
盐的消耗和诸如此类的事情。
In broad terms, how do these things link up?
从广义上讲，这些事情是如何联系起来的？
Meaning, are there instances in which what we really need is salt, and we end up eating a bunch of Parmesan cheese?
意思是，是否存在我们真正需要的是盐的情况，而我们最终却吃了一堆帕尔马干酪？
I got teased yesterday by my team because occasionally when I'm on the road, I don't like most of the foods available in most airports and stuff, so I'll bring a chunk of really nice Parmesan cheese.
昨天我被我的团队取笑了，因为偶尔当我在路上时，我不喜欢大多数机场提供的大多数食物和东西，所以我会带一块非常美味的帕尔马干酪。
I'll just break off a piece and eat it.
我就掰一块来吃。
I'll have half a cucumber, and I'll have, not a can of tuna, but there are these wonderful jarred filet of tunas that are available that are in olive oil.
我要半根黄瓜，我要的不是一罐金枪鱼罐头，但是有这些美妙的罐装金枪鱼片，里面有橄榄油。
They taste really good.
它们味道真的很好。
This is not canned tuna.
这不是金枪鱼罐头。
It's really good.
真的很好。
And I'd rather eat that in most cases until I can get to a decent meal than what's put in front of me on an airplane, most of the time.
在大多数情况下，我宁愿吃这些东西，直到我能吃上一顿像样的饭菜，而不是大多数时候在飞机上摆在我面前的东西。
So I get teased about this, but I notice that, for instance, sometimes I'll eat the cheese and I think, "Oh, actually, what I really just want is the salt."
所以我为此被取笑，但我注意到，例如，有时我会吃奶酪，然后我想，“哦，实际上，我真正想要的是盐。”
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
I really want the salt.
我真的很想要盐。
I've been drinking a lot of coffee today.
我今天喝了很多咖啡。
I've had a couple extra glasses of water.
我多喝了几杯水。
Maybe I'm just craving salt, and I'm confused, and I'm over-consuming this cheese-
也许我只是想吃盐，我很困惑，而且我过度食用了这种奶酪——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes
是的
Andrew Huberman:
安德鲁·休伯曼：
...
...
when in fact what I'm going for is the salt.
事实上我想要的是盐。
As you point out, our understanding of exactly what we need is fairly crude, and oftentimes we overshoot the margin.
正如您所指出的，我们对我们到底需要什么的理解相当粗略，而且我们常常超出了限度。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Especially when foods are in combination.
尤其是当食物混合在一起时。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
So salt, water, and let's just say calories.
盐、水，我们就说卡路里吧。
How do we accurately or inaccurately pursue those at the level of biology?
我们如何准确或不准确地在生物学层面上追求这些目标？
Dr. Zachary Knight:
扎卡里·奈特博士：
Okay.
好的。
So I would s-
所以我会-
Andrew Huberman:
安德鲁·休伯曼：
I'm throwing tough questions at you.
我正在向你提出棘手的问题。
Dr. Zachary Knight:
扎卡里·奈特博士：
I know.
我知道。
This feels-
这感觉——
Andrew Huberman:
安德鲁·休伯曼：
But you're-
但你是——
Dr. Zachary Knight:
扎卡里·奈特博士：
This feels like my qualifying exam.
这感觉就像我的资格考试。
Well, there are thought to be separate systems that control salt appetite, thirst for water, and hunger for calories.
好吧，人们认为有单独的系统来控制盐的食欲、对水的渴求和对卡路里的饥饿。
And so they involve different brain regions for the most part, different neurons, different signals from the body.
因此，它们大部分涉及不同的大脑区域、不同的神经元、来自身体的不同信号。
In general, hunger and thirst are pretty separable, though I would say the instance where they interact is in phenomena such as dehydration anorexia.
一般来说，饥饿和口渴是完全分开的，尽管我想说它们相互作用的例子是脱水厌食等现象。
This is the idea that if I give you some dry food, but I don't give you any water, you're going to eat less food because basically you're going to get dehydrated, and you're going to decide, "I need to preserve my fluid balance, even if I eat less calories."
这个想法是，如果我给你一些干食物，但不给你任何水，你就会吃更少的食物，因为基本上你会脱水，你会决定，“即使我吃的卡路里更少，我也需要保持液体平衡。”
Andrew Huberman:
安德鲁·休伯曼：
So we prioritize hydration.
所以我们优先考虑补水。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
You will at some point-
你会在某个时候——
Andrew Huberman:
安德鲁·休伯曼：
At the level of survival
在生存层面
Dr. Zachary Knight:
扎卡里·奈特博士：
...
...
at some point, you will prioritize hydration.
在某些时候，你会优先考虑补水。
That's related also to the concept of prandial drinking.
这也与餐时饮酒的概念有关。
So many animals, including humans, drink most of their water during meals because you basically want to counteract the osmolytes that are in your food.
许多动物，包括人类，在进餐时喝大部分水，因为你基本上想抵消食物中的渗透剂。
Salt balance, though, and thirst, so the thirst for water and the desire for salt, are much more tightly linked because the purpose of both systems is to maintain the composition of the blood at its right concentration.
然而，盐平衡和口渴，即对水的口渴和对盐的渴望，联系更为紧密，因为这两个系统的目的都是将血液成分维持在正确的浓度。
So you want to have the right osmolality of the blood, which you can just think of in simple terms as sort of the total concentration of all the salts.
因此，您希望血液具有正确的渗透压，您可以简单地将其视为所有盐的总浓度。
It's a little more complicated than that, but it doesn't really matter.
比这稍微复杂一点，但这并不重要。
And you also specifically need to maintain the sodium concentration at the right level.
您还特别需要将钠浓度维持在正确的水平。
And there are really powerful innate mechanisms that drive both.
确实存在强大的先天机制来驱动这两者。
I think thirst is very intuitive to people.
我认为口渴对于人们来说是非常直观的。
You get dehydrated, you lose water, you become thirsty.
你会脱水、失水、口渴。
And we know now that there are a very small set of neurons in a few brain regions that control that.
我们现在知道，大脑的几个区域中有一小部分神经元可以控制这一点。
And the way they're thought to work is they contain osmo sensors.
人们认为它们的工作方式是它们包含渗透传感器。
So basically, these neurons are sensors for the osmolality of the blood, and they're activated when the blood osmolality gets too high.
基本上，这些神经元是血液渗透压的传感器，当血液渗透压过高时它们就会被激活。
And it's an incredibly sensitive system.
这是一个极其敏感的系统。
So you can perceive an increase in your blood osmolality of 1% as the sensation of thirst.
因此，您可以将血液渗透压增加 1% 视为口渴的感觉。
So remarkable.
太了不起了。
Andrew Huberman:
安德鲁·休伯曼：
Wow.
哇。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
That's how critical it is to maintain salt balance.
这就是维持盐平衡的重要性。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
And so you get to 10% increase in blood osmolality, and you're in extreme discomfort.
所以你的血液渗透压会增加 10%，你会感到极度不适。
At 20%, you're in the hospital.
20% 时，您已住院。
Andrew Huberman:
安德鲁·休伯曼：
So if I took, let's just say a half an ounce sip of seawater-
所以如果我喝了半盎司海水——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes
是的
Andrew Huberman:
安德鲁·休伯曼：
...
...
inadvertently.
不经意间。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
It's extremely aversive.
这是非常令人厌恶的。
Dr. Zachary Knight:
扎卡里·奈特博士：
It is.
是的。
Andrew Huberman:
安德鲁·休伯曼：
It's like, ugh.
就像，呃。
You want to drink some non-salty water.
您想喝一些不含盐的水。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Some nice clean water.
一些干净的水。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes, exactly.
是的，完全正确。
Andrew Huberman:
安德鲁·休伯曼：
Immediately.
立即。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
So I should emphasize that there's two components to the fluid homeostasis system, to the water homeostasis system.
所以我应该强调，液体稳态系统有两个组成部分，即水稳态系统。
One is this desire to drink, but the other is, of course, the kidney.
一是这个喝酒的欲望，但另一个当然是肾。
And so the reason the drinking of the saltwater won't put you in a really bad situation is your kidney would then filter out a lot of that salt and cause you just to pee it out, and then you'd be fine.
因此，喝盐水不会让你陷入非常糟糕的境地，因为你的肾脏会过滤掉大量的盐，导致你把它尿出来，然后你就没事了。
And so those two work in balance, the kidney's controlling how much of the salt gets reabsorbed into the blood, and then this desire for thirst, this desire to drink allowing you to replenish the blood with water at various intervals.
所以这两者是平衡工作的，肾脏控制着有多少盐被重新吸收到血液中，然后这种渴求、这种喝水的欲望让你在不同的时间间隔用水补充血液。
And so, yeah, the experiments led to the discovery of this thirst circuitry are amazing.
所以，是的，发现这种口渴电路的实验是令人惊奇的。
It was this guy, Bengt Andersson, working in the 1950s, and he just had this hypothesis that there was an osmo sensor in the brain, right?
就是这个人，Bengt Andersson，在 20 世纪 50 年代工作，他只是假设大脑中有一个渗透压传感器，对吗？
Which there was some evidence to suggest it, but it was not really strongly supported at the time by the data.
有一些证据表明这一点，但当时并没有得到数据的有力支持。
And so he took these goats, and he just started infusing small amounts of salt into various places in their brain, reasoning that if there was an osmo sensor, then-
所以他拿了这些山羊，然后开始将少量的盐注入它们大脑的不同部位，推断如果有渗透传感器，那么——
Andrew Huberman:
安德鲁·休伯曼：
Sorry to chuckle.
抱歉笑了。
That was wild.
那太疯狂了。
I wasn't chuckling at ingest.
我吃东西的时候并没有笑。
I feel for the goats.
我对山羊有感觉。
I feel for everyone involved in that experiment, but what a wild experiment, just to put salt directly into the brain.
我同情参与该实验的每个人，但这是一个多么疯狂的实验，只是将盐直接放入大脑中。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
A concentrated saline solution, yeah.
浓缩盐溶液，是的。
Andrew Huberman:
安德鲁·休伯曼：
My goodness.
天哪。
Dr. Zachary Knight:
扎卡里·奈特博士：
And he found this tiny region in and around the hypothalamus that if you infuse salt in this region, the goats will drink like eight liters of water in five minutes.
他发现下丘脑内部和周围有一个很小的区域，如果你在这个区域注入盐，山羊会在五分钟内喝掉八升水。
Just crazy, right?
简直太疯狂了，对吧？
And so he reasoned, "Okay, this must be the osmo sensor." And then he went back and stimulated those neurons, and it's just the same thing.
所以他推断，“好吧，这一定是渗透传感器。”然后他回去刺激这些神经元，结果是一样的。
The goat just drinks like crazy.
山羊疯狂地喝水。
And so now we know there's these couple small regions in and around the hypothalamus.
现在我们知道下丘脑内部和周围有这几个小区域。
One's called the subfornical organ.
一个叫做穹窿下器官。
Another one's called, well, it doesn't really matter what they're called, but basically, that have these osmo sensors.
另一个叫做，好吧，它们叫什么并不重要，但基本上，它们有这些渗透传感器。
One of the interesting things about the regulation of fluid balance is you face some of the same challenges we just talked about with the regulation of food consumption, which is that you have this behavior, this ingestive behavior that leads to replenishment of the body, but there are these delays, right?
关于液体平衡调节的一个有趣的事情是，你面临着我们刚才谈到的食物消耗调节的一些相同的挑战，那就是你有这种行为，这种导致身体补充的摄入行为，但存在这些延迟，对吗？
So if you're thirsty and you drink a glass of water, it can take on the order of sort of 20 to 30 minutes for the water to be absorbed into your blood, for the blood to be rehydrated, and then for these osmo sensors that Bengt Andersson discovered in your brain to sort of sense that and return to normal activity.
因此，如果你口渴，喝了一杯水，水可能需要大约 20 到 30 分钟的时间才能被吸收到你的血液中，血液得到补充，然后 Bengt Andersson 在你的大脑中发现的渗透传感器会感觉到这一点并恢复正常活动。
But of course, if you had the experience of drinking a glass of water, you know that you can quench your thirst within minutes, right?
当然，如果你有过喝一杯水的经历，你就知道几分钟之内就能解渴，对吧？
And so how does that work within seconds, even?
那么它是如何在几秒钟内发挥作用的呢？
So one of the sort of experiments we did early in my lab was to ask that question by basically recording for the first time the activity of these neurons that Bengt had discovered by putting the salt in the goats.
因此，我们早期在实验室所做的实验之一就是通过首次记录这些神经元的活动来提出这个问题，这些神经元是本特通过将盐放入山羊体内而发现的。
We went back into them now in mice, mice have the same neurons, you have the same neurons, and recording their activity when a thirsty mouse drinks and asks what happens.
我们现在回到老鼠身上，老鼠有相同的神经元，你也有相同的神经元，当口渴的老鼠喝水时记录它们的活动并询问会发生什么。
And what we saw was that the neurons don't wait until the blood is rehydrated.
我们看到的是，神经元不会等到血液重新水化。
They also don't do what the AgRP neurons do, meaning they don't look at the water and predict how much water they're going to drink.
它们也不做 AgRP 神经元所做的事情，这意味着它们不会观察水并预测它们将喝多少水。
But instead, they get a signal from the mouth, which every time the mouse takes a lick of water, their activity goes down a little bit.
但相反，它们从嘴里得到一个信号，每当老鼠舔一口水时，它们的活动就会下降一点。
And basically, they track in that way the volume of water that's passed through the mouth.
基本上，他们通过这种方式追踪通过口腔的水量。
They also get the signal from the blood, relaying the osmolarity of the blood, and they compare these two.
他们还从血液中获取信号，传递血液的渗透压，并对两者进行比较。
And basically, when the mouse has drank enough in order for the animal to predict that the blood osmolarity is going to return to normal, then the animal stops drinking.
基本上，当小鼠喝了足够的水以便动物预测血液渗透压将恢复正常时，动物就会停止饮酒。
Andrew Huberman:
安德鲁·休伯曼：
Beautiful.
美丽。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Andrew Huberman:
安德鲁·休伯曼：
It's just beautiful, right?
很漂亮，对吧？
Dr. Zachary Knight:
扎卡里·奈特博士：
It's incredible.
太不可思议了。
Andrew Huberman:
安德鲁·休伯曼：
The brain is essentially predicting with, it sounds like a high degree of accuracy, how much water one needs to drink, linking it to the pleasure-
大脑本质上是在预测，听起来精度很高，一个人需要喝多少水，并将其与愉悦感联系起来——
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah
是啊
Andrew Huberman:
安德鲁·休伯曼：
...
...
of ingesting good, clean water under conditions where we're thirsty In anticipation of adjusting blood osmolarity in 20 minutes?
在我们口渴的情况下摄入优质、干净的水并期望在 20 分钟内调整血液渗透压？
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
Yeah, this is the kind of thing that just, it delights me because it just means that the brain as a predictive organ is just so accurate.
是的，这让我很高兴，因为这意味着大脑作为一个预测器官是非常准确的。
Dr. Zachary Knight:
扎卡里·奈特博士：
It also explains some sort of funny aspects of thirst that you may have noticed from everyday experience.
它还解释了您可能从日常经验中注意到的口渴的一些有趣方面。
So, one idea is that just cooling your mouth can sort of quench your thirst, right?
所以，一个想法是，只要冷却一下你的嘴就可以解渴，对吗？
So if you're in the hospital and you're not allowed to drink any fluids, they'll give you ice chips to suck on to sort of quench your thirst.
因此，如果您在医院并且不允许喝任何液体，他们会给您冰片来吸食以缓解口渴。
So why is that?
那么这是为什么呢？
And so one idea is that perhaps because water is usually cooler than your body, that sensation of water passing, it always cools your mouth.
所以一个想法是，也许因为水通常比你的身体凉爽，水流过的感觉总是让你的嘴凉爽。
And so you learn, or maybe it's innate, that just cooling of my mouth means that basically I'm going to be rehydrated.
所以你知道，或者也许这是与生俱来的，只要我的嘴变凉就意味着我基本上会补充水分。
So Chris, this was an experiment done by a grad student, Chris Zimmerman.
克里斯，这是研究生克里斯·齐默尔曼（Chris Zimmerman）所做的一个实验。
Chris did the same thing where he was recording these thirst neurons, but just put a cold piece of metal on the mouse's tongue.
克里斯做了同样的事情，他记录了这些口渴神经元，但只是将一块冰冷的金属放在老鼠的舌头上。
And you can see when you do that, these thirst neurons go down in activity, and then you remove the cold piece of metal, and they go back up.
你可以看到，当你这样做时，这些口渴神经元的活动会下降，然后你移除冰冷的金属片，它们就会恢复活动。
Andrew Huberman:
安德鲁·休伯曼：
Amazing.
太棒了。
Dr. Zachary Knight:
扎卡里·奈特博士：
So a lot of these sort of oddities of everyday experience have to do with how the system has evolved to make the prediction about what's going to happen to the body.
因此，日常经验中的许多奇怪现象都与系统如何进化以预测身体将要发生的事情有关。
Andrew Huberman:
安德鲁·休伯曼：
Few things are as rewarding as the sensation of drinking really nice, clean, cold water when one is very thirsty.
当一个人非常口渴时，没有什么比喝上一杯好喝、干净、凉水的感觉更令人满足的了。
When my lab was in San Diego, I used to take my dog hiking Palomar Mountain, and one day, I really screwed up.
当我的实验室在圣地亚哥时，我经常带着我的狗去帕洛玛山徒步，有一天，我真的搞砸了。
He was a bulldog mastiff.
他是一只斗牛犬獒犬。
They overheat easily, and it was a lot warmer than we thought.
它们很容易过热，而且比我们想象的要暖和得多。
We ran out of water.
我们的水用完了。
It was an actually dangerous situation for him.
这对他来说实际上是一个危险的处境。
We got down to the bottom of the hill, thankfully, with him still alive, and there's this pump that pumps what I was told was spring water, and it came out really cold.
谢天谢地，我们到了山脚下，他还活着，有一个水泵抽出我听说是泉水的水，出来的水真的很冷。
And you could just see him fill back up with life.
你可以看到他又恢复了生机。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
I filled back up with life knowing he was filling back up with life, and it was unlike the kind of reward that one experiences with food when you're hungry.
我知道他正在重新充满生命，这与人们在饥饿时通过食物所体验到的那种奖励不同。
Dr. Zachary Knight:
扎卡里·奈特博士：
Absolutely.
绝对的。
Andrew Huberman:
安德鲁·休伯曼：
It's like that basic critical need for water-
这就像对水的基本需求——
Dr. Zachary Knight:
扎卡里·奈特博士：
Absolutely
绝对
Andrew Huberman:
安德鲁·休伯曼：
...
...
under conditions where you're clearly dehydrated is like nothing else.
在你明显脱水的情况下，这是独一无二的。
It's delicious in a way that no food is delicious.
它的美味程度是任何食物都不美味的。
Dr. Zachary Knight:
扎卡里·奈特博士：
I would like to actually say something about this.
对于这个问题我其实很想说几句。
So that distinction you made is really interesting between hunger and thirst.
所以你对饥饿和口渴的区分非常有趣。
So when you stimulate these neurons that make an animal thirsty, the mice hate it.
因此，当你刺激这些使动物口渴的神经元时，老鼠会讨厌它。
They will do anything to avoid something that artificially makes them thirsty.
他们会尽一切努力来避免人为地让他们口渴的事情。
So we can artificially stimulate these thirst neurons, create a state of virtual thirst.
所以我们可以人为地刺激这些口渴神经元，创造一种虚拟口渴的状态。
They'll lever press hundreds of times to make it stop.
他们会按杠杆数百次才能让它停下来。
The same neurons, the neurons that I talked about that control hunger, the AgRP neurons, they actually don't care so much.
同样的神经元，我谈到的控制饥饿的神经元，AgRP 神经元，它们实际上并不太关心。
They won't really do much of anything to shut them off.
他们实际上不会采取任何措施来关闭它们。
That raises the question, well, why do the animals eat then when you stimulate the hunger neurons?
这就提出了一个问题，那么当你刺激饥饿神经元时，为什么动物会吃东西呢？
And we think the primary thing that the hunger neuron stimulation does is it makes food itself more attractive.
我们认为饥饿神经元刺激的首要作用是使食物本身更具吸引力。
It makes the food more delicious, more of an attractive motivational magnet, and it makes the experience of eating more pleasurable.
它让食物变得更加美味，更具吸引力，也让用餐体验更加愉悦。
But it is not itself the most unpleasant state.
但这本身并不是最不愉快的状态。
At least the mice aren't willing to do that much.
至少老鼠不愿意做那么多。
Whereas for thirst, I think dehydration and thirst is really just unpleasant, and animals just want to avoid that.
至于口渴，我认为脱水和口渴确实令人不快，而动物只是想避免这种情况。
And so I think the distinction is very real.
所以我认为这种区别是非常真实的。
I think there are two different motivational mechanisms for hunger and thirst.
我认为饥饿和口渴有两种不同的动机机制。
Hunger is mostly about the reward of food.
饥饿主要是关于食物的奖励。
Thirst is mostly about this is just really unpleasant.
口渴主要是因为这真的很不愉快。
Andrew Huberman:
安德鲁·休伯曼：
And removing that unpleasant state.
并消除那种不愉快的状态。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
And you had a paper, which I was going to ask you about, so I will, entitled "The forebrain thirst circuit drives drinking through negative reinforcement."
你有一篇论文，我本来想问你，所以我会问你，题为“前脑口渴回路通过负强化驱动饮酒”。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
And I'm guessing that paper illustrates exactly the point you just made.
我猜这篇论文准确地说明了您刚才提出的观点。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
So it's a forebrain circuit.
所以这是一个前脑回路。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
So does that mean that there's some elements of learning and cognition around this, or are we broadly speaking about the forebrain, for instance, the hypothalamus being in the forebrain?
那么，这是否意味着存在一些与此相关的学习和认知要素，或者我们广义上谈论的是前脑，例如，下丘脑位于前脑中？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah, it's interesting.
是的，这很有趣。
So the thirst circuit, for whatever reason, is mostly in the forebrain.
因此，无论出于何种原因，口渴回路主要位于前脑。
So we talked about the NTS and the area postrema being important for hunger and signals from the gut.
所以我们讨论了 NTS 和后区对于饥饿和肠道信号的重要作用。
The area postrema is a circumventricular organ, meaning it's outside the blood-brain barrier.
后区是一个室周器官，这意味着它位于血脑屏障之外。
There's only a couple of these in the brain.
大脑中只有其中几个。
The neurons that control thirst are located in the two circumventricular organs in the forebrain.
控制口渴的神经元位于前脑的两个室周器官中。
One is called the subfornical organ, the other one is called the OVLT, but they're just acronyms.
一个称为穹窿下器官，另一个称为 OVLT，但它们只是缩写词。
So why it evolved to have the thirst neurons more in the forebrain and the neurons that sense nutrients more in the hindbrain is a little bit unclear.
因此，为什么它进化成在前脑中有更多的口渴神经元，在后脑中有更多感知营养的神经元，目前还不清楚。
And so there is definitely an element of learning, but a lot of this is those neurons are also just directly sensing the blood and sensing changes in both the concentration of salt in the blood and then also hormones like angiotensin that drive thirst.
因此，肯定有学习的因素，但其中很多是这些神经元也只是直接感知血液并感知血液中盐浓度的变化，然后还有引起口渴的血管紧张素等激素的变化。
Andrew Huberman:
安德鲁·休伯曼：
I was going to ask you this earlier, but it seems appropriate to ask now.
我本来想早点问你这个问题的，但现在看来是合适的。
A colleague of mine at Stanford in the psychology department, Dr. Ali Crum, who studies mindsets, has done some interesting experiments where people are told that a given milkshake is calorically dense.
我在斯坦福大学心理学系的一位同事 Ali Crum 博士研究心态，他做了一些有趣的实验，告诉人们某种奶昔的热量很高。
Other people are told that a milkshake is calorically sparse.
其他人则被告知奶昔的热量很少。
Both groups independently consume the milkshake, and then they measure things like hormone responses in the bloodstream that are associated with satiety.
两组人独立饮用奶昔，然后测量血液中与饱腹感相关的激素反应等。
And what she finds is that even hormone responses to the same shake, meaning the same amount of calories, fat, sugar, et cetera, can be significantly modulated based on what we're told.
她发现，即使是对同一种奶昔（即相同量的卡路里、脂肪、糖等）的激素反应，也可以根据我们被告知的情况进行显着调节。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
And it extends into some other perhaps even more interesting areas, in my opinion, whereby if people are told that, let's say, a given meal that has a small piece of fish, a serving of vegetables, and a carbohydrate is, yes, perhaps a little bit calorically sparse compared to what one would normally eat at a given meal, but they're told, "This is a highly nutritious meal.
在我看来，它还延伸到了其他一些可能更有趣的领域，如果人们被告知，比方说，一顿包含一小块鱼、一份蔬菜和碳水化合物的膳食，是的，与人们通常在某一顿饭中吃的食物相比，热量可能有点少，但他们被告知，“这是一顿营养丰富的饭菜。
This is good for you."
这对你有好处。”
Dr. Zachary Knight:
扎卡里·奈特博士：
Yes.
是的。
Andrew Huberman:
安德鲁·休伯曼：
Then just that mere knowledge can drive more satiety, better feelings about the meal, even, I believe, I have to double-check on this, but as I recall, a heightened sense of it tasting really good.
然后，仅仅知道这一点就可以带来更多的饱腹感，对这顿饭有更好的感觉，甚至，我相信，我必须仔细检查这一点，但据我回忆，一种强烈的感觉，它的味道真的很好。
So humans are very susceptible to the, in this case, the either inaccurate, in the case of the milkshake experiment, or accurate descriptions of food, meaning they shape our perception of whether or not something is good for us, tastes good or not, and whether or not it leads to more or less satiety.
因此，在这种情况下，人类很容易受到对食物的不准确（如奶昔实验）或准确描述的影响，这意味着它们影响了我们对某种东西是否对我们有益、味道好坏以及它是否会导致或多或少的饱腹感的看法。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
And I think this is important given the obesity crisis, to say nothing of these drugs that are coming out, whereby people often associate dieting with deprivation and pain, but if they understand that certain foods are nutritious, that can at least partially offset some of the pain of caloric restriction.
我认为考虑到肥胖危机，这一点很重要，更不用说正在推出的这些药物了，人们经常将节食与剥夺和痛苦联系起来，但如果他们了解某些食物是有营养的，那至少可以部分抵消热量限制带来的一些痛苦。
What are your thoughts on that?
您对此有何看法？
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah.
是的。
Well, one thing I've been talking about is how a lot of these circuits are anticipatory.
嗯，我一直在谈论的一件事是，这些电路中有很多是可预测的。
They're making predictions.
他们正在做出预测。
They're trying to estimate what's happening in the future.
他们试图估计未来会发生什么。
And I talked about how these AgRP hunger neurons, how they can sort of see the food or get input about the sight smell of food, and that way predict how many calories the mouse is going to eat.
我谈到了这些 AgRP 饥饿神经元如何看到食物或获得有关食物气味的输入，并通过这种方式预测老鼠将吃多少卡路里。
But this is a mouse.
但这是一只老鼠。
This is all based on a mouse, and a mouse has 1,000 times fewer neurons than you do as a person.
这一切都是基于小鼠，而小鼠的神经元比人类少 1000 倍。
So the computational capacity that the human brain has to make these predictions is just vast compared to these mice.
因此，与这些小鼠相比，人脑做出这些预测所需的计算能力是巨大的。
And these mice are already doing amazing things.
这些老鼠已经做出了令人惊奇的事情。
So when you think about then, what is the human brain able to do in terms of anticipating changes in nutritional state and how information that you're given can change the expected physiologic outcomes, you're right.
因此，当您考虑一下，人类大脑在预测营养状态的变化方面能够做什么以及您获得的信息如何改变预期的生理结果时，您是对的。
There's just this whole other element that is very hard to study because it's happening in the brains of humans, and we can't do these kinds of experiments.
还有另外一个元素很难研究，因为它发生在人类的大脑中，而我们无法进行此类实验。
But I'm sure that's very important.
但我确信这非常重要。
So I talked a little bit about these flavor nutrient conditioning experiments.
所以我就讲了一下这些风味营养调理实验。
These are the experiments where essentially an animal learns to consume a certain flavor because it learns it's going to be associated with nutrients later.
在这些实验中，动物基本上学会了吃某种味道，因为它知道这种味道稍后会与营养物质相关。
Sort of the paradigm for how you learn to consume bitter vegetables because they're good for you and you get nutrients.
这有点像你学习如何食用苦菜的范例，因为它们对你有好处并且你可以获得营养。
So people have also done those experiments in humans, and that does work, but what they've discovered is it's very sensitive to what you tell the humans about the thing that they're going to consume.
人们也在人类身上进行了这些实验，这确实有效，但他们发现，它对你告诉人类他们将要消费的东西非常敏感。
So if you put nutritional labels where you show the different numbers of calories, then basically they sort of adjust their expectations and nothing happens.
因此，如果你在营养标签上显示不同的卡路里数量，那么基本上他们会调整他们的期望，但什么也不会发生。
So it really has to be that it's very sensitive to what information you give them before the experiment happens.
所以它确实必须对你在实验发生之前向他们提供的信息非常敏感。
So, I think that's an example of that kind of thing.
所以，我认为这就是此类事情的一个例子。
Andrew Huberman:
安德鲁·休伯曼：
Without any pressure for it to be prescriptive, how do you approach eating given the knowledge that you have about food?
在没有任何规定性压力的情况下，考虑到你对食物的了解，你如何对待饮食呢？
I like to assume that you can sit down to a meal and not think about your AgRP neurons too much or any of that.
我喜欢假设你可以坐下来吃饭，而不用过多地考虑你的 AgRP 神经元或任何其他事情。
But given that you have deep knowledge in this, has it shaped how you think about food cravings, your own, you don't have to reveal what those are, even if they exist, how you observe the eating behavior of others, and how has knowledge shaped your feeding behavior?
但考虑到你对此有深入的了解，它是否影响了你对食物渴望的看法，你自己的，你不必透露这些是什么，即使它们存在，你如何观察别人的饮食行为，以及知识如何影响你的进食行为？
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, I try not to think too much about my AgRP neurons when I'm eating because-
好吧，当我吃饭的时候，我尽量不要过多地考虑我的 AgRP 神经元，因为——
Andrew Huberman:
安德鲁·休伯曼：
I would hope.
我希望。
Dr. Zachary Knight:
扎卡里·奈特博士：
I think the circuitry is so complex, and we're just beginning to see what's happening, so I wouldn't use that kind of information at this stage, when we're just beginning, too prescriptively.
我认为电路非常复杂，我们才刚刚开始了解发生了什么，所以在我们刚刚开始的这个阶段，我不会太规范地使用此类信息。
But I think there is a set of basic recommendations from physiology and neuroscience, very simple things, that you've probably talked about with people on your podcast before, for shaping your diet to be healthier, to limit food intake.
但我认为有一系列来自生理学和神经科学的基本建议，非常简单的事情，你可能之前在播客上与人们讨论过，让你的饮食变得更健康，限制食物摄入量。
So, one we've already talked about is limiting consumption of ultra-processed food, eating more whole foods, for lots of different reasons.
因此，我们已经讨论过，出于多种不同的原因，限制超加工食品的消费，多吃天然食品。
Because they're more satiating, because they don't have this sort of engineered palatability that causes you to overeat.
因为它们更容易让人产生饱腹感，因为它们不具有这种经过精心设计的适口性，不会导致您吃得过多。
Another big one, which I'm sure you've talked about with some of your guests, is protein consumption, making sure you get adequate protein consumption, both because there's this concept of protein leveraging, so if you don't eat a minimum amount of protein, that's going to cause you to eat more calories just to try to achieve that minimum amount of protein.
另一个重要的问题，我相信您已经与一些客人谈论过，是蛋白质消耗，确保您摄入足够的蛋白质，这都是因为存在蛋白质利用的概念，所以如果您不吃最低量的蛋白质，这将导致您摄入更多的卡路里，只是为了达到最低量的蛋白质。
Also, just because protein's more satiating, and also because there's this idea of thermic effect of food, and so you basically burn more calories metabolizing protein than sugar or fat.
另外，仅仅因为蛋白质更让人有饱腹感，也因为食物的热效应，所以你在代谢蛋白质时燃烧的卡路里基本上比糖或脂肪多。
Andrew Huberman:
安德鲁·休伯曼：
How about consumption of fluids during meals?
吃饭时喝水怎么样？
I've heard it said before that we're not supposed to consume too many fluids because it's going to dilute the enzymes that allow us to digest our food.
我以前听人说过，我们不应该摄入太多液体，因为它会稀释让我们消化食物的酶。
I've heard other people say that's complete myth.
我听其他人说这完全是神话。
Dr. Zachary Knight:
扎卡里·奈特博士：
That's a myth, I think.
我认为这是一个神话。
So humans don't have a perfect capacity to determine whether they're hungry or thirsty, and so drinking water will ensure you're not eating because you're thirsty.
因此，人类没有完美的能力来确定自己是否饥饿或口渴，因此喝水可以确保您不会因为口渴而进食。
And there's no idea of diluting it.
而且没有稀释它的想法。
And distention itself, even though water provides a very limited distention signal, the expansion of your stomach and intestines is one important way-
而膨胀本身，尽管水提供的膨胀信号非常有限，但胃和肠道的扩张是一种重要的方式——
Andrew Huberman:
安德鲁·休伯曼：
Interesting
有趣
Dr. Zachary Knight:
扎卡里·奈特博士：
...
...
that you terminate feeding.
你停止喂食。
Andrew Huberman:
安德鲁·休伯曼：
Hmm.
嗯。
Dr. Zachary Knight:
扎卡里·奈特博士：
And so there is some component of that where you can get distention just from drinking water.
因此，在某些方面，仅仅喝水就会引起腹胀。
I say-
我说——
Andrew Huberman:
安德鲁·休伯曼：
Sorry, I blurted out interesting because I didn't realize that a fluid consumption only provides a limited signal for distention.
抱歉，我脱口而出很有趣，因为我没有意识到液体消耗只能提供有限的扩张信号。
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, it's not fluids, it's water.
嗯，这不是液体，而是水。
And so the idea is that you can fill your stomach up with fluids, but the rate at which fluids empty out of your stomach depends on their calorie content.
因此，我们的想法是，你可以用液体填满你的胃，但液体从胃中排空的速度取决于它们的卡路里含量。
So basically, if you drink water, it empties very rapidly into your intestine, and then it goes through your intestine and is gradually absorbed.
所以基本上，如果你喝水，水会很快排空到你的肠道，然后它通过你的肠道并逐渐被吸收。
If you drink something like a glass of orange juice, it will empty much more slowly, and if you drink something that's really high in fat and really high in calories, it'll empty extremely slowly over hours.
如果你喝一杯橙汁之类的东西，它的排空速度会慢得多，如果你喝一些脂肪含量很高、热量很高的东西，它的排空速度会在几个小时内极其缓慢。
And that's because there's a negative feedback loop from the intestine that controls gastric emptying.
这是因为肠道有一个负反馈回路控制胃排空。
So as those first nutrients leave your stomach and enter your intestine, that produces hormones that go back and then slow down the rate of gastric emptying.
因此，当这些第一批营养物质离开胃并进入肠道时，会产生激素，这些激素会返回并减慢胃排空的速度。
And the purpose for this is that you don't want nutrients entering the intestine too fast.
这样做的目的是不希望营养物质过快地进入肠道。
That's really unsafe.
那样确实不安全。
It feels very unpleasant, and your intestine can only metabolize nutrients so fast.
感觉非常不愉快，而且你的肠道只能这么快地代谢营养。
And so if there's calories, then it slows down gastric emptying a lot, but water just kind of goes through.
因此，如果有卡路里，那么它会大大减慢胃排空速度，但水却会通过。
Andrew Huberman:
安德鲁·休伯曼：
What a beautiful system.
多么美丽的系统啊。
There's regulation at every point.
每个环节都有监管。
Dr. Zachary Knight:
扎卡里·奈特博士：
Right.
对。
Andrew Huberman:
安德鲁·休伯曼：
Hypothalamus, brain stem, gut, the rate of emptying based on the difference between water and orange juice.
下丘脑、脑干、肠道的排空速度取决于水和橙汁之间的差异。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
It's just awesome.
太棒了。
Dr. Zachary Knight:
扎卡里·奈特博士：
Yeah, and that's part of the reason I think it's so hard to outsmart the system, right?
是的，这就是我认为很难智胜系统的部分原因，对吧？
Because- These neurons are making predictions based on the sight and smell of food, but then the gut is doing its own thing.
因为——这些神经元根据食物的视觉和气味做出预测，但肠道却在做自己的事情。
It's calculating it separately and relaying that information.
它单独计算并转发该信息。
So at every step, there are these checks.
所以每一步都会有这些检查。
Basically, they're just confirming that what you thought happened the first time actually was really going on.
基本上，他们只是确认你第一次认为发生的事情确实发生了。
And so, which makes sense because it's so important for survival, these homeostatic systems.
因此，这是有道理的，因为这些稳态系统对于生存非常重要。
They're the product of so much natural selection.
它们是自然选择的产物。
Andrew Huberman:
安德鲁·休伯曼：
Which I think at least partially explains why thousandfold increases in peptide hormones like GLP-1 are required to see significant long-lasting changes in weight.
我认为这至少部分解释了为什么需要增加数千倍的肽类激素（如 GLP-1）才能看到显着且持久的体重变化。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
Because the system is so strongly regulated.
因为这个系统受到如此严格的监管。
Dr. Zachary Knight:
扎卡里·奈特博士：
Exactly.
正是如此。
Andrew Huberman:
安德鲁·休伯曼：
It's hard to beat homeostasis.
很难打破体内平衡。
And hard to beat it safely.
并且很难安全地击败它。
But it sounds like you're more or less optimistic about where that whole field of, let's call it anti-obesity drugs, is headed.
但听起来您对整个领域（我们称之为抗肥胖药物）的发展方向或多或少持乐观态度。
Dr. Zachary Knight:
扎卡里·奈特博士：
I'm very optimistic.
我很乐观。
Look, I think that you couldn't have asked for more so far at this stage with these GLP-1 drugs.
听着，我认为到目前为止，您对这些 GLP-1 药物的要求已经不能再高了。
Incredible weight loss, unexpected health benefits, really safe as far as we can tell.
令人难以置信的减肥效果，意想不到的健康益处，据我们所知确实安全。
It's always possible that some new side effect will emerge, but these drugs are in millions of people, and they've been in a lot of people for a long time now, and nothing seems to have shown up.
总是有可能会出现一些新的副作用，但这些药物已经在数百万人中使用，而且已经在很多人体内使用了很长一段时间，而且似乎没有任何效果。
So, I'm very optimistic.
所以，我非常乐观。
And I think even beyond that, just now that the pharmaceutical industry is reinvigorated to investigate this question.
我认为除此之外，制药行业现在正在重新振作起来，以研究这个问题。
In five years, people will have so many different options.
五年后，人们将会有很多不同的选择。
It won't just be Ozempic or Mounjaro.
它不仅仅是 Ozempic 或 Mounjaro。
There'll be five different, 10 different drugs that they can choose from that have slightly different side effect profiles, slightly different efficacy, perhaps used for people with slightly different metabolic conditions.
他们可以选择五种、十种不同的药物，这些药物的副作用略有不同，疗效也略有不同，也许用于代谢状况略有不同的人。
And so it'll really be a whole palette of medicines you can take that will adjust your physiology and hunger.
因此，这实际上是您可以服用的一整套药物，可以调节您的生理机能和饥饿感。
Andrew Huberman:
安德鲁·休伯曼：
And it's amazing how well it squares with the understanding of the basic biology.
令人惊奇的是，它与对基础生物学的理解如此吻合。
Dr. Zachary Knight:
扎卡里·奈特博士：
Mm-hmm.
嗯嗯。
Andrew Huberman:
安德鲁·休伯曼：
And that's a perfect opportunity for me to really just say what is in my mind, and clearly in the minds of everyone listening and watching, which is thank you so much for this absolutely encyclopedic- ...
这对我来说是一个绝佳的机会，可以真正说出我的想法，并在每个听众和观看者的心中清楚地表达出来，非常感谢您提供这本绝对百科全书式的内容-...
and exceptionally clear explanation of feeding and thirst and salt regulation and these new drugs that are in everyone's minds and everyone's hearing about.
对喂养、口渴、盐调节以及这些新药的解释异常清晰，这些都在每个人的脑海中，每个人都听说过。
I've learned so much today.
今天我学到了很多东西。
I know everyone else has.
我知道其他人都有。
You run an incredible laboratory.
你经营着一个令人难以置信的实验室。
I've tracked your career for a very long time.
我跟踪你的职业生涯很长时间了。
Every paper is spectacular, and you're in a very competitive field, and you've contributed in enormous ways to our understanding of these important processes.
每篇论文都非常精彩，你们处于一个竞争非常激烈的领域，你们为我们对这些重要过程的理解做出了巨大的贡献。
And I don't just say that as a formality.
我这么说并不只是一种形式。
I know that to be true given that we are from the same field and have known each other for a long time, and I'm familiar with your work at a deep level.
我知道这是真的，因为我们来自同一领域并且认识很长时间，而且我对你的工作也很熟悉。
Today has just been an absolute privilege and a gift to learn from you, and I know everyone feels the same way.
今天向您学习是一种绝对的荣幸和礼物，我知道每个人都有同样的感觉。
So thank you for taking time out of your busy research schedule and the other important areas of your life to come here and educate us all.
因此，感谢您从繁忙的研究日程和生活中的其他重要领域中抽出时间来到这里教育我们所有人。
I learned so much basic and practical knowledge, and I know everyone else did as well.
我学到了很多基础知识和实践知识，我知道其他人也学到了很多。
Thank you so much.
太感谢了。
Dr. Zachary Knight:
扎卡里·奈特博士：
Well, thank you.
嗯，谢谢。
This has been really fun.
这真的很有趣。
I'm really glad we had a chance to do this.
我真的很高兴我们有机会这样做。
We talked about some of my favorite topics, so it's always a pleasure, and to talk with another neuroscientist about these things is fantastic.
我们讨论了一些我最喜欢的话题，所以这总是一种乐趣，与另一位神经科学家谈论这些事情真是太棒了。
Andrew Huberman:
安德鲁·休伯曼：
All right.
好吧。
Well, please come back again.
好吧，请你再回来吧。
Meanwhile, thanks for everything you do.
同时，感谢你所做的一切。
Dr. Zachary Knight:
扎卡里·奈特博士：
All right.
好吧。
Thanks.
谢谢。
Andrew Huberman:
安德鲁·休伯曼：
Thank you for joining me for today's discussion with Dr. Zachary Knight.
感谢您参加今天与 Zachary Knight 博士的讨论。
To learn more about his research or to support his laboratory's work, please see the links in the show note captions.
要了解有关他的研究的更多信息或支持他的实验室的工作，请参阅显示注释标题中的链接。
If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel.
如果您正在学习和/或喜欢此播客，请订阅我们的 YouTube 频道。
Please also subscribe to the podcast on both Spotify and Apple by clicking the follow button.
另请点击“关注”按钮订阅 Spotify 和 Apple 上的播客。
That's a terrific zero-cost way to support us.
这是支持我们的绝佳零成本方式。
Also on both Spotify and Apple, you can leave us up to a five-star review.
此外，您还可以在 Spotify 和 Apple 上给我们留下五星级的评价。
Please also check out the sponsors mentioned at the beginning and throughout today's episode.
另请查看今天节目开头和整个节目中提到的赞助商。
That's the best way to support this podcast.
这是支持这个播客的最佳方式。
If you have questions for me or comments about the podcast or topics or guests you'd like me to consider for the Huberman Lab podcast, please put those in the comments section on YouTube.
如果您对我有疑问或对播客有意见，或者希望我为 Huberman Lab 播客考虑主题或嘉宾，请在 YouTube 上的评论部分留言。
I do read all the comments.
我确实阅读了所有评论。
If you're not already following me on social media, I am Huberman Lab on all social media platforms.
如果您还没有在社交媒体上关注我，我是所有社交媒体平台上的 Huberman Lab。
So that's Instagram, X, formerly known as Twitter, Threads, Facebook, and LinkedIn.
这就是 Instagram、X，以前称为 Twitter、Threads、Facebook 和 LinkedIn。
And on all those channels, I cover science and science-related tools, some of which overlaps with the contents of the Huberman Lab podcast, but much of which is distinct from the contents on the Huberman Lab podcast.
在所有这些频道上，我介绍了科学和科学相关的工具，其中一些与胡伯曼实验室播客的内容重叠，但其中大部分与胡伯曼实验室播客的内容不同。
So again, that's Huberman Lab on all social media platforms.
再说一遍，这就是所有社交媒体平台上的 Huberman Lab。
And if you haven't already subscribed to our Neural Network Newsletter, our Neural Network Newsletter is a zero-cost monthly newsletter that includes podcast summaries, as well as brief one to three-page PDFs of what we call protocols.
如果您还没有订阅我们的神经网络新闻通讯，我们的神经网络新闻通讯是一份零成本的每月新闻通讯，其中包括播客摘要以及我们所说的协议的一到三页的简短 PDF。
Those protocols cover everything from learning and neuroplasticity to dopamine regulation to improving your sleep.
这些协议涵盖了从学习和神经可塑性到多巴胺调节再到改善睡眠的方方面面。
We also have a foundational fitness protocol that details cardiovascular training and resistance training sessions right down to the details.
我们还有一个基本的健身方案，详细介绍了心血管训练和阻力训练课程的细节。
Again, all of that is available completely zero cost.
同样，所有这些都是完全零成本的。
You simply go to hubermanlab.com, go to the Menu tab, scroll down to Newsletter, and enter your email.
您只需访问 hubermanlab.com，转到“菜单”选项卡，向下滚动到“时事通讯”，然后输入您的电子邮件即可。
And I should point out that we do not share your email with anybody.
我应该指出，我们不会与任何人分享您的电子邮件。
Thank you once again for joining me for today's discussion with Dr. Zachary Knight.
再次感谢您参加今天与 Zachary Knight 博士的讨论。
And last but certainly not least, thank you for your interest in science.
最后但并非最不重要的一点是，感谢您对科学的兴趣。