The Science of Hunger & Medications to Combat Obesity | Dr. Zachary Knight

Andrew Huberman 0:00 (uptempo music) Welcome to the Huberman Lab Podcast, where we discuss science and science-based tools for everyday life. I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine. My guest today is Dr. Zachary Knight. Dr. Zachary Knight is a professor of physiology at the University of California San Francisco and an investigator with the Howard Hughes Medical Institute. 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. 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. Today, we mainly focus on hunger. 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. And he explains the biological mechanisms for satiety. That is, the sense that one has had enough of a particular food or food group. 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. 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. 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. 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. 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.

Andrew Huberman 2:38 Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. 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. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is BetterHelp. BetterHelp offers professional therapy with a licensed therapist carried out entirely online. Now, I've been doing weekly therapy for well over 30 years. Initially, I didn't have a choice. It was a condition of being allowed to stay in high school. But quickly, I realized that therapy is an extremely important component to our overall health. 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. Now, there are essentially three things that great therapy provides. 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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. 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. Many people start a meditation practice and experience some benefits, but many people also have challenges keeping up with that practice. 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. 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. There's always something new to explore and to learn about yourself and about the effectiveness of meditation. And you can always fit meditation into your schedule, even if you only have two or three minutes per day in which to meditate. 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. 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. Again, that's wakingup.com/huberman to access a free 30-day trial. And now for my discussion with Dr. Zachary

Andrew Huberman 7:07 Knight. Dr. Zachary Knight, welcome.

Dr. Zachary Knight 7:09 Great to be here.

Andrew Huberman 7:11 Today we're gonna talk about hunger, appetite, thirst, other motivated behaviors, the role of dopamine, the vagus nerve. These are terms and topics that a lot of people hear nowadays, and for which there's a ton of interest, 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? You know, I think most people just assume that, okay, that my stomach's full, is what we say.

Dr. Zachary Knight 7:46 Right.

Andrew Huberman 7:47 I've had enough. Um, or we self-regulate it for some other reason, you know, caloric restriction or, or monitoring in some cases. What's happening in the brain in terms of the circuitries, um, and what have you discovered about what that process looks like in terms of its, um, kind of universality across people, and then maybe how it sometimes differs between people?

Dr. Zachary Knight 8:11 Okay. There's a lot in that that I'll try to unpack. (laughs)

Andrew Huberman 8:13 Yeah, and I can remind of some of the nuance here, but just y- y- in other words, as a biologist, as a neuroscientist-

Dr. Zachary Knight 8:18 Yeah.

Andrew Huberman 8:18 ... how do you think about this thing that we call hunger and feeding?

Dr. Zachary Knight 8:20 Absolutely, absolutely. 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, uh, and the other on the timescale of sort of weeks to months to years, and tracks levels of body fat. And these two systems sort of interact so that, so that these short-term behaviors we do eating are matched to our long-term need for energy. And so, um, uh, uh, I think one of the, uh, one of the initial experiments that really led to this idea is this great experiment by Harvey Grill, um, about 50 years ago. Uh, it's called the decerebrate rat, and so essentially what he did was, uh, he made a cut in the rat brains. 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, basically got rid of, you know, 80% of the rat's brain. So this, basically creating these zombie rats, right? All they have is a brainstem and asked, you know, what can these rats still do? And as you might imagine, they can't do a lot of things, right? Because they basically have lost most of their brain. Um, but he discovered that one thing they can still do is regulate the size of a meal. And so, um, and so... (laughs)

Andrew Huberman 9:40 (laughs) A very informative experiment.

Dr. Zachary Knight 9:42 And so, and, and, and so, um, and, and we have to be careful how we talk about this 'cause 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. Um, but eventually at some point they'll start spitting it out, and that basically is an indication that in some sense they're becoming sated, uh, and they're, uh, they're just using the brainstem that they have left, they're able to sense those signals from the gut and, uh, drive the termination of a meal. 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, these decerebrate rats just have a brainstem, um, if you inject those or manipulate the gut in, in those ways, it can, in an appropriate way, change how much the rat eats. Now, what can't the rat do when it doesn't have a forebrain? 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 days, this decerebrate rat, then start putting food in its mouth, the amount that it eats doesn't change. So basically it doesn't eat a larger meal the way you would if you were fasted for several days and then re- refed. And that experiment, along with other evidence, has led to the idea that in the brainstem and then the most posterior part of your brain, there are neural circuits that control sort of a meal and then the, the timescale of 10 minutes or 20 minutes deciding when a meal should end, and in the forebrain, primarily in the hypothalamus, there are neural circuits that then track what is my overall level of energy reserves-

Andrew Huberman 11:08 Mm-hmm.

Dr. Zachary Knight 11:09 ... what is my level of body fat, things that would fluctuate on a timescale of, say, days when you're fasting, 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. So that's at the highest level how I think about the neural circuitry that controls feeding. Um, there's obviously a lot more going on underneath that.

Andrew Huberman 11:27 Mm-hmm.

Dr. Zachary Knight 11:28 But...

Andrew Huberman 11:29 Fascinating. You mentioned body fat and that somehow the brain is tracking the amount of body fat. Um, that caught my ear, uh, because while it makes total sense, I'd like to know how that happens, if we happen to know the mechanism, and the second question is...Why body fat and not body fat and muscular mass, or body fat and overall body weight? 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? I realize it represents an energy reserve, but certainly there are other things about the bodily state that are important.

Dr. Zachary Knight 12:10 Yeah, 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. Um, but body fat is, is unique because it represents this energy reserve. So, the neural circ- circuitry that regulates eating behavior is in some, some ways very unique because it has this reserve of energy. So if you, we also study thirst in my lab, and drinking, and you don't have a reserve of water in your body, right? Um, and that's true for basically everything else, but for fat, we have this, this, this reserve of energy, and so it's very important that, uh, the brain know, uh, how much remains and then adjust behavior, uh, uh, in accordance with that so that, so that, you know, you know how urgent it is to get the next meal. Um, and so the thought is that the major signal of the level of body fat that we have is leptin. It's this hormone, uh, 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. So, the, the story behind leptin is that, um, there's, uh, a facility called Jackson Labs that you, I'm sure are familiar with in, in Maine that, um, since the 1920s has been raising mice and selling them to academics basically who study physiology and behavior. And so they breed thousands of mice, they're sort of a nonprofit organization that distributes mice to the scientific community. And at some point in, in the 1950s, um, they spontaneously, just because they were breeding so many mice, they came across some spontaneous mutations, um, mutant mice that were extremely fat, like the fattest mice they had ever seen. These mice just eat constantly, they're just enormous, three times the size of a, of a normal mouse, and, um, it's all body fat, so they're just, they're just these huge, uh, uh, uh, fat mice. And they came across several different, um, mutate- mutant strains that, um, all had the same phenotype in the sense that they were all extremely fat, all extremely hyperphagic, but they could tell even in the 1950s that these mutations were on different chromosomes. They didn't know anything about how to identify the genes at that point, that was just science fiction, but they knew that there were chromosomes and they were on different chromosomes. And so they labeled one obese, one of these mouse strains obese, and the other one diabetes, but they were basically the same. And so people wondered for a long time, well, what, 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? Because at that point insulin was known, glucagon was known. There were some hormones that were known that were involved in metabolism, so it was logical that there could be a hormone that, uh, perhaps regulates body fat levels. And what they found, which was, which was remarkable, when you attach the OB strain to the DB strain, so you basically connect their circulations so hormones are, are tr- are transmitted between the two, um, the OB mouse, that strain dramatically loses weight. In fact, within a couple weeks, it looks like a normal mouse. It just stops eating, it loses almost all of its body fat, and essentially in all respects becomes a normal mouse. The DB mouse, nothing really happens. It still remains obese and still remains hyperphagic. 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. The OB mouse had a mutation in the recep- 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, and the DB mouse has a mutation in the receptor, so it can't sense the hormone. Um, and that was just an idea, it was a hypothesis, um, but, you know, in the 1980s as technology advanced, as it became p- you know, there's molecular biology had been invented, it became possible to clone genes. Um, a number of people tried to identify what are the genetic mutations, uh, uh, that are occurring in these mice to make them so obese. And Jeff basically cloned leptin and showed that in fact Doug was exactly right. The, the OB mutation is a mutation in this hormone leptin. Uh, and later, uh, Millennium Pharmaceuticals showed that the, the DB mutation is in fact a receptor. And it was an important discovery for a couple ways, for a couple reasons. One, because this OB gene is just expressed in fat. It's exclusively impressed- expressed in adipose tissue, and, uh, how much it's expressed is directly proportional to how much body fat you have. So as you gain weight, the expression of this hormone increases in a linear manner and then it's secreted into the blood. So the level of leptin in your blood is a direct readout of your body fat reserves. This receptor for leptin, the leptin receptor, the, 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. So basically the expression of this receptor gives you a map in the brain of the neurons that control hunger. And so what happens is basically when you lose weight, uh, the levels of leptin in your blood fall because basically you've lost adipose tissue. The absence of that hormone sends a signal to all these neurons that have leptin receptors in the brain, they're not getting that signal that, uh, "I'm starving." And it basically, that initiates this entire homeostatic response to starvation. So a big part of that is, um, obviously increased hunger, but it's also decreased energy expenditure, decreased body temperature, um, even decreased fertility, um, because you don't wanna reproduce if you're starving.

Andrew Huberman 17:32 Less spontaneous movement.

Dr. Zachary Knight 17:34 Less spontaneous movement, all of this. Um, and so, um, and so the thought is, which I think is absolutely correct, is that this, this hormone leptin is, 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.

Andrew Huberman 17:50 Fascinating.

Andrew Huberman 17:51 As I recall, um, Amgen Pharmaceuticals owned the patent for leptin in hopes that it would become the blockbuster diet drug.

Dr. Zachary Knight 17:59 Yes.

Andrew Huberman 17:59 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, uh, basically be less hungry, eat less, and lose body fat.

Dr. Zachary Knight 18:16 Yes.

Andrew Huberman 18:16 What happened with that? Do we know why it did not work?

Dr. Zachary Knight 18:19 Yeah. So that's a great question. So um, there was a lot of excitement when leptin was cloned 'cause it was thought basically we've cured obesity. Um, there was an auction, uh, for the patent. Amgen won, I think it was something like 20 million upfront payment plus royalties, which at the time was... I mean, it still is a lot of money, but even more money-

Andrew Huberman 18:35 Nowadays it would be, it would be, um, a drop in the ocean compared to what companies will invest-

Dr. Zachary Knight 18:40 Exactly.

Andrew Huberman 18:40 ... into potential diet drugs.

Dr. Zachary Knight 18:41 Exactly. So but, but, you know, at the time, um, and still a l- a lot of money today. Um, and, uh, they did a clinical trial, gave obese people leptin, subcutaneous injections of this hormone, and they didn't lose a lot of weight. Um, and the question was why. And so what was subsequently revealed is that the challenge with leptin is that individuals who are obese, um, do not have low levels of leptin for the most part. They actually have high levels of leptin. And so what they have is a state of leptin resistance. So it's analogous to someone who has type two diabetes. 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. And the thought is that it's the same way in, in obesity and leptin. Now subsequently, they went back and did, um, an, 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?" So some people have relatively low levels of leptin, some have higher, some have really high levels of leptin. And then ask, "If we reanalyze the data, um, how, uh, how effective is leptin?" 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. So there is a rationale there for why, um, for, for a scenario in which leptin could work, either among the subset of people who just have for some reason lower levels of leptin. These aren't people with mutations like the OB mouse. They have some leptin, they just don't have unusually high levels. Or alternatively, after weight loss. So after you've lost a lot of weight, your leptin levels plummet, they become very low. And that, part of the reason, it's a big part of the reason, it's so difficult to keep weight off is because those leptin levels are so low. And so it's been thought for a long time that, that that is a scenario where treatment, treating people with leptin, uh, uh, could be really useful to help them keep the weight off. Why it never made it as a drug for that application, I really don't understand. It has something to do, I think, with the pharmaceutical industry, with the economics, with a, a bunch of other issues that aren't necessarily scientific. Um, 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 wanna transition to a different kind of drug, uh, to keep the weight off.

Andrew Huberman 20:52 Well, we are definitely going to talk about GLP-1, Ozempic, and, um, some of the related compounds in a, in a few minutes. 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. Are there separate circuitries or at least separate neurons for each of those steps? And, um, if you would, uh, 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-

Dr. Zachary Knight 21:23 Yeah.

Andrew Huberman 21:23 ... multiple times per day. What's going on in our brain and body as we think about and approach a meal-

Dr. Zachary Knight 21:29 Sure.

Andrew Huberman 21:30 ... consume a meal-

Dr. Zachary Knight 21:30 Sure.

Andrew Huberman 21:30 ... and decide enough?

Dr. Zachary Knight 21:32 Sure. So, um, there are different neurons that are preferentially involved in different aspects of those processes. So, so I think peop- we often divide feeding behavior and many other kinds of motivated behaviors into appetitive and consummatory phases. So appetitive is the phase of the behavior where you're, for example, searching for food, it's foraging. It's all the actions that lead up to the actual behavior itself, which then we call the consummatory phase. That's actually putting the food in your mouth and eating it. And the general thought is that these forebrain circuits in the hypothalamus are more important, p- particularly in the hypothalamus, but other parts of the forebrain as well, are more important for the appetitive phase, and the brainstem circuits are more important for the consummatory phase, the actual putting it in your mouth and licking, chewing, swallowing, and all of that. Within the hypothalamus, there's a population of neurons called AgRP neurons. So it's a, it's just an acronym, AgRP, and stands for agouti-related peptide, but it doesn't really matter. Um, 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. Um-

Andrew Huberman 22:39 May, sorry, just to, um, 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? Because I think about, um, when I get hungry if I'm at my desk or something, um, I need to get up and find food, need to walk to lunch or go to the refrigerator. Are they somehow linked to the circuits that, um, promote locomotion?

Dr. Zachary Knight 23:01 Well, they have to promote those things, um, but they're not directly linked to any of those circuits. They're linked directly to other forebrain circuits involved in motivation. So the way we think, we think about, you know, 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. They're rather creating this general problem that the animal has to solve, which is that, "I'm hungry. I need to get food. It would be really great if I could have a sandwich." And then the animal uses all of its mental capacities, right, to solve that problem. So they're just there to set the goal, not so much to direct the solution.

Andrew Huberman 23:37 Mm-hmm.

Dr. Zachary Knight 23:38 And so, uh, but these AgRP neurons, yeah, there are a few thousand neurons at the base of the hypothalamus, so basically the, the, the most ventral, the most bottom part of the forebrain. Um, uh, so tiny population of cells, but outsized importance for the control of feeding behavior. So if you stimulate these cells in a mouse or a rat that's not hungry, um, the animal will voraciously eat like it's starving.... uh, if you silence these cells, uh, animals will starve to death. So you can basically give them food, they just won't eat it voluntarily until basically th- you have to euthanize them because they're, uh, uh, they've lost so much weight. Um, and the activity of these, these AgRP neurons, uh, um, is thought to track the body's need for energy. One reason that's thought is that, um, uh, they express these receptors for leptin, this hormone that I was just talking about that, that comes from fat and signals the level of body fat reserves. And leptin inhibits AgRP neurons. So as you might expect, if you have lots of body fat, um, then, uh, a neuron that expresses, that controls hunger should be less active than if you have very little body fat. So that's one mechanism by which leptin controls hunger. Um, we in my lab have investigated the role of these AgRP neurons, um, uh, 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, and to ask, what are their activity patterns? What is the natural sort of firing of this population of neurons when an animal eats a meal? It's a very basic question. Uh, something I think we've wanted to know for a long time. Um, 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. Um, 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? And so, uh, one of my first graduate students, Yiming Chen, he, uh, he used a technology called fiber photometry, which allows us to put a fiber optic into the mouse's brain so th- then we could record fluorescence from these AgRP neurons, which we could use as a readout of their activity. It's basically using a calcium sensor. So calcium is a surrogate for neural activity. And very, one of the very first experiments he did, we said, "Let's make the animal hungry. These AgRP neurons will be very active 'cause the animal's hungry. And then let's give it some food and see what happens during a meal." 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, uh, feeding back to inhibit these neurons. What we found was really surprising. I remember the, when, when he made this discovery, basically him running into my office and saying, "Zak, I, I, I gave the mouse the piece of food, but the weirdest thing happened. The neurons shut off almost immediately." And I said, "Yiming, you've made a mistake. It's okay. You're just starting off in graduate school. This happens, go back and repeat the experiment and then we'll discuss it." But he did it several times. He said, "You know, Zak, every single time I do it, this happens. I give a hungry mouse food, and the AgRP neurons, within just a few seconds, uh, their activity has, uh, 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. 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. The mouse looks at, at the, 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. And so essentially, these neurons know how much the mouse is going to eat before the mouse even takes the first bite. And, uh, you can show this in very simple, by very simple analysis in which you, you give the mouse different foods and you look at how much these AgRP neurons drop when the mouse sees and smells the food. And then you plot that against this hap- this drop happens in three seconds, four seconds, something like that. Then you look at how much does the mouse go on to eat in the next 30 minutes? You can just draw a straight line. So this was one of the first results from my lab, and it was really surprising to all of us, and I think everyone. Um, 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. They can sense these signals from the body that tell you about what's happened, but those signals are slow and, 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. You want to f- try to figure that out as soon as you can, right? 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 gonna eat about this much." And then that information is all transmitted to these circuits to start the process of s- satiation before the meal begins.

Andrew Huberman 28:15 Is it satiation or it's, um, ceasing of foraging so that-

Dr. Zachary Knight 28:19 Yeah.

Andrew Huberman 28:20 ... the animal, or if I translate to a person, decides, "Okay, now I'm going to consume this sandwich, this package of food"?

Dr. Zachary Knight 28:26 Yeah, that's a great question. So, um, we don't fully know the answer. So one interpretation of the data I just showed you is what you, exactly what you said, is that what these neurons do is they control foraging alone. They don't control eating. And so this is perfect. You see the f- food, you know it's, it's got enough calories, the neurons shut off, and then you stay there and eat it. You transition from this appetitive to this consummatory phase. 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. So you can't fully separ- Although we like to make this distinction between appetitive and consummatory, and we know that, that, that in different parts of the brain there's more important for one versus the other, the reality is that the entire behavior is linked and you can't fully separate them. So there's a number of ideas about what, what this means. So one idea that I just mentioned is that starting the process of satiety before the meal begins. Another idea which, which you mentioned, which could have, could be part of the answer, is that it is reducing this appetitive drive and allowing the transition to consummatory behavior. Um, another idea is that... And I call these ideas because we don't really fully know the answer yet for exactly what the, the purpose is. And in biology, it's always hard to answer why something happens. You can figure out once it happens, but then you can... the, the reason why it evolved that way is challenging. Um, another idea is, is it's involved in these what we call cephalic phase responses that are necessary to prepare you for a meal, right? So this, the famous example of this is Pavlov, right? Basically, uh, trains the dog to associate the ringing of the bell with the, uh, uh, uh, presentation of food, and then eventually the ringing of the bell alone causes the dog to salivate in the absence of any food. And-Salivation is one example of a cephalic face response. The purpose of that is to have enzymes in your mouth that basically are gonna digest the food and get them there right before you need them. But there's all sorts of other things, like basically a secretion of insulin occurs in res- response to food cues, changes in gastric acid, d- gut motility. All these things are getting ready for the, for the meal to happen, and so another idea is, is it could be part of that. But it probably is doing all of these things.

Andrew Huberman 30:26 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. To be clear, I don't take AG1 because they're a sponsor. Rather, they are a sponsor because I take AG1. In fact, I take AG1 once and often twice every single day, and I've done that since starting way back in 2012. 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. 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. Now, I personally am an omnivore, and I strive to get most of my food from unprocessed or minimally processed sources, 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, et cetera, but it also has adaptogens to help me cope with stress. It's basically a nutritional insurance policy meant to augment, not replace quality food. 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, 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. So while many supplements out there are really directed towards obtaining one specific outcome, AG1 is foundational nutrition designed to support all aspects of wellbeing related to mental health and physical health. If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs with your order plus a year's supply of vitamin D3 K2. Again, that's drinkag1.com/huberman.

Andrew Huberman 32:15 It's so interesting. I have a number of questions, but I think the one that I'll, uh, put at the top of the list is, the other night we were out to dinner in New York, and, um, I was very hungry. I hadn't eaten much that day, and I was looking forward to a nice steak. Uh, they brought out bread, French bread. It was a French restaurant. I took one bite. I realized it was absolutely delicious French bread. The butter was fantastic, and so I had some bread and butter, which I love.

Dr. Zachary Knight 32:40 Yes.

Andrew Huberman 32:41 Then they brought more, and then they started bringing out, I don't know who ordered them, 'cause I didn't, appetizers, and I realized that this was going to be a much more extensive calorically dense meal-

Dr. Zachary Knight 32:53 (laughs)

Andrew Huberman 32:53 ... and suddenly my appetite for the appetizers w- I- it sort of went down because I, I knew there was more food coming, right?

Dr. Zachary Knight 32:59 Yes.

Andrew Huberman 33:00 Had I not known that there was more food coming, I think-

Dr. Zachary Knight 33:02 Yes.

Andrew Huberman 33:02 ... I would've consumed more of the appetizers, which also looked great. So clearly there's something going on with these AgRP neurons-

Dr. Zachary Knight 33:08 Correct.

Andrew Huberman 33:08 ... at the moment. You're sort of, um, integrating based on new information.

Dr. Zachary Knight 33:12 Exactly.

Andrew Huberman 33:13 Um, on the other end of the spectrum, um, 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 o- on this and the scientists who work on this, is that, um, people with anorexia are unbelievably tuned to the caloric content of food.

Dr. Zachary Knight 33:38 Huh.

Andrew Huberman 33:38 That their visual system and presumably other systems, um, have become, like, almost, um, uh, hyperaccurate calculators of the amount of calories in food. Uh, they've devoted a lot of cognition to it. It sometimes can-

Dr. Zachary Knight 33:52 Interesting.

Andrew Huberman 33:52 ... you know, border on or, or be placed within the obsessive realm. But that they see food and they, they c- they can tell you a tremendous amount about the caloric amounts within these foods, even food combinations to-

Dr. Zachary Knight 34:03 Right.

Andrew Huberman 34:04 ... uh, you know, with a v- in a very small margin of error.

Dr. Zachary Knight 34:07 Okay.

Andrew Huberman 34:07 Um, so, and, and that drives, in, in that condition, obviously, a food avoidance.

Dr. Zachary Knight 34:13 Yeah.

Andrew Huberman 34:14 Um, so I have to assume that these AgRP neurons are involved in this kind of thing. One represents a regulation in the case of the example I gave, and in the other case, a, a, let's just call it what it is because anorexia nervosa is the most deadly of the psychiatric conditions sadly-

Dr. Zachary Knight 34:28 Yes.

Andrew Huberman 34:28 ... a, uh, pathologic dysregulation, a maladaptive dysregulation. So, uh, what is known about these AgRP neurons in humans, meaning do they exist in humans? Um, presumably they express the leptin receptor. Um, sounds like they are able to integrate information both cognitive, um, based on immediate experience, visual, olfactory, but also a lot of prior experience.

Dr. Zachary Knight 34:53 Mm-hmm.

Andrew Huberman 34:54 Um, you know, a hamburger patty, I don't, can't tell you how many calories it has. All I know is that it's mostly protein and some fat. Um, you know, w- what are these neurons doing? What do they have access to? They sound like, you know, when any time we hear about hypothalamus, I think very basic drives, but you're talking about a pretty sophisticated analysis of a real-time event-

Dr. Zachary Knight 35:15 Yeah.

Andrew Huberman 35:15 ... that is driving fairly nuanced behavioral decisions and updating that-

Dr. Zachary Knight 35:20 Yeah.

Andrew Huberman 35:21 ... which is, which is a big deal.

Dr. Zachary Knight 35:22 Yeah.

Andrew Huberman 35:23 I- i- you know, we're both neuroscientists, but for everyone listening and watching, this is a big deal. This is as nuance as deciding whether or not somebody is friend or foe or deciding whether or not you, y- y- you like a movie or you don't. I mean, this i- this is some, um, some pretty sophisticated processing. This isn't eat, don't eat, or eat less, eat more.

Dr. Zachary Knight 35:41 Exactly. Exactly.

Andrew Huberman 35:41 These aren't switches.

Dr. Zachary Knight 35:42 Exactly.

Andrew Huberman 35:42 Um, these are dials.

Dr. Zachary Knight 35:44 Exactly. Yeah, so there's, there's a lot there. I'll, I'll try to ans- uh, unpack that. Um, so the first thing I would say is they are present in humans, and humans, uh, do, humans have AgRP neurons. Human AgRP neurons express the leptin receptor, and we think the functions are very similar. Um, so 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, right? 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. They're labeled by specific genes and those are conserved through evolution. Um, we also know that this pathway, this AgRP neuron pathway, um, is important in humans due to human genetics. So, uh, just to add a little bit more information here, there's a companion set of neurons called POMC neurons that promote satiety, so they're sort of the yin and yang of hunger. AgRP neurons promote hunger, POMC neurons promote satiety. They're intermingled in the same part of the hypothalamus. They, their axons that project to th- the exact same downstream brain regions, and then it's thought that these two neurons compete with each other, uh, to control appetite. And that competition occurs through neuropeptides that they release, one of which is a- an agonist for a downstream receptor and the other one of which is an antagonist. Um, we know from human genetics that the- these, um, that amongst severely obese people, mutations in this pathway, AgRP, POMC neurons, and their direct downstream targets are quite common. So-

Andrew Huberman 37:18 Really?

Dr. Zachary Knight 37:19 ... so, and -

Andrew Huberman 37:19 So is it fair to say that a f- that some amount of obesity is genetic in, in nature at the level of neuronal firing or circuitry?

Dr. Zachary Knight 37:29 I think a lot of body weight regulation is genetic. It's highly heritable. Um, there's a question of how much of it is due to single genes. And the number of people quote, and th- this is among people who are severely obese, so not just people who you've seen someone who's overweight, but people that have sort of syndromes where they're very obese from a very young age. Um, among those people, something on the order of 10% have mutations in this pathway, and it can either be th- this, this hormone POMC, um, or a, a, an enzyme within those cells that processes POMC into the right form, or in the down, and this is the most common mutation, in the downstream receptor for POMC. It's called the melanocortin-4 receptor. And so, um, and so among the severely obese people who have sort of genetically inherited severe obesity from childhood, uh, something on the order of 10% have mutations in this pathway. So it's very clear that this, uh, that this, this pathway is involved in body weight regulation in humans. Most obesity, although there is a very strong genetic component, um, uh, is not associated with single gene mutations, like, this, it's associated effects of many mutations. Um, but we know that even in the, in that sort of polygenic obesity that has many different, uh, genetic causes, um, that, uh, uh, the brain is important. 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, something on the order of a thousand genes have been linked to body weight regulation. Um, and the vast majority of those are expressed in the brain and they're highly enriched for brain processes, which makes sense because body weight is controlled by food intake, right? And the, the brain controls behavior and also the brain controls energy expenditure. So, so maybe it's not so surprising, but it's clear that, um, that, that mutations in, in, in genes in the brain, uh, are, are important for body weight and which is consistent with the results of, you know, twin studies. So if you look at monozygotic versus dizygotic twins, the estimates for the heritability of body weight is something on the order of 80%. Uh-

Andrew Huberman 39:28 We should explain monozygotic, dizygotic.

Dr. Zachary Knight 39:30 Which-

Andrew Huberman 39:30 I've talked about it before on the podcast just to-

Dr. Zachary Knight 39:32 Sure.

Andrew Huberman 39:33 ... brush people up.

Dr. Zachary Knight 39:33 Just identical versus fraternal twins, basically. And so, um, uh, and by comparing their, uh, basically their, um, their body weight when they become adults, you can get a sense for how much of this is genetic versus environmental. And, um, uh, something on the order of, uh, 80% is thought to, the variation between individuals is thought to be, have a genetic component.

Andrew Huberman 39:54 Wow.

Dr. Zachary Knight 39:54 Um, so-

Andrew Huberman 39:55 I d- I don't think most people appreciate that.

Dr. Zachary Knight 39:57 Yeah. It's-

Andrew Huberman 39:57 And a lot of the debate we hear nowadays is, um, because there are things that people can do to lose body fat, exercise, eat differently, et cetera, maybe embrace pharmacology if-

Dr. Zachary Knight 40:08 Yeah.

Andrew Huberman 40:08 ... if that's, um, appropriate, um, there seems to be this, to me, silly debate as to whether or not people should be eating better and exercising or, um, assuming that all of the obesity they might have, um, arises through genetic causes, um, and therefore take a prescription drug. I mean, why wouldn't it be a combination of things?

Dr. Zachary Knight 40:31 Yeah.

Andrew Huberman 40:31 Like to me, it just seems like why wouldn't people, um, embrace s- some or all of the tools that they could afford and that are safe for them? So I just wanna get that out there-

Dr. Zachary Knight 40:39 Yeah.

Andrew Huberman 40:39 ... because the moment this comes up, people start thinking, "Oh, well, uh, the moment we assign a genetic source to something, we're removing, um, personal responsibility."

Dr. Zachary Knight 40:47 Yeah.

Andrew Huberman 40:47 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-

Dr. Zachary Knight 40:55 Yeah.

Andrew Huberman 40:55 ... like Ozempic, have provided them the opportunity to finally be able to, uh, lose weight and feel better and exercise safely-

Dr. Zachary Knight 41:02 Yeah.

Andrew Huberman 41:03 ... for instance.

Dr. Zachary Knight 41:04 I, I completely agree with that. Um, 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, and that's the idea that, you know, if you look at people, say, 75 years ago, right, they were much leaner, right? And you look at people today and there's been a, this, starting sometime around, you know, the 1970s, there's this explosion in body weight and increase in obesity. In, in-

Andrew Huberman 41:28 Is that when, that's when it started, mid '70s?

Dr. Zachary Knight 41:30 Sort of the 1970s is around when a lot of that started to happen.

Andrew Huberman 41:33 Snack food, snacking. (laughs)

Dr. Zachary Knight 41:33 So there's lots of ex-

Andrew Huberman 41:34 Snacking.

Dr. Zachary Knight 41:34 ... there's lot of explanations.

Andrew Huberman 41:35 Seed oils. Snacking. By the way, I don't think (laughs) that's the reason, folks. I, I think there are a lot of reasons, but the theories that, that abound right now on social media-

Dr. Zachary Knight 41:43 Yeah.

Andrew Huberman 41:43 ... are the... I have a list of the theories-

Dr. Zachary Knight 41:45 (laughs)

Andrew Huberman 41:46 ... as to why the ob- obesity has increased. You get everything from seed oils to snacking to, uh, smartphones to, uh, conspiracies to... It's wild.

Dr. Zachary Knight 41:55 Yeah. Yeah.

Andrew Huberman 41:55 It's wild. The range of, of hypotheses is wild.

Dr. Zachary Knight 41:59 Yeah. I mean, and the ch- the challenge is, I mean, some of them could be true, but it's just very hard to test those things experimentally-

Andrew Huberman 42:03 Sure. Sure.

Dr. Zachary Knight 42:03 ... 'cause they're happening in the whole population, right?

Andrew Huberman 42:05 Yup.

Dr. Zachary Knight 42:05 But, 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-... which is the environment has changed, but human genetics has not changed in that amount of time, just not fast enough for people to evolve. So it can't be due to mutations in humans, correct?

Andrew Huberman 42:22 What about devolve? My understanding is that within a species, um, evolving new traits is very slow.

Dr. Zachary Knight 42:29 Yes.

Andrew Huberman 42:29 But mutations arise like the OB, OB mutation, and then you can get very fat versions of a, of an animal very quickly, right?

Dr. Zachary Knight 42:37 Yeah.

Andrew Huberman 42:38 All you need is a-

Dr. Zachary Knight 42:39 Su- sure.

Andrew Huberman 42:39 ... you know, if, if it's a, um, if it's a recessive allele, you need two copies, and the n- next thing you know, you've got a mouse that's four times larger than a typical mouse-

Dr. Zachary Knight 42:46 Sure.

Andrew Huberman 42:47 ... and, and it's all explained by increased body weight. So that happen- can happen very quickly-

Dr. Zachary Knight 42:51 Sure.

Andrew Huberman 42:51 ... within a species. What's rare to find, uh, is an entire new branch of a species-

Dr. Zachary Knight 42:57 Sure.

Andrew Huberman 42:57 ... that has a, a very, uh, a new adaptive function.

Dr. Zachary Knight 43:00 Sure.

Andrew Huberman 43:00 That seems more rare.

Dr. Zachary Knight 43:01 Uh, so, so that's true. So definitely there's some things that take longer to evolve than others, but with humans, we're talking about just two generations. There just isn't enough time for any evolution of any significance to happen.

Andrew Huberman 43:10 Yeah. We went Baby boo- Baby Boomers, right? Generation X.

Dr. Zachary Knight 43:14 Generation X. (laughs)

Andrew Huberman 43:14 That's me, right? And then whatever is Y, Z Millennial.

Dr. Zachary Knight 43:17 Exactly.

Andrew Huberman 43:17 I lose track after that.

Dr. Zachary Knight 43:18 Exactly.

Andrew Huberman 43:19 Um.

Dr. Zachary Knight 43:19 So, so I think the thing that people find h- hard to wrap their heads around is how can it be that this is ha- this is... That n- that, that increase in body weight is clearly environmental, right? Th- 'cause that's all that's changed is the environment. It's... The... Nothing's changed genetically. Yet it's also true what I said that body weight is extremely heritable. It's one of the most heritable features and something on the order of 80%. The only thing, uh, one of the only things we know about that's actually more heritable than body weight is height, right? Most diseases are not as heritable as body weight. How can you explain that? And the idea is this. There's a distribution of body weights among people. So in any given satiety- society at any point in time, some people are gonna be leaner, some people are gonna be more obese. That distribution, where you lie on that distribution is determined primarily by genetics. So you may be the person who has the thrifty genes, so they basically cause you to save energy, and so you would be more on the obese side. Or you may be, may be a person who has different genes that cause you to be a little bit less hungry, so you would be on the lean side. 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. And so sort of a, uh, phrase that people sometimes use is that, is that, um, genetics loads the gun and environment pulls the trigger. So basically genetics sensor- sets your propensity, and then environment can, can basically unmask that. 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, uh, just various other things that you mentioned, seed oils, who knows if that's important. Um, uh, uh, certain people had these latent mutations that made them, say, very sensi- sensitive to, to palatable food. And in an earlier time, they may have been lean, but now because they have that latent capacity to be sensitive to, to, to ultra-processed food, they now gain tons of weight in the, in the environment that we're in. It's still because of genetics, but it also requires the environmental component. I mean, just take a step back, right? You can make anyone lean by just putting them conf- con- putting them, you know, in prison and just only feeding them 1500 calories. I mean, we've done those kinds of experiments. There's this famous experiment, the Minnesota starvation experiment, right? They basically, this is... Th- they put people in prison, but this is in World War II. They took a bunch of healthy volunteers, fed them 1600 calories a day and just asked what would happen if you basically semi-starved people. And unsurprisingly, they lose an incredible amount of weight. All they think about is food. They basically, their body temperature goes down, their heart rate goes down. They just become obsessed with food. And you, you could always do that for anyone, right? But, but, um, in a given environment where you're not in that kind of situation, then your propensity to gain weight will be determined by genetics. So that's the idea.

Andrew Huberman 45:48 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, um, has not been described with that level of accuracy and detail with respect to the interactions between genetics and the environment.

Andrew Huberman 46:05 Is it fair to say that what's changed in our environment is the free availability of food? You know, I was walking through an airport yesterday and every 20 meters or so there's a vending machine or a restaurant. Um, the cost of calories-

Dr. Zachary Knight 46:20 Yeah.

Andrew Huberman 46:20 ... is fairly low, right?

Dr. Zachary Knight 46:22 Yeah.

Andrew Huberman 46:22 Getting high quality nutritious food that tastes great is expensive-

Dr. Zachary Knight 46:27 Yeah.

Andrew Huberman 46:27 ... I would argue, but getting calories is fairly inexpensive.

Dr. Zachary Knight 46:32 Yeah. I think that's a plausible hypothesis. Um, it's one of several plausible hypotheses, and it would be surprising to me if it didn't contribute. But the reality is these population level questions is just so hard to actually know because you can't do an experiment, right? You, we, we can't create a parallel socie- society where we manipulate one of these variables and see if the people become obese. So I think probably the availability of food, of... the free availability, the low cost is one part of it. Another part of it is probably, although again, it's, it's, it's, it's not proven, is that these ultra-processed foods have a number of features that, um, make them, make people prone to gain weight. And this really beautiful work, I don't know if you know about this, from Kevin Hall at the NIH who's investigated this. 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. And he did this, 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, but had them take a lot of care so that when they gave the foods to independent raters, to people to test, they would say, "This is about equally palatable." So I like the... this ultra-processed dish as much as, as this non-ultra-processed dish.

Andrew Huberman 47:46 What's an example of an ultra-processed dish? Like a out-of-package macaroni and cheese-

Dr. Zachary Knight 47:50 Exactly. That kind of stuff.

Andrew Huberman 47:51 ... with, with bacon kind of thing?

Dr. Zachary Knight 47:52 Exactly.

Andrew Huberman 47:53 Versus, um, some pasta sitting next to a vegetable and some-

Dr. Zachary Knight 47:56 Exactly.

Andrew Huberman 47:56 ... a nice piece of-

Dr. Zachary Knight 47:58 Piece of-

Andrew Huberman 47:58 ... salmon or something?

Dr. Zachary Knight 47:58 Exactly.

Andrew Huberman 47:59 Okay.

Dr. Zachary Knight 47:59 Exactly. Um, and, uh, um, took people into the, into the hospital, basically allowed them to eat just as much as they would like first of the ultra-processed meals, so they had this selection of ultra-processed meals for a couple weeks, and then switched them to the, 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.What he found out is that even though, um, uh, uh, people rated the foods as equally palatable, they ate much more of the ultra-processed food and they actually gained weight when, during that two-week period when they were g- being given the ultra-processed foods. And then when you switch them, they lost weight. So, the idea being that you can have two sets of food that you get sort of equal pref- you have equal preferences for but something about the ultra-processed food is making you eat more of it when you actually consume it.

Andrew Huberman 48:44 Mm-hmm.

Dr. Zachary Knight 48:44 And there's a number of ideas about why that could be. 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, so that could be part of it. Another idea is that, you know, a big thing about whole foods is that they take more energy to digest and they have more volume. 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 and that's just because whole foods are bigger, because they're not so energy-dense. So, and we know that, for example, volume is a major signal in the short term for regulating food intake. So if you just eat more volume, that could be valuable. And so there's lots of things like that. So the, so then I think that's another hyp- plausible hypothesis, but the truth is we don't really know.

Andrew Huberman 49:32 I have a hypothesis, and I don't wanna 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. So, I've been paying a lot of attention to the landscape of what the general public think about, um, let's call them elimination diets, where people will just eat meat.

Dr. Zachary Knight 50:03 Yes.

Andrew Huberman 50:03 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 ther- thermodynamics and consume fewer calories than they, um, than they burn.

Dr. Zachary Knight 50:20 Yeah.

Andrew Huberman 50:20 Right? I do believe in calories in, calories out.

Dr. Zachary Knight 50:23 Yes.

Andrew Huberman 50:23 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. But l- 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.

Dr. Zachary Knight 50:44 Yes.

Andrew Huberman 50:44 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. A piece of fish is mostly protein, has some fat.

Dr. Zachary Knight 51:00 Mm-hmm.

Andrew Huberman 51:01 A bowl of rice is mostly carbohydrate, has some protein.

Dr. Zachary Knight 51:04 Yeah.

Andrew Huberman 51:05 Put a pat of butter on it, has some fat also, right? It's sort of obvious. But taste, macronutrient content, calories, which we already know people with anorexia are exquisitely good at counting with their eyes.

Dr. Zachary Knight 51:23 Mm-hmm.

Andrew Huberman 51:24 So it's possible they represent a, again, a pathologic extreme of this. And micronutrient content. Maybe even amino acid content, like how much leucine is there. 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. It's, um, present in certain proteins and not others. You're gonna find less of it in a vegetable typically than you would in a piece of chicken, and, and so on. 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, ugh, sounds disgusting, right? Broccoli, rice, and a chicken breast blended together just sounds horrible. Eating them separately if there's some olive oil and a little pat of butter involved, like that sounds pretty good.

Dr. Zachary Knight 52:10 Mm-hmm.

Andrew Huberman 52:11 But a highly processed food in some ways is a blending together of macronutrients, micronutrients if there are any, um, and other features of the food that neurons in the brain seem to pay attention to, and then giving it a unified taste. A Dorito, right?

Dr. Zachary Knight 52:29 Yes.

Andrew Huberman 52:29 Um, a candy bar, that we attach to the product, we attach to the name of the processed food, to the packaging. But, uh, I could imagine, and here's the hypothesis, that that is c- quote unquote "confusing"-

Dr. Zachary Knight 52:43 Mm-hmm.

Andrew Huberman 52:43 ... 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. Whereas when I eat a piece of steak and a vegetable, I actually want less carbohydrate afterwards. If I eat the carbohydrate first, it, for me it's difficult 'cause I love the taste of carbohydrates-

Dr. Zachary Knight 53:03 Yeah.

Andrew Huberman 53:03 ... especially when they're combined with fat. But there's 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, um, they're trying to be healthier. That might be what stimulates the, the shift, but that the brain starts to learn the relationship between food volume, smell, taste, um, what these things look like, and satiation at the level of, "Oh, that's enough amino acids because I had a piece of fish." So maybe I don't-

Dr. Zachary Knight 53:34 Yeah.

Andrew Huberman 53:34 ... need to consume as much of some other things. Or the vegetables provide volume and fiber, and often vegetables can taste really delicious too. So that there's a, there's a linking of nutrients, calories, and taste in a way that's more appropriately matched to the energetic demands of the organism-

Dr. Zachary Knight 53:51 Yeah.

Andrew Huberman 53:51 ... in this case us, humans, that highly processed foods bypass.

Dr. Zachary Knight 53:56 Yeah.

Andrew Huberman 53:56 Okay? Now, I realize that was long-winded, and forgive me, but my audience is used to that. 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, and feeding behavior, that for a lot of people is just really confusing, and here's why, and this is the last thing I'll say. I have several friends who have been very overweight their entire lives-

Dr. Zachary Knight 54:23 Yeah.

Andrew Huberman 54:23 ... 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. 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, um, see fit based on your food intake. And without fail, they all lose a ton of weight, they're very happy with that, they add back in a minimum of starches, they keep the weight off, and they're, they're also exercising, but not more than they were before in most cases. 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, in terms of what they actually need. And without fail, they all say, "Oh, you know, on, 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. So I just would like your thoughts on this. We're not defining any new diets. I don't sell any diets. I don't do any of that.

Dr. Zachary Knight 55:23 (laughs) .

Andrew Huberman 55:23 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 a, an unconscious understanding about what food is providing them or not, and that highly processed foods basically sh- bypass all of this and just get you to consume more-

Dr. Zachary Knight 55:43 Yeah.

Andrew Huberman 55:43 ... 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.

Dr. Zachary Knight 55:50 Yeah. There's several interesting ideas there. So there's two that come to mind, just thinking about what you just said. So the one is the idea of what's going on when these people, uh, consume simpler diets, more of, of whole foods. And, and one, one thing I think that's very likely going on is this phenomenon of sensory-specific satiety as being engaged.

Andrew Huberman 56:11 Mm-hmm.

Dr. Zachary Knight 56:12 And so, um, uh, sensory-specific satiety is just the idea that as you expose yourself repeatedly to a certain flavor or taste, you, um, you basically lose appetite for that. You get specific loss of appetite for that flavor or taste. This is why, as you said, basically if you start off eating the protein, after a while you're like, "I don't want any more salmon, but I would like some carbohydrates now," because you have this sensory-specific satiety. And so, um, it's well known actually that if you simplify your diet, make your diet really simple so there's just a few things, then sensory-specific satiety alone can cause you to eat less basically because there's just less variety in your diet and you don't wanna eat more of that same thing. And so, 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 variabil- the, the variety in the diet, and eventually, you just get sick of eating the same thing. And, you know, this is... The thought behind that idea is that it's, it's important evolutionarily so that you eat a diverse diet. It's the reason probably that you want sweets after you've eaten a savory meal and so on. A second idea though that, that comes to mind is just as you mentioned, this idea of learning. And, and so much about our, our preferences for food are, they're not innate, they're driven by learning, right? And so, so, you know, there are some things that are innate. So if you put sugar on a baby's to- uh, tongue, you know, it'll smile, indicating that it likes it, and if you, uh, put something bitter, it'll frown, and a rat will do the same thing, a n- neonate rat. But most of flavor and the perception of food is not just sweet or bitter. 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. 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. And so, you know, there's lots of examples of this that you can just imagine from everyday experience. 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, but then we come to crave these things because we know what they do to our body, we like what they do to our body, and that doesn't just make us take them like their medicine. We actually somehow change our very perception of how that flavor is. We actually come to savor that flavor we previously found disgusting, and it's because our sensation of what is, what is wha- whether something is good or bad depends on our internal state. And so it's an interesting idea, you know, perhaps if these ultra-processed foods that have so many different ingredients in 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... The brain's used to saying, you know, "This is a piece of chicken and this is primarily protein." And so I can gauge, you know, from this fla- I can connect this flavor to an amino acid content, but something that's so diverse, it, it might be harder to do.

Andrew Huberman 58:55 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, uh, primary colors of, of nutrients, and nutrients are, uh, the way in which we can persist, um, on a day-to-day basis?

Dr. Zachary Knight 59:22 Yeah.

Andrew Huberman 59:22 Right?

Dr. Zachary Knight 59:22 Yeah.

Andrew Huberman 59:22 I mean, I'm not trying to sound more sophisticated where simpler terms would suffice. What I'm basically saying is that the neurons in our brains that control these, uh, behaviors, both eating and cessation of, 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, uh, or to lentils, um, 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, right? I mean, like, if we really break it down into biology, eating is for a purpose, and my understanding is that the purpose of eating is to, uh, replace those things as needed-

Dr. Zachary Knight 1:00:04 Yeah.

Andrew Huberman 1:00:04 ... um, rather than to, uh, you know, taste savory or taste, um-

Dr. Zachary Knight 1:00:10 Absolutely.

Andrew Huberman 1:00:11 ... you know? Yeah.

Dr. Zachary Knight 1:00:11 Absolutely, absolutely. Those are just, those, those thing, those sensory cues are just markers that tell the brain what might be in that substance.

Andrew Huberman 1:00:17 Mm-hmm.

Dr. Zachary Knight 1:00:18 I think if you, if you look at 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. So they, they can... Like, 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.

Andrew Huberman 1:00:41 Really?

Dr. Zachary Knight 1:00:42 Yeah.

Andrew Huberman 1:00:42 So a little drop of olive oil into the belly that has, o- of an animal that has, um, let's, drop, let's say a little bit more. Let's say, um, 120 calories of olive oil is equal potent to 120 calories of chicken breast?

Dr. Zachary Knight 1:00:59 At the level of these AgRP neurons, it is. So we-

Andrew Huberman 1:01:02 So they don't care about-

Dr. Zachary Knight 1:01:03 They don't care about the macro-

Andrew Huberman 1:01:04 ... the macronutrient.

Dr. Zachary Knight 1:01:04 No. They're really concerned about-

Andrew Huberman 1:01:05 Okay. So I'm probably wrong (overlapping)

Dr. Zachary Knight 1:01:06 They're really concerned about energy.

Andrew Huberman 1:01:08 Uh-huh.

Dr. Zachary Knight 1:01:08 Um, there are circuitries that are more concerned with macronutrients individually, although I don't think we know nearly as much about how that works. And I think the evidence is clear that the, the strongest defended macro- macronutrient by far is protein. So protein, um, you know, I don't think really sugar and fat intake are strongly defended in the sense that you can, y- you're fine if you go without eating sugar, right? Basically, you can synthesize sugar from other, from amino acids, for example, um, and you don't develop an, a specific sugar appetite in the same way you do, for example, if you deprive yourself of hunger and you develop a protein hunger or essential... And I think the, the difference is that, you know, proteins consists of essential amino acids. There's this, I forget if it's nine, I think, amino acids that, um, uh, your body cannot synthesize. You absolutely need them or you will die. And so, um, whereas sugar and fat can be interchanged with other macronutrients. So, um, and there's other things also that you absolutely need to ingest, like sodium chloride, right? So sodium. So, uh, uh, there's very few, deprive an animal of, of sodium, they'll develop this salt appetite that's incredible, basically, and that's completely innate. Um, uh, but that's, I think salt appetite and, and, and protein appetite are the things that are probably the most strongly regulated at the level of the macro and micronutrients.

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Andrew Huberman 1:03:58 pack. If we could talk about body weight homeostasis for a moment, that, I think that would be useful. So let's say somebody decides they want to lose some weight. They caloric restrict s- slightly either by exercising more or eating less or both. Their body weight drops by a bit. Let's say they lose 10 pounds, eight of which are body fat. They lose a little bit of lean mass also. They're now at a new lower body weight. Are the AgRP neurons motivated to have them seek out more food? 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"?

Dr. Zachary Knight 1:04:42 No, I mean, th- the idea is that the AgRP neurons are more active when you lose weight and that, that chronic activation of those neurons, in, in part because leptin levels are lower in the blood because you've lost weight, is that drive, that, that, that counterregulatory drive that drives you to then consume more food.

Andrew Huberman 1:04:57 But then how do people ever keep weight off?

Dr. Zachary Knight 1:04:59 Well, so part of the answer is they don't. (laughs) I mean, so, so there's, so-

Andrew Huberman 1:05:03 Really?

Dr. Zachary Knight 1:05:04 ... there's, so, so...

Andrew Huberman 1:05:05 Because I, I, I would argue, like I have these friends who were very heavy. Most of the excess weight was body, body fat for a long time. They seem to be doing great-

Dr. Zachary Knight 1:05:13 Yeah.

Andrew Huberman 1:05:14 ... uh, eating the way that I described before. By the way, I'm not a proponent of any one particular diet. I have vegan friends, carnivore friends, et cetera. But that, but that pattern of eating I described before has been e- enormously successful for them. I haven't run a, uh, you know, a randomized control trial. That's not my job to do that in the realm of nutrition, but they're doing great. They claim to be sated.

Dr. Zachary Knight 1:05:32 Yeah.

Andrew Huberman 1:05:32 They are so happy with the way things are going, and, um-

Dr. Zachary Knight 1:05:38 Uh-

Andrew Huberman 1:05:38 ... I, I don't hear that they're constantly hungry. I hear that they're constantly sated.

Dr. Zachary Knight 1:05:41 Well, so I would say that, that, you know, there have been efforts for a long time to develop diets that would help people consistently lose weight, and it has been very unsuccessful. Um, 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, what about them is different that makes them successful.

Andrew Huberman 1:06:04 Some also quit drinking alcohol.

Dr. Zachary Knight 1:06:06 Yeah. So there's other things.

Andrew Huberman 1:06:06 Right.

Dr. Zachary Knight 1:06:07 So, you know, I think-

Andrew Huberman 1:06:07 So behavioral regulation is better when you're-

Dr. Zachary Knight 1:06:10 If you-

Andrew Huberman 1:06:10 ... sober as opposed to-

Dr. Zachary Knight 1:06:11 Yeah.

Andrew Huberman 1:06:11 ... inebriated.

Dr. Zachary Knight 1:06:11 You can change your environment.

Andrew Huberman 1:06:12 Yeah, yeah.

Dr. Zachary Knight 1:06:12 But, you know, so what this is sort of getting at is what is the counterregulatory response to weight loss? And so this has been studied. Um, it was first studied, um, uh, in the context of energy expenditure, and, um, 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 if they're free living humans and they have to fill out a questionnaire. But, um, and the idea is that, um, for every, uh, kilogram of weight you lose, so it's about-... 2.2 pounds, I think, um, your energy expenditure decreases by about 30 kilocalories a day. Now, so not a ton, but that is significant, right? 30 calories. And then if you lose, as you said, 10 pounds, then that's 150 calories and that adds up over time. 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. Um, take people who lost like 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. Compare their energy expenditure. The energy expenditure in the, in the people that lost all the weight is about 25% lower than the people who never were obese. And so th- those people who lost the weight, we call them the reduced obese, or that's what they were called in th- in those studies. And the idea is that, that there's this, now this chronic deficit. They have to eat 25% less than someone who looks the same as them, is the same height as them, the same weight as them, in order to maintain that body weight. 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. Um, but there have been studies looking at it at least a year, and it doesn't seem to come back within a year, that difference in energy expenditure. Now our question is, is that really the big effect? Is that why it's so hard to lose weight, energy expenditure, or is it because you're hungrier? And that's actually much harder to measure. Um, but there's r- another really nice study, again by Kevin Hall, investigating this. Um, he used a really clever approach, this drug. So basically what he wanted to do was, is, um, he reasoned that, um, you can measure people's body weight and you can measure people's energy expenditure. 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. Um, so let's see what happens when you have people lose weight. How does their food intake change? 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 always, they're, they're thinking about the fact that they're doing this. 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. So they gave them these, uh, drugs, these SGLT2 inhibitors, and it's a pill you can take. They're used for diabetes. They block this, this, this protein, SGLT2, in the kidney that is necessary for glucose to be reabsorbed into the blood. And so basically what happens is you pee out about, like, 90 grams of glucose a day, but you don't know that you're doing that, and that causes you to lose energy, and so these people would lose some weight and then measure how their food intake changes. And what that showed is that for every two pounds or so of weight you lose, your h- hunger goes up by 100 calories per day. So basically you've got a 30 kilocalorie decrease in that energy expenditure, 100 kilocalorie decrease in appetite for every two pounds you lose, on average. Some people will be exceptions, right? They won't experience that at all for aspects of their physiology we don't understand. Um, and so the increased hunger seems to be the main reason people find it so difficult to keep weight off.

Andrew Huberman 1:09:50 That seems the perfect segue to talk about GLP-1, glucagon-like peptide-1, Ozempic, Mounjaro, and similar drugs. Um, my understanding of the back history on these is that a biologist obsessed with Gila monsters-

Dr. Zachary Knight 1:10:06 (laughs)

Andrew Huberman 1:10:07 ... uh, a reptile that doesn't need to eat very often discovered a peptide within their bloodstream called extendin-

Dr. Zachary Knight 1:10:15 Yeah.

Andrew Huberman 1:10:16 ... that, um, allowed them to eat very seldom. It curbed appetite in the Gila monster, of all things, and it has a analog homolog. You know, we don't know, uh, I don't know the sequence homology exactly, but a s- there's a similar peptide made in mice and in humans that suppresses appetite. Um, if you would, could you tell us about what is known about how GLP-1 works to suppress appetite, where in the body and/or brain?

Dr. Zachary Knight 1:10:45 Sure.

Andrew Huberman 1:10:46 And, uh, your sort of read of, um, these drugs and what's happening there, um, good, bad, exciting-

Dr. Zachary Knight 1:10:55 Sure.

Andrew Huberman 1:10:55 ... ugly.

Dr. Zachary Knight 1:10:56 Sure. I'd be happy to.

Andrew Huberman 1:10:57 Um, and anything else.

Dr. Zachary Knight 1:10:58 So, um, the story of GLP-1, so the Gila monster's an important turn, and I'll talk about that. It actually goes back before that quite a ways. So, so I should take a step back and say, you know, these were developed as drugs for diabetes, right? And so, 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, is not effective. And so back in, in sort of the 1920s, right around the time insulin was discovered, um, there was this phenomenon discovered known as the incretin effect. Um, and, uh, what it was-

Andrew Huberman 1:11:29 In cretin?

Dr. Zachary Knight 1:11:30 Incretin, yeah.

Andrew Huberman 1:11:31 Not the cretin effect.

Dr. Zachary Knight 1:11:31 Not the cretin effect.

Andrew Huberman 1:11:32 We can observe the cretin effect in numerous places-

Dr. Zachary Knight 1:11:35 (laughs)

Andrew Huberman 1:11:35 ... in daily life and online. Just kidding.

Dr. Zachary Knight 1:11:37 So it's-

Andrew Huberman 1:11:37 Yeah.

Dr. Zachary Knight 1:11:37 It's called the incretin effect. You can think of it as increase insulin because that's what the effect is.

Andrew Huberman 1:11:42 Mm-hmm.

Dr. Zachary Knight 1:11:43 Um, and the idea was that if you take glucose by mouth, if you consume glucose orally, um, 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, suggesting something about the process of ingesting, uh, the glucose causes more insulin to be released and causes you to, to lower your body sugar more accurately and more, more, more strongly.

Andrew Huberman 1:12:08 Interesting.

Dr. Zachary Knight 1:12:09 Um, which is a little bit counterintuitive because in the pancreas, right, so insulin is released from the pancreas, from the beta cell. The pancreas senses the glu- glucose concentration in the blood directly, and so it suggests that, that insulin is being released not just in response to changes in blood glucose but in response to a second factor, and so they call that an incretin. And through various experiments, it was, it was, uh, 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-... uh, sugar goes through your intestine, that boosts this insulin response to glucose in the blood. And people immediately realized this could potentially be very valuable. And the reason is that, you know, you can treat diabetes with insulin injections, but insulin is dangerous, right? Because if you inject too much insulin, you can kill yourself by making yourself hypoglycemic, right? So this, there's, you have to be very careful. But the thing about in- 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. So it's sort of an amplifier on the natural insul- insulin release. So basically, in the years that followed, whenever someone would find a new hormone, they would test it. Is it this incretin? And there was lots of failures. They weren't the incretin. Um, but then so there's this other hormone that comes from, from the, the, um, pancreas called glucagon, all right? And so glucagon, which was also discovered in the 1920s, glucagon is kind of the anti-insulin. So, um, when blood sugar goes low, glucagon is released in order to cause your liver to release glucose into the blood. So glucose, glucagon and insulin are these two opposing hormones. Glucagon was known for a long time, but, but, but people discovered sort of in the 1980s that the glucagon gene is expressed in other tissues