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

1. 0:00 – 2:38

   Dr. Zachary Knight

   1. AHAndrew Huberman0:00

      (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.

2. 2:38 – 7:07

   Sponsors: BetterHelp, Helix Sleep & Waking Up

   1. AHAndrew Huberman2:38

      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. 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. 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. 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. With BetterHelp, they make it very easy to find the therapist with whom you can have those three essential and highly effective components. If you'd like to try BetterHelp, you can go to betterhelp.com/huberman to get 10% off your first month. Again, that's betterhelp.com/huberman. Today's episode is also brought to us by Eight Sleep. Eight Sleep makes smart mattress covers with cooling, heating, and sleep tracking capacity. 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. One of the best ways to ensure a great night's sleep is to control the temperature of your sleeping environment, 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. And in order to wake up feeling refreshed and energized, your body temperature actually has to increase by about one to three degrees. 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. 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. Eight Sleep recently launched their newest generation pod cover, the 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. 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. Eight Sleep currently ships to the USA, Canada, UK, select countries in the EU, and Australia. Again, that's eightsleep.com/huberman. Today's episode is also brought to us by Waking Up. Waking Up is a meditation app that offers hundreds of guided meditation programs, mindfulness trainings, yoga nidra sessions, and more.I started practicing meditation when I was about 15 years old, and it made a profound impact on my life. 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

3. 7:07 – 11:28

   Hunger & Timescales

   1. AHAndrew Huberman7:07

      Knight. Dr. Zachary Knight, welcome.

   2. ZKDr. Zachary Knight7:09

      Great to be here.

   3. AHAndrew Huberman7:11

      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.

   4. ZKDr. Zachary Knight7:46

      Right.

   5. AHAndrew Huberman7:47

      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?

   6. ZKDr. Zachary Knight8:11

      Okay. There's a lot in that that I'll try to unpack. (laughs)

   7. AHAndrew Huberman8:13

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

   8. ZKDr. Zachary Knight8:18

      Yeah.

   9. AHAndrew Huberman8:18

      ... how do you think about this thing that we call hunger and feeding?

   10. ZKDr. Zachary Knight8:20

       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)

   11. AHAndrew Huberman9:40

       (laughs) A very informative experiment.

   12. ZKDr. Zachary Knight9:42

       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-

   13. AHAndrew Huberman11:08

       Mm-hmm.

   14. ZKDr. Zachary Knight11:09

       ... 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.

   15. AHAndrew Huberman11:27

       Mm-hmm.

4. 11:28 – 17:51

   Body Fat, Leptin, Hunger

   1. AHAndrew Huberman11:28

   2. ZKDr. Zachary Knight11:28

      But...

   3. AHAndrew Huberman11:29

      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.

   4. ZKDr. Zachary Knight12:10

      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.

   5. AHAndrew Huberman17:32

      Less spontaneous movement.

   6. ZKDr. Zachary Knight17:34

      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.

   7. AHAndrew Huberman17:50

      Fascinating.

5. 17:51 – 20:52

   Leptin Resistance & Obesity

   1. AHAndrew Huberman17:51

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

   2. ZKDr. Zachary Knight17:59

      Yes.

   3. AHAndrew Huberman17:59

      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.

   4. ZKDr. Zachary Knight18:16

      Yes.

   5. AHAndrew Huberman18:16

      What happened with that? Do we know why it did not work?

   6. ZKDr. Zachary Knight18:19

      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-

   7. AHAndrew Huberman18:35

      Nowadays it would be, it would be, um, a drop in the ocean compared to what companies will invest-

   8. ZKDr. Zachary Knight18:40

      Exactly.

   9. AHAndrew Huberman18:40

      ... into potential diet drugs.

   10. ZKDr. Zachary Knight18:41

       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.

6. 20:52 – 30:26

   Hunger, Food Foraging & Feeding Behaviors, AgRP Neurons

   1. AHAndrew Huberman20:52

      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-

   2. ZKDr. Zachary Knight21:23

      Yeah.

   3. AHAndrew Huberman21:23

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

   4. ZKDr. Zachary Knight21:29

      Sure.

   5. AHAndrew Huberman21:30

      ... consume a meal-

   6. ZKDr. Zachary Knight21:30

      Sure.

   7. AHAndrew Huberman21:30

      ... and decide enough?

   8. ZKDr. Zachary Knight21:32

      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-

   9. AHAndrew Huberman22:39

      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?

   10. ZKDr. Zachary Knight23:01

       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.

   11. AHAndrew Huberman23:37

       Mm-hmm.

   12. ZKDr. Zachary Knight23:38

       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.

   13. AHAndrew Huberman28:15

       Is it satiation or it's, um, ceasing of foraging so that-

   14. ZKDr. Zachary Knight28:19

       Yeah.

   15. AHAndrew Huberman28:20

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

   16. ZKDr. Zachary Knight28:26

       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.

7. 30:26 – 32:15

   Sponsor: AG1

   1. ZKDr. Zachary Knight30:26

   2. AHAndrew Huberman30:26

      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.

8. 32:15 – 39:54

   Body Weight & Obesity, Genes & POMC Neurons

   1. AHAndrew Huberman32:15

      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.

   2. ZKDr. Zachary Knight32:40

      Yes.

   3. AHAndrew Huberman32:41

      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-

   4. ZKDr. Zachary Knight32:53

      (laughs)

   5. AHAndrew Huberman32:53

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

   6. ZKDr. Zachary Knight32:59

      Yes.

   7. AHAndrew Huberman33:00

      Had I not known that there was more food coming, I think-

   8. ZKDr. Zachary Knight33:02

      Yes.

   9. AHAndrew Huberman33:02

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

   10. ZKDr. Zachary Knight33:08

       Correct.

   11. AHAndrew Huberman33:08

       ... at the moment. You're sort of, um, integrating based on new information.

   12. ZKDr. Zachary Knight33:12

       Exactly.

   13. AHAndrew Huberman33:13

       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.

   14. ZKDr. Zachary Knight33:38

       Huh.

   15. AHAndrew Huberman33:38

       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-

   16. ZKDr. Zachary Knight33:52

       Interesting.

   17. AHAndrew Huberman33:52

       ... 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-

   18. ZKDr. Zachary Knight34:03

       Right.

   19. AHAndrew Huberman34:04

       ... uh, you know, with a v- in a very small margin of error.

   20. ZKDr. Zachary Knight34:07

       Okay.

   21. AHAndrew Huberman34:07

       Um, so, and, and that drives, in, in that condition, obviously, a food avoidance.

   22. ZKDr. Zachary Knight34:13

       Yeah.

   23. AHAndrew Huberman34:14

       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-

   24. ZKDr. Zachary Knight34:28

       Yes.

   25. AHAndrew Huberman34:28

       ... 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.

   26. ZKDr. Zachary Knight34:53

       Mm-hmm.

   27. AHAndrew Huberman34:54

       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-

   28. ZKDr. Zachary Knight35:15

       Yeah.

   29. AHAndrew Huberman35:15

       ... that is driving fairly nuanced behavioral decisions and updating that-

   30. ZKDr. Zachary Knight35:20

       Yeah.
9. 39:54 – 46:05

   Obesity, Genetics & Environmental Factors

   1. ZKDr. Zachary Knight39:54

   2. AHAndrew Huberman39:54

      Wow.

   3. ZKDr. Zachary Knight39:54

      Um, so-

   4. AHAndrew Huberman39:55

      I d- I don't think most people appreciate that.

   5. ZKDr. Zachary Knight39:57

      Yeah. It's-

   6. AHAndrew Huberman39:57

      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-

   7. ZKDr. Zachary Knight40:08

      Yeah.

   8. AHAndrew Huberman40:08

      ... 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?

   9. ZKDr. Zachary Knight40:31

      Yeah.

   10. AHAndrew Huberman40:31

       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-

   11. ZKDr. Zachary Knight40:39

       Yeah.

   12. AHAndrew Huberman40:39

       ... 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."

   13. ZKDr. Zachary Knight40:47

       Yeah.

   14. AHAndrew Huberman40:47

       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-

   15. ZKDr. Zachary Knight40:55

       Yeah.

   16. AHAndrew Huberman40:55

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

   17. ZKDr. Zachary Knight41:02

       Yeah.

   18. AHAndrew Huberman41:03

       ... for instance.

   19. ZKDr. Zachary Knight41:04

       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-

   20. AHAndrew Huberman41:28

       Is that when, that's when it started, mid '70s?

   21. ZKDr. Zachary Knight41:30

       Sort of the 1970s is around when a lot of that started to happen.

   22. AHAndrew Huberman41:33

       Snack food, snacking. (laughs)

   23. ZKDr. Zachary Knight41:33

       So there's lots of ex-

   24. AHAndrew Huberman41:34

       Snacking.

   25. ZKDr. Zachary Knight41:34

       ... there's lot of explanations.

   26. AHAndrew Huberman41:35

       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-

   27. ZKDr. Zachary Knight41:43

       Yeah.

   28. AHAndrew Huberman41:43

       ... are the... I have a list of the theories-

   29. ZKDr. Zachary Knight41:45

       (laughs)

   30. AHAndrew Huberman41:46

       ... 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.
10. 46:05 – 49:32

    Whole Foods, Ultra-Processed Foods & Palatability

    1. AHAndrew Huberman46:05

       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-

    2. ZKDr. Zachary Knight46:20

       Yeah.

    3. AHAndrew Huberman46:20

       ... is fairly low, right?

    4. ZKDr. Zachary Knight46:22

       Yeah.

    5. AHAndrew Huberman46:22

       Getting high quality nutritious food that tastes great is expensive-

    6. ZKDr. Zachary Knight46:27

       Yeah.

    7. AHAndrew Huberman46:27

       ... I would argue, but getting calories is fairly inexpensive.

    8. ZKDr. Zachary Knight46:32

       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.

    9. AHAndrew Huberman47:46

       What's an example of an ultra-processed dish? Like a out-of-package macaroni and cheese-

    10. ZKDr. Zachary Knight47:50

        Exactly. That kind of stuff.

    11. AHAndrew Huberman47:51

        ... with, with bacon kind of thing?

    12. ZKDr. Zachary Knight47:52

        Exactly.

    13. AHAndrew Huberman47:53

        Versus, um, some pasta sitting next to a vegetable and some-

    14. ZKDr. Zachary Knight47:56

        Exactly.

    15. AHAndrew Huberman47:56

        ... a nice piece of-

    16. ZKDr. Zachary Knight47:58

        Piece of-

    17. AHAndrew Huberman47:58

        ... salmon or something?

    18. ZKDr. Zachary Knight47:58

        Exactly.

    19. AHAndrew Huberman47:59

        Okay.

    20. ZKDr. Zachary Knight47:59

        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.

    21. AHAndrew Huberman48:44

        Mm-hmm.

    22. ZKDr. Zachary Knight48:44

        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.

11. 49:32 – 58:55

    Increasing Whole Food Consumption, Sensory Specific Satiety & Learning

    1. ZKDr. Zachary Knight49:32

    2. AHAndrew Huberman49:32

       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.

    3. ZKDr. Zachary Knight50:03

       Yes.

    4. AHAndrew Huberman50:03

       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.

    5. ZKDr. Zachary Knight50:20

       Yeah.

    6. AHAndrew Huberman50:20

       Right? I do believe in calories in, calories out.

    7. ZKDr. Zachary Knight50:23

       Yes.

    8. AHAndrew Huberman50:23

       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.

    9. ZKDr. Zachary Knight50:44

       Yes.

    10. AHAndrew Huberman50:44

        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.

    11. ZKDr. Zachary Knight51:00

        Mm-hmm.

    12. AHAndrew Huberman51:01

        A bowl of rice is mostly carbohydrate, has some protein.

    13. ZKDr. Zachary Knight51:04

        Yeah.

    14. AHAndrew Huberman51:05

        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.

    15. ZKDr. Zachary Knight51:23

        Mm-hmm.

    16. AHAndrew Huberman51:24

        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.

    17. ZKDr. Zachary Knight52:10

        Mm-hmm.

    18. AHAndrew Huberman52:11

        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?

    19. ZKDr. Zachary Knight52:29

        Yes.

    20. AHAndrew Huberman52:29

        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"-

    21. ZKDr. Zachary Knight52:43

        Mm-hmm.

    22. AHAndrew Huberman52:43

        ... 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-

    23. ZKDr. Zachary Knight53:03

        Yeah.

    24. AHAndrew Huberman53:03

        ... 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-

    25. ZKDr. Zachary Knight53:34

        Yeah.

    26. AHAndrew Huberman53:34

        ... 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-

    27. ZKDr. Zachary Knight53:51

        Yeah.

    28. AHAndrew Huberman53:51

        ... in this case us, humans, that highly processed foods bypass.

    29. ZKDr. Zachary Knight53:56

        Yeah.

    30. AHAndrew Huberman53:56

        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-
12. 58:55 – 1:02:23

    Calories vs. Macronutrients, Protein & Salt

    1. AHAndrew Huberman58:55

       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?

    2. ZKDr. Zachary Knight59:22

       Yeah.

    3. AHAndrew Huberman59:22

       Right?

    4. ZKDr. Zachary Knight59:22

       Yeah.

    5. AHAndrew Huberman59:22

       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-

    6. ZKDr. Zachary Knight1:00:04

       Yeah.

    7. AHAndrew Huberman1:00:04

       ... um, rather than to, uh, you know, taste savory or taste, um-

    8. ZKDr. Zachary Knight1:00:10

       Absolutely.

    9. AHAndrew Huberman1:00:11

       ... you know? Yeah.

    10. ZKDr. Zachary Knight1:00:11

        Absolutely, absolutely. Those are just, those, those thing, those sensory cues are just markers that tell the brain what might be in that substance.

    11. AHAndrew Huberman1:00:17

        Mm-hmm.

    12. ZKDr. Zachary Knight1:00:18

        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.

    13. AHAndrew Huberman1:00:41

        Really?

    14. ZKDr. Zachary Knight1:00:42

        Yeah.

    15. AHAndrew Huberman1:00:42

        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?

    16. ZKDr. Zachary Knight1:00:59

        At the level of these AgRP neurons, it is. So we-

    17. AHAndrew Huberman1:01:02

        So they don't care about-

    18. ZKDr. Zachary Knight1:01:03

        They don't care about the macro-

    19. AHAndrew Huberman1:01:04

        ... the macronutrient.

    20. ZKDr. Zachary Knight1:01:04

        No. They're really concerned about-

    21. AHAndrew Huberman1:01:05

        Okay. So I'm probably wrong (overlapping)

    22. ZKDr. Zachary Knight1:01:06

        They're really concerned about energy.

    23. AHAndrew Huberman1:01:08

        Uh-huh.

    24. ZKDr. Zachary Knight1:01:08

        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.

13. 1:02:23 – 1:03:58

    Sponsor: LMNT

    1. AHAndrew Huberman1:02:23

       I'd like to take a brief break and acknowledge one of our sponsors, LMNT. LMNT is an electrolyte drink that has everything you need. That means the electrolytes sodium, magnesium, and potassium in the correct amounts and ratios and nothing you don't, which means no sugar. Now, I and others on this podcast have talked about the critical importance of hydration for proper brain and body functioning. Even a slight degree of dehydration can diminish cognitive and physical performance. It's also important that you get adequate electrolytes. The electrolytes, sodium, magnesium, and potassium, are critical for the functioning of all the cells in your body, especially your neurons, your nerve cells. Drinking LMNT dissolved in water makes it very easy to ensure that you're getting adequate hydration and adequate electrolytes. 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. 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. They have a bunch of different great tasting flavors of LMNT. My favorite is the watermelon, although I confess I also like the raspberry and the citrus. Basically, I like all the flavors. And LMNT has also just released a new line of canned sparkling 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. 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. Again, that's DrinkLMNT.com/huberman to claim a free sample

14. 1:03:58 – 1:09:50

    Challenges of Weight Loss: Hunger & Energy Expenditure

    1. AHAndrew Huberman1:03:58

       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"?

    2. ZKDr. Zachary Knight1:04:42

       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.

    3. AHAndrew Huberman1:04:57

       But then how do people ever keep weight off?

    4. ZKDr. Zachary Knight1:04:59

       Well, so part of the answer is they don't. (laughs) I mean, so, so there's, so-

    5. AHAndrew Huberman1:05:03

       Really?

    6. ZKDr. Zachary Knight1:05:04

       ... there's, so, so...

    7. AHAndrew Huberman1:05:05

       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-

    8. ZKDr. Zachary Knight1:05:13

       Yeah.

    9. AHAndrew Huberman1:05:14

       ... 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.

    10. ZKDr. Zachary Knight1:05:32

        Yeah.

    11. AHAndrew Huberman1:05:32

        They are so happy with the way things are going, and, um-

    12. ZKDr. Zachary Knight1:05:38

        Uh-

    13. AHAndrew Huberman1:05:38

        ... I, I don't hear that they're constantly hungry. I hear that they're constantly sated.

    14. ZKDr. Zachary Knight1:05:41

        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.

    15. AHAndrew Huberman1:06:04

        Some also quit drinking alcohol.

    16. ZKDr. Zachary Knight1:06:06

        Yeah. So there's other things.

    17. AHAndrew Huberman1:06:06

        Right.

    18. ZKDr. Zachary Knight1:06:07

        So, you know, I think-

    19. AHAndrew Huberman1:06:07

        So behavioral regulation is better when you're-

    20. ZKDr. Zachary Knight1:06:10

        If you-

    21. AHAndrew Huberman1:06:10

        ... sober as opposed to-

    22. ZKDr. Zachary Knight1:06:11

        Yeah.

    23. AHAndrew Huberman1:06:11

        ... inebriated.

    24. ZKDr. Zachary Knight1:06:11

        You can change your environment.

    25. AHAndrew Huberman1:06:12

        Yeah, yeah.

    26. ZKDr. Zachary Knight1:06:12

        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.

15. 1:09:50 – 1:19:03

    GLP-1 Drug Development, Semaglutide, Ozempic, Wegovy

    1. ZKDr. Zachary Knight1:09:50

    2. AHAndrew Huberman1:09:50

       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-

    3. ZKDr. Zachary Knight1:10:06

       (laughs)

    4. AHAndrew Huberman1:10:07

       ... uh, a reptile that doesn't need to eat very often discovered a peptide within their bloodstream called extendin-

    5. ZKDr. Zachary Knight1:10:15

       Yeah.

    6. AHAndrew Huberman1:10:16

       ... 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?

    7. ZKDr. Zachary Knight1:10:45

       Sure.

    8. AHAndrew Huberman1:10:46

       And, uh, your sort of read of, um, these drugs and what's happening there, um, good, bad, exciting-

    9. ZKDr. Zachary Knight1:10:55

       Sure.

    10. AHAndrew Huberman1:10:55

        ... ugly.

    11. ZKDr. Zachary Knight1:10:56

        Sure. I'd be happy to.

    12. AHAndrew Huberman1:10:57

        Um, and anything else.

    13. ZKDr. Zachary Knight1:10:58

        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-

    14. AHAndrew Huberman1:11:29

        In cretin?

    15. ZKDr. Zachary Knight1:11:30

        Incretin, yeah.

    16. AHAndrew Huberman1:11:31

        Not the cretin effect.

    17. ZKDr. Zachary Knight1:11:31

        Not the cretin effect.

    18. AHAndrew Huberman1:11:32

        We can observe the cretin effect in numerous places-

    19. ZKDr. Zachary Knight1:11:35

        (laughs)

    20. AHAndrew Huberman1:11:35

        ... in daily life and online. Just kidding.

    21. ZKDr. Zachary Knight1:11:37

        So it's-

    22. AHAndrew Huberman1:11:37

        Yeah.

    23. ZKDr. Zachary Knight1:11:37

        It's called the incretin effect. You can think of it as increase insulin because that's what the effect is.

    24. AHAndrew Huberman1:11:42

        Mm-hmm.

    25. ZKDr. Zachary Knight1:11:43

        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.

    26. AHAndrew Huberman1:12:08

        Interesting.

    27. ZKDr. Zachary Knight1:12:09

        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 other than the pancreas, and it's differentially processed. The protein is differentially processed to produce different hormones, hormones other than glucagon. 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. It's cut up slightly differently. And this hormone was an incretin. So basically, if you, uh, put it on beta cells, um, you get this increased response of insulin in response to glucose. And so there was the idea, okay, this could be a great diabetes drug, right? And there, there I should say, there was one other incretin that's, that's been found is, it's called GIP, G-I-P. And that will be important to talking about some of these other drugs. Also a h- hormone that comes from the intestine. And so, um, the challenge with making GLP-1 into a drug is that it has an extremely short half-life. So it has a half-life of about two minutes in the blood. Um, and so even if you inject people with GLP-1, it won't really be useful for anything. You don't decrease appetite, you don't affect blood sugar 'cause it's just degraded too fast. And the reason it's degraded is because there's an enzyme, DPP-4 is what it's called, that degrades 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, uh, uh, uh, gl- diabetes drugs. They're called gliptins. You've probably heard about them. Januvia is the most common one. And those boost the level of GLP-1, the natural GLP-1 in the, in the, in produced from the intestine by about threefold. And they're effective in treating diabetes. As a matter of fact- Do people lose weight? People do not lose weight. Interesting. And, and that's one of the key reasons that we know- Mm-hmm. ... 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. Millions of people have taken them. They do not lose weight. That's a great question. So but, you know, a threefold is great, but like, you'd like to increase it even more, right? And to do that, you can't block this enzyme. You have to actually produce a GLP-1 that, uh, uh, is more stable in the blood. And that's where this, this lizard that you're talk- you mentioned comes into play (laughs) . It produces a stabilized form of GLP-1 in its venom. No one knows why. One hypothesis is that it's something to do with the lizard, uh, as you said, basically having this long time period between meals and it needs to regulate its blood glucose. Who knows if that is true? But it turned out to be fortuitous because then this GLP-1 from this lizard, it has a half-life of like two hours. And so the first GLP-1 drug that was approved was just this molecule from this lizard, basically. And it, um, it's called exenatide, and it was approved in 2005 for d- works well for diabetes, um, has a half-life of two hours. Uh, you inject it and, um, uh, doesn't cause a ton of weight loss. But two hours is good, but it's not so great. So then pharmaceutical industry tri- said, "Can we, you know, basically improve this even further?" And so they start engineering this hormone, making mutations, attaching lipid tails to make it bind to s- proteins in the blood that would stabilize it. Chemistry jockey stuff. Yeah, exactly. Yeah. And I think the next big advance was this compound liraglutide. Mm-hmm. Um, and liraglutide was approved for diabetes in 2010 and for, and then for weight loss in 2014. And so liraglutide has a half-life of about 13 hours in the blood. So now you're getting up to something serious. We've gone from two minutes, two hours, 13 hours, and you get better effects on di- on, on aspects of blood glucose and diabetes control, and they started to see that some people were losing weight. Very variable responses. Not everyone loses weight on liraglutide. And one of the things they noticed that I think is just, is fascinating just sort of example of how drug discovery works in the real world, um, you know, 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, and it's a known side effect of these GLP-1 drugs. It causes nausea and sort of this gastrointestinal distress. But they noticed that over time, the nausea would just sort of go away. And so they would start dose escalating, sort of raising the, the dose that the person would take. So you would go, you know, 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. And then once you got up to the highest doses, then people really started losing weight. And so there's a couple things there. Pharmaceutical industry realized, "Wow, these are potentially really effective weight loss drugs, and also this nausea, which we thought was, was, you know, a killer, people are able to just get used to it and then it just goes away." It undergoes the, the worst tachyphylaxis. So is, the idea is that the receptor, uh, that's affecting the, the, the, in the gut that's effe- causing th- these effects, it undergoes some sort of down regulation w- with chronic, chronic exposure. So liraglutide, you know, was, it's been around, you know, it's been on the market for 14 years now. Um, was used, but still you're only getting sort of like 7 to 10% weight loss, which is good, but not like, you know, amazing. Impressive. Um, but then semaglutide came along, um, and that, that was approved for diabetes in 2017. And semaglutide is Ozempic, uh, or also m- als- also, uh, marketed as, uh, Wegovy for weight loss.... and semaglutide now has a half-life of seven days. So now we've gone from two ho- two minutes, two hours, 13 hours, seven days. And you can really jack up the concentration with a seven-day, uh, uh, uh, half-life. And then they saw people started really losing weight. And so, in some of those trials, people lost, you know, 16% of their body weight, which previously had been unattainable, right?

Episode duration: 2:18:56