Philip Pape: 0:01

Maybe you're putting in the work, tracking your meals, training four days a week, eating more whole foods but no matter what you do, the body fat isn't coming off. It's frustrating and you can't help but wonder is it all my fault? Am I not working hard enough? Is there something more at play? You might be tempted to blame your lack of discipline, but what if I told you the real culprit is hiding in your jeans, pulling strings in your brain that make fat loss feel like an uphill battle. Today we're getting into the cutting edge neuroscience of body fatness, with a leading obesity researcher who spent over a decade studying why some of us struggle more than others to maintain a healthy weight and body composition. You'll discover why willpower alone often isn't enough, how your brain's reward system might be sabotaging your efforts and, most importantly, what you can actually do about it if you have health and physique goals. Get ready to learn why your genetics play a bigger role than you thought and how to work with your biology, not against it, to finally achieve the results you've been after. To finally achieve the results you've been after.

Philip Pape: 1:11

Welcome to Wits and Weights, the podcast that blends evidence and engineering to help you build smart, efficient systems to achieve your dream physique. I'm your host, philip Pape, and today we're bridging the fascinating worlds of neuroscience and body composition with Dr Stephan Guyenet. Now, stephan is a neuroscientist and obesity researcher. He's also a proficient science communicator who has spent well over a decade studying the connections between our brains and our waistlines. He has a PhD in neuroscience and his work has been cited, let's just say, thousands of times. Dr Guyenet is also the author of the Hungry Brain and the founder of Red Pen Reviews, which scores nutrition and health books based on their scientific accuracy. Today, you'll learn how our genes and brain pathways influence our weight and body fat levels and what strategies we can use to manage them, despite our genetic predispositions. We'll also explore where muscle mass fits into all of this and address other theories of obesity and body fatness you may have heard about Stefan.

Philip Pape: 2:05

Welcome to the show. Thanks for having me, philip. So I want to start with a thought experiment, because you've probably been asked every question I could have thought of here with the circuit that you're on with podcasts. But imagine we have two people that are, let's say, 20 years old and they have just about everything is the same gender, weight, height, muscle mass, even their environment and you fast forward 30 years or 50 years old, and one has significantly more body fat than the other. Where would you start to speculate as to the primary cause or causes that got them to that point?

Dr. Stephan Guyenet: 2:37

So you're describing two people who have very similar, if not identical, environment, right? Yes, am I getting okay? Okay, so if you're holding environment relatively constant, then the thing that's really going to be determining differences in body fatness is genetics. So, really, what we are is a gene by environment interaction. So either it's genes are differing to cause us to be different or environment is differing, and if you're holding environment constant, then it's going to be genes, and so what I would expect is that those two people differ in the genetics that predispose them to gain body fat and that those genetics are primarily expressed in how their brains developed and operate. So, primarily, genetics related to brain function, and the brain functions that are impacted are primarily, but not exclusively, brain functions related to eating behavior that result in differences in calorie intake, particularly relative to calorie needs.

Philip Pape: 3:41

Okay, yeah, perfect. So you set it up nicely. There was no surprise there, fortunately, that we're talking about genetics being a determinant and we'll get into why that matters and what people can do about it. But you mentioned when the brain develops, how early in one's life, maybe to the embryo phase and maybe like it's just predetermined, so to speak. Does that matter and is it influenced? And maybe environment comes into play there with epigenetics. But you help us understand when you say develops. What are the key factors there?

Dr. Stephan Guyenet: 4:12

Yeah. So I will start off by saying that there is a lot left to learn about how genetics impacts brain activity in a way that determines differences in body fatness. So we've identified a lot of the genetic locations that differ between people who are leaner and people who are fatter and we've been able to trace most of those differences, to necessarily trace those differences in brain activity back to exactly you know how those are causing people to become fatter. So in many cases the genes that are causing differences in body fatness are like some neurotransmitter, that is, you know some neurotransmitter receptor that's expressed in many parts of the brain and it's not really clear exactly what it's doing to make people fatter or leaner, probably having you know a thousand different effects on the brain, and the net result of all that is somebody's slightly you know slightly more likely to put the fork to their mouth again at a meal. And you know most of these genetic differences are only having very small effects on body fatness individually. It's only when you aggregate them, aggregate probably thousands of different genetic differences that it results in differences in body fatness.

Dr. Stephan Guyenet: 5:34

But let me try to answer your question in a different way. So I'm getting that. What you're asking is something about like when do these things start to be expressed in the developmental cycle? Is that kind of what you're asking? Is something about like when did these things start to be expressed at in the developmental cycle? Is that? Is that kind of what you're asking?

Philip Pape: 5:49

Yeah, I'm so curious about all this stuff. It's not like we're going to design designer babies here or anything. People ultimately want to know what they can do about this. But yeah, I'm just understanding. Is it like when you're born and how you're born? Is it how you're raised? Do you have pets and you play outside? A lot of the things, like when we talk about gut health and epigenetics, for example. You almost change the genes trajectory as you grow up. That's what I was curious about.

Dr. Stephan Guyenet: 6:14

Yeah, I mean. So we don't have a complete picture, but we do know that there are some genes that will have a lifelong effect and there are some genes that seem to only cause differences in body fatness in adulthood or even in infancy, in specific parts of your life. So we know, for example, that there are mutations in melanocortin-4 receptor, which is part of the appetite and body fatness regulating system in the brain, that cause early onset obesity. So you can identify if you look specifically for children with unusual children who have an unusually large amount of body fat, and you screen them for this mutations, you're going to find that a pretty significant percentage of them have these melanocortin for receptor mutations.

Dr. Stephan Guyenet: 7:08

Yeah, those basically cut a line of communication between your body's energy status and your brain, so your brain can't really hear about all the energy that you have in your body and your brain tends to think you're starving all the time. So those people, throughout their entire lives, will have a higher level of body fatness. But there are other genes that will make a fat baby but not a fat adult. And then there are other genes that will make a fat adult but not a fat baby, and so there's really like almost everything you can imagine is present there in that picture of the relationship between genetics and body fatness.

Philip Pape: 7:45

Yeah, I think it's fascinating that we're even more unique than we think. Like we say, we're unique individuals, but when you combine the thousands or millions of interactions going on, it's incredible. So I guess I want to take a step back now before we go forward. And that is why do we have these conversations? Why do you go out and communicate about body fatness in general? Why do we care? You know, it might sound, might seem obvious, but like what's the big deal, and I know there's a lot of factors there, like obesity and whatnot. But kind of at the individual level, why do, why do we care about this?

Dr. Stephan Guyenet: 8:15

So wait, you're asking why do I personally care, or why should we all care?

Philip Pape: 8:19

Sure, why do you care? Why should we care? Why should an individual care?

Dr. Stephan Guyenet: 8:29

Well, for me, I care simply because, yeah, I mean it's a great question to ask me why I care, because I don't get paid for this. This has, you know, all the science communication I do has nothing. You know, very little money is flowing into my coffers from these activities. So I mean, I just think it's important for people to have accurate information from these activities. So I mean, I just think it's important for people to have accurate information, and I think that the diet, nutrition, health, weight loss space is one where there's a ton of misinformation. We've been documenting that thoroughly in our reviews at Red Pen Reviews and quantifying it, and what we can see is that the information that the nutrition information environment that the public is bathing in is low to moderate quality. So any particular claim that you hear in your nutrition information environment is likely to be a low to moderate quality claim. There's a lot of variability, so some of the information is excellent, some of it is absolute garbage and everything in between, but on average it's not very good, and so, for me, I just think people deserve to have accurate information and particularly working as a scientist and also a communicator a science communicator I see the gap between what's happening in the scientific community and what's happening in the scientific community and what's happening in the popular nutrition and health and weight loss sphere, and not to say that scientists always have the right answers. There's a lot of bad information in the scientific community too, but the information tends to be higher quality than what you see in the public sphere. And so, yeah, I just think it's important for people to have information that's as accurate as possible so they can make the best decisions they can make. So that's what motivates me to be in this space.

Dr. Stephan Guyenet: 10:16

As far as why anyone should care, I mean, I think body fatness is important, right, like that's an important variable that you can modify to achieve whatever your goals are for your own health and well-being in your life, and I would say it's one of the more important levers there is for modifying your health.

Dr. Stephan Guyenet: 10:38

And, furthermore, I think that it's interesting, right? We just like to learn about ourselves, and particularly, you know, the links between brain and body fatness. To me, that's very, very interesting because it links the brain, which is the organ, more than anything else, that makes us who we are, right, like, more than anything else about us, the brain is what makes us who we are, and it's a little bit counterintuitive, like most people don't intuitively understand that the brain has a lot to do with body fatness, even though the brain is what generates all of our behaviors, including our eating behavior. It's just like, for some reason, the you know two and two doesn't come together necessarily without a little bit of education. And yeah, I think it's just a really interesting connection. Yeah, I do as well. That's why I wanted to talk to you and yeah, I think it's just a really interesting connection.

Philip Pape: 11:26

Yeah, I do as well. That's why I wanted to talk to you and I love hearing the history behind this and how, even since you wrote your book the Hungry Brain, even some of your thoughts have evolved with, for example, the additive versus the constrained model and other things that interact with our metabolism and our energy system and the accurate information piece. I'm glad you started there, because I was technically just asking about body fat as a mechanism and what you pointed out is that let's even go at a higher level. Are we even trusting the right sources for information before we even go there? You said it's one of the most important levers there is for modifying your health. I totally agree. What I'm curious about now is where does it rank when compared to muscle mass? And maybe part of the answer is that they're actually kind of go hand in hand, Because when we talk about body fat, we're also talking about percentage of body fat in your body which is relative to muscle mass. So what are your thoughts on that?

Dr. Stephan Guyenet: 12:21

Yeah. So let me just start off by saying that I'm not as much of an expert on muscle mass, so just want to caveat with that. I think being physically fit is really important. I think definitely using your body and staying strong and fit is a very important determinant of physical function and health as we age physical function and health as we age.

Dr. Stephan Guyenet: 12:48

So my kind of high level concept of the problem with our health in the modern world. The main problem is that we are suffering from energy overload. So there's our cells and tissues are bathed in too much energy and essentially the way that happens is we eat too much. Our fat tissue can absorb the excess for a certain amount of time but, depending on your own genetic makeup, eventually your fat tissue runs out of room and it's no longer that's the professional energy storage site in your body right, the primary one and once that runs out of room, that energy spills over onto your other tissues that are not equipped to handle it and that's when you start getting things like insulin resistance, beta cell failure, all the other problems that arise as a result of energy excess and insulin dysregulation. So how do you get there? How do you get to an energy overload state.

Dr. Stephan Guyenet: 13:44

I just said one thing which I think is the most important thing, which is overconsumption of energy. But the other one is your muscles are not enough of an energy sink. So your muscles are the biggest energy sink in your body, right? So if you're doing physical activity, that's a huge amount of energy need that you're generating, that is pulling energy out of the circulation and reducing exposure to your other tissues, and so to a large extent, physical activity can mitigate that energy excess and even in the face of higher body fat, if you're highly physically active, you can mitigate that excess energy exposure. And in the face of excess energy intake you can mitigate that energy exposure. So it's kind of a way being physically active is a way of kind of cutting down on, or it's a way of like balancing that seesaw, right, balancing that energy exposure seesaw. And so to me really the not over consuming calories and the physical activity really go hand in hand and preventing modern non-communicable disease like diabetes, cardiovascular disease and all the things related to that.

Philip Pape: 15:02

The way you explain that with the spillover. It's probably the listeners haven't heard to explain that way. We talk about muscle as a sink for glucose and energy, but the visual you just gave us is like you know, you're over consuming, you're just going to increase your body fat. Worse than that, you're going to go past your capacity of your fat cells and start causing damage in other areas. But if you have more muscle mass or you have more activity, it mitigates that. I mean that is a nice visual.

Philip Pape: 15:29

I could see that on a nice PowerPoint slide really getting the message across as to why all of those things are important, despite the fact that there's some energy compensation and all these little things that happen when you move more. There's another phrase I've used Stevan energy flux, and I know certain circles use that to talk about moving more and eating more. But you're kind of doing them hand in hand, not to over-consume, but really to give yourself all the energy and nutrients and macros you need, plus mitigating it at the same time. So it's really a nice kind of way to get there. Let's go back to the brain pathways, because that's really your expertise, right?

Dr. Stephan Guyenet: 16:05

I just wanted to say that I think the physical activity is probably more important than the higher muscle mass per se, because if you have just genetically high muscle mass and you're not using it, that might protect you to some degree, but that muscle is not acting as a very powerful energy sink if you're not using it, because muscle actually has a pretty low resting metabolic rate.

Dr. Stephan Guyenet: 16:30

It's only when you're using it that it has a high metabolic rate, and you know. Another point I'll make along these lines is that people with obesity on average, have higher muscle mass than people who are lean. Yet that muscle mass is not, that excess muscle mass is not protecting them. So I mean, you know they're not necessarily like bodybuilders or anything, but they have more muscle mass. So I think what's most important is actually using your muscles rather than having high muscle mass, although you know, in terms of metabolic health, obviously there are benefits to having higher muscle mass in terms of being stronger and, you know, more physically capable, but just in terms of the metabolic benefits, I think it's more about using it than having it.

Philip Pape: 17:15

Yeah, fair point Using it, building it and also mitigating the loss of it as we age, which inevitably happens. So, yeah, great point, fully on board with you there. So, talking about the brain and the brain-related genes and pathways, we can get a little technical, but we don't want to have to go all the way. How are they associated with weight gain and body fatness? What are the ones we really care about? That's written into our genes.

Dr. Stephan Guyenet: 17:36

When we talk about our genes being to blame to some extent, so you're asking me to get into the kind of brain functions that are related to body fatness?

Philip Pape: 17:48

Yes, thank you for helping me clarify the way I ask questions. That's science communication 101. So thank you, Stephan.

Dr. Stephan Guyenet: 17:54

Yeah, so I mean this is essentially the thesis of my book, the Hungry Brain that we have these non-conscious brain circuits that evolved in an environment that's very different than the one that we're in today. They evolved to regulate things like appetite, things like cravings, which directs us towards certain types of nutrients or foods, and other things like satiety at a meal, how full we eat, based on how much food we eat, and then some other related functions and those brain regions just kind of operate. They're designed to operate kind of in the background. So you know, you don't have to think, oh, today at noon I want to start feeling hungry. You know that's not something you have to worry about consciously. It's this automated process in your brain that does all this processing measures, your body's energy status measures, takes cues from what's around in your environment and generates an appropriate response, in this case hunger. At least it would have been appropriate if we were living in the environment that it evolved for right, the environment that it calibrated for, because these more basic non-conscious brain functions they're to a large extent they're hardwired, so not to say they're completely hardwired, so they can learn, they are flexible, but to a larger extent than our higher brain functions. They have a lot of hardwiring and that means that no matter whether you're born on a spaceship headed for Alpha Centauri or in the time of our distant ancestors, they're going to be functioning approximately the same way. And that's tough because our food environment has changed a lot, right, and so we have these non-conscious brain regions that are calibrated for an ancestral environment when food was a lot less appealing and a lot harder to come by. And I don't think most people quite grasp the degree to which our ancestors' diet was not very appealing compared to what we eat today.

Dr. Stephan Guyenet: 20:03

So if you really look at what hunter-gatherers are eating, so what our distant ancestors would have eaten even before agriculture, 10, know 10,000 years ago Most of the time they're not doing much except cooking Like they're not putting salt on it, they're not putting flavors on it, they're just taking a piece of meat or a fish, putting it in the fire or next to the fire until it's mostly cooked, maybe part of it's burned, maybe there's some sand on it, maybe part of it's burned, maybe there's some sand on it. Eating it just like that, eating raw, fresh fruit, digging up tubers, roasting them and eating them plain. So you can imagine eating plain sweet potatoes, plain potatoes, except often a lot more fibrous than that right and maybe with some bitter flavors. Climbing up trees, getting honey, eating roasted nuts, roasted unsalted nuts. So not necessarily all foods that are unappealing, not necessarily terrible, but very simple, very, very simple foods that have not been cooked to the standards of a modern kitchen and don't have the flavorings and accoutrements of modern kitchen. That's kind of what our brains are calibrated for. They're calibrated to generate a motivational response to get food that is strong enough that you're going to do it, even though the food you're going after is not very appealing and even though it takes a lot of work to get there. So that's kind of what our brain regions are calibrated for, and so I think there are a few regions that I'll talk about that are particularly important in this context.

Dr. Stephan Guyenet: 21:37

One of them is the hypothalamus, which is the primary brain region that regulates body fatness. So the hypothalamus parts of the hypothalamus specialize in what's called homeostatic regulation. So that means they're taking some variable in the body and trying to hold it constant, or either constant or trying to regulate it in an adaptive way. So one of the things they regulate, for example, is body temperature. So there's a part of your hypothalamus that's essentially a thermostat for your body. There's another part of your hypothalamus that regulates your body fat and you can kind of compare it to a thermostat. It doesn't work exactly like a thermostat, but it measures the level of body fat in your body using the hormone leptin, and it tries to keep it relatively constant. And particularly when that leptin starts to drop, when you're losing fat, when your calorie intake is going down, your leptin drops.

Dr. Stephan Guyenet: 22:33

Your brain detects that and initiates an orchestrated behavioral and physiological response to regain the lost fat. And that is probably the main reason why it's so hard for people to lose fat and keep it off is because you're fighting against that physiological response. And the main arm of that response, the main lever the brain is using, is appetite. So when your body fat starts to drop, your brain will increase your appetite. It will also lower your metabolic rate to some degree, but primarily it will increase your appetite until that fat comes back. And it'll do that by increasing your hunger, by increasing your attention toward food, by increasing your cravings toward certain types of calorie-dense foods. So that's one system. You can call that the lipostat.

Dr. Stephan Guyenet: 23:26

And then there's another system in your brainstem that's also regulating your body's energy status, but it's instead of doing it on a long-term basis by regulating your body fat, it's doing it on a meal-to-meal basis by regulating your meal size.

Dr. Stephan Guyenet: 23:42

That's in the brainstem, primarily in the NTS, nucleus tractus solitarius, and that's collecting information from your digestive tract, proletariat, and that's collecting information from your digestive tract. So information from your mouth, from your stomach, from your small intestine, is converging in your NTS and that's kind of as you're eating your meal, that information is building up, building up, building up, until finally it says, okay, you've had enough. And you know. A lot of people imagine that you know I eat until my stomach's full and that's when I know to stop. But really your stomach has a lot bigger capacity than you're usually tapping into at any particular meal. I mean, I'm sure, philip, you can think back to a meal where you were super hungry, maybe you did like lots of physical activity or couldn't eat for a while, and all of a sudden it felt like your stomach was just bottomless right.

Philip Pape: 24:36

Oh yeah.

Dr. Stephan Guyenet: 24:37

Yeah, but that wouldn't happen at a normal meal, like you wouldn't. You would feel like your stomach's full before that at a normal meal, right, yeah? And so that goes to show you, I mean, human stomach capacity is not even close to maxed out at a typical meal. Our stomachs are big. What makes it feel like it's maxed out is this neurobiological processing that's happening in the brainstem. So when your brainstem decides that you've had enough at a meal, that's when it's like okay, I feel really stuffed. If I eat anymore, I'm going to start feeling nauseous. I have lost interest in food. It doesn't taste as good anymore. I don't want to. You know, I'm not staring at it anymore, I'm not feeling that motivational response and I just feel physically stuffed.

Dr. Stephan Guyenet: 25:27

That is regulated, all that is regulated by your brainstem, based on when your brainstem has decided that you've had enough.

Dr. Stephan Guyenet: 25:35

And so, interestingly, you know, on a practical level, I think that's one of the main things that we can target if we're trying to regulate our total energy intake, because the perception of fullness that you feel isn't actually very closely linked to the number of calories that you've eaten. So there's certain food properties that will cause you to feel more or less full per calorie that you've eaten. So, for example, the calorie density, how many calories per gram or per volume of food that you've eaten the more calorie dense it is, the less fullness per calorie that you will feel. And it's kind of counterintuitive to people because they think of eating rich foods and feeling very full. And you do feel full after eating rich foods, but you've also eaten a lot more calories to get there. And so I like to compare crackers versus oatmeal, for example. The macronutrient composition is very similar crackers versus oatmeal, but oatmeal has a lot of water and crackers don't. To get to the same level of fullness, you'd have to eat a lot more crackers than you would oatmeal.

Philip Pape: 26:45

It's like the sweet potato versus the Pop-Tart same macros, but I could eat 10 Pop-Tarts easy.

Dr. Stephan Guyenet: 26:51

Yeah, hi, my name is Lisa, but I could eat 10 pop-tarts easy.

Lisa: 26:53

Yeah, Hi, my name is Lisa and I'd like to give a big shout out to my nutrition coach, Philip P. With his coaching, I have lost 17 pounds. He helped me identify the reason that I wanted to lose weight, and it's very simple longevity. I want to be healthy, active and independent until the day I die. He introduced me to this wonderful app called Macro Factor. I got that part of my nutrition figured out. Along with that is the movement part of nutrition. There's a plan to it and he really helped me with that. The other thing he helped me with was knowing that I need to get a lot of steps in. So the more steps you have, the higher your expenditure is and the easier it is to lose weight. When it's presented to you like he presents it, like he presents it, it makes even more sense. And the other thing that he had was a hunker guide and that really helped me.

Dr. Stephan Guyenet: 27:35

So thank you. And so the calorie density is part of that. There's also the palatability, so the better something tastes, the less filling it is per calorie. It's like your brain recognizes that that's a highly desirable food on some level and tries to take the brakes off a little bit so you can eat more of it. And then fiber increases satiety per calorie and protein increases satiety per calorie.

Dr. Stephan Guyenet: 28:06

So if you're eating foods that you know how this kind of breaks down at a high level is, I think it breaks down to common sense, which is that if you're talking about unrefined, simple foods more similar to what our distant ancestors would have eaten, like fresh meats, fish, eggs, fresh fruit, whole grains, vegetables, those are going to be the kinds of foods that have higher satiety per calorie. And if you're talking about kinds of foods that have higher satiety per calorie and if you're talking about highly processed foods that most of us would recognize as junk food or play food, like bakery items, especially like dessert items, like brownies, cookies, cakes, candy, pizza, fried foods, those are the foods that have the lower satiety per calorie. So I think when you add it up, it kind of adds up to to common sense, which a lot of people would recognize that some of those foods are more fattening and some are less, but they might not necessarily know that a big part of the reason is that some of those are generating a lot more satiety per calorie than others.

Philip Pape: 29:13

Yeah, there's a lot there. And I totally agree with the satiety thing, because my wife she's a great cook. She'll cook really delicious whole food meals. She'll give me this giant plate of, you know, two fillets of fish and a huge thing of cauliflower and a giant scoop of uh, quinoa and I'm stuffed and and I'm like and I logged my macros and it's like 400 calories. You know, you're like, wait a minute, I actually need more calories. There's not enough there.

Philip Pape: 29:38

You know, and it's, and it's so true, and it's one of the tricks, tricks of the trade right Is when you're in fat loss, to really load up on the veggies and you get a two for one or three or four for one. When you talk about, like you said, um, the satiety, the nutrient density and, uh, the, the brain relationship. And this is one of the first times, I guess, in this episode where we're, I guess, empowering people to know that it's not a lost cause that your genes are this way. It's just the awareness of it now can inform some behaviors and some choices. What else did you say?

Philip Pape: 30:08

And then breaking it down into both the homeostasis piece, the lipostat, that part is really interesting, especially when we're losing weight, because people think in terms of statically, as if maintenance and losing weight are the same thing and there are some very different mechanisms happening. I want to touch on that for a bit, because we talk about metabolic adaptation quite a bit. You said that there's a little bit of that going on. Is that driven by multiple factors besides the hypothalamus and the leptin? In other words, are there, are there two or three factors that cause your metabolism to decline during fat loss?

Dr. Stephan Guyenet: 30:44

Yes, there are. So you know, the simplest thing is simply that you have less tissue on your body, and if you have less tissue, your energy needs typically go down. So you know, if we're talking about the average person who is going on a diet and not starting a bodybuilding program, at the same time, their lean mass is going to go down as they diet, and that's not necessarily a bad thing, because as you gain fat, your lean mass goes up. So you're really just losing. This is the way I see it. You're just losing the excess that you had accumulated. I mean, better to do strength training than not to, but I don't think it's a concern to be losing that excess lean mass.

Dr. Stephan Guyenet: 31:28

And so, yeah, your metabolic rate is going to go down just from losing mass. Then, when you are below your set point, that is to say, the level of body fat that your hypothalamus is accustomed to, it's going to kick in that kind of starvation response which is going to reduce your metabolic rate, in addition to increasing your hunger. So that's another component. So that means that even for the lean mass that you have, your metabolic rate is going to be a little bit lower. And then the third thing is, if you're eating less food, metabolic rate's going to be a little bit lower. And then the third thing is if you're eating less food, you're going to have less thermal effect of eating. Yeah, and that's going to be a very small amount, but that's the third component.

Philip Pape: 32:15

Yeah, no, it's a good point. It all adds up and I mean I'm still surprised because I take it for granted. When someone says is it okay or does it make sense that my metabolism has dropped a hundred calories over the last month, I'm like yeah, it's totally normal. Don't freak out, you know, because there's a lot of misconceptions in the industry about that. You mentioned a spaceship to Alpha Centauri. I was just thinking. That came back to me and I'm like I don't know if I'd rather eat that food. I think I'd rather eat the food our ancestors ate.

Lisa: 32:41

But, anyway.

Philip Pape: 32:42

So when we talk about the theories about body fat and weight loss, it does seem it's common sense, even if there's some counterintuitive aspects to it. But when you describe the brain and the more, we learn about the brain and also the gut and just these major systems that are complex. But there are other theories that still float around, like the carbohydrate-insulin model, that's the big one. And you had a big debate with he who shall not be named, mr GT, on the Joe Rogan podcast. Just address that for folks so that they understand what we're talking about and why that may not be the right mechanism here causing obesity. And then I don't know if there are any others that still get a lot of attention.

Dr. Stephan Guyenet: 33:23

Yeah, I want to start off by defining what I'm arguing against here, because there are many different versions of the carb insulin model at this point, and so I think it's really important to define what we're talking about. So this is the version that states that the primary cause of obesity so not just a minority contributor primary cause of obesity is dietary carbohydrate, increasing insulin secretion and leading to the accumulation of body fat. And so this is an idea that Gary Taubes has championed and some others have picked up, and the most notable researcher in the scientific community that has been associated with this idea is David Ludwig, although I think my understanding is at this point he's not defending the more extreme version of the idea anymore. He's not defending the idea that this is the cause of common obesity. That's my understanding, but I also don't want to put words in his mouth because I'm not 100% sure. But yeah, but Gary Taubes is definitely like 100% died in the wool. This is the cause of obesity. You know, that's what his books have revolved around, and anybody who disagrees with diets you know.

Dr. Stephan Guyenet: 34:43

And they're not all low. You know, they're not all low-glycemic index carbohydrate diets. Some of them are high in high-glycemic carbs, like potatoes, other types of root vegetables, white rice, and people just aren't getting fat. They're not getting any fatter than people in cultures that eat higher fat diets. In fact, if you look at most historical trends leading up to obesity in countries around the world, what you're going to see is that in most of those cases, cultures were transitioning from lower fat, higher carbohydrate diets to more carb and fat balanced diets, and this is part of why I think it's really in that middle zone, where you have abundant fat and carbohydrate, that's really the most fattening zone, and you see this really clearly in rodent studies. It's very, very clear in rodent studies, john Speakman has done the best studies on this, most rigorous, largest studies. It's very, very clear in rodent studies, john Speakman has done the best studies on this, most rigorous, largest studies.

Dr. Stephan Guyenet: 36:06

Essentially, if you take mice on a low-fat diet and you start adding fat to it, they'll get fatter and fatter and fatter, fatter, fatter the more fat you add and then at a certain point, they'll start getting leaner. So once it gets so high fat that you're crowding out the carbs and it's turned into a low-carb diet where there's not a lot of carbs anymore, then they start getting leaner again and so there's this peak fatness level. It may not be exactly the same for humans and mice, but I think it's a similar concept, where you bring those together abundantly, both of those, the carbs and the fat, and that's what's going to generate the highest level of body fat. And you might say, well, we're not mice, I'll give you that. But mice have insulin right and they have fat cells, and those systems work in very similar ways to how they work in humans. They're very conserved. When mice eat carbs, it increases their insulin and so why does the carb-insulin hypothesis not apply to them? Why wouldn't it apply to them?

Dr. Stephan Guyenet: 37:11

But it's not just in mice. We have human intervention studies that show the same thing. You put people on a low-carb diet, low-carb, higher-fat diet they lose weight. You put people on a low-fat, high-carb diet, they lose weight. You put people on a low fat, high carb diet, they lose weight. It's in the middle where people gain weight, and just in terms of the macronutrients, which is not, of course, the only variable. So that's one thing. The other thing I would say I mean there's just so much evidence from just like basic common sense all the way to really advanced experimental evidence refuting this idea.

Dr. Stephan Guyenet: 37:43

The other thing I would point to and I kept hammering on this in my debate with Gary on the Joe Rogan show, because it's just such a key point is the genetic studies, the genome-wide association studies. So these are studies that look in an unbiased way across the entire genome to see what genes are associated with a particular trait, and so, in this case, higher body mass index, a measure of body fatness, and what you see is, when you look at the genetic locations that are associated with higher body fatness, you see that those are primarily related to brain activity, not to insulin, not to fat cells, which is what you would expect if the biology of obesity revolved around insulin and fat cells, like the carb-insulin model says it does. Now, when you do these studies, these genome-wide association studies on other traits, like you do it on intelligence, you get brain genes. You do it on schizophrenia, you get brain genes. Do it on diabetes, you get pancreas genes. You do it on height, you get bone and connective tissue genes. Like you do it on autoimmune disease, you get immune genes, like these studies are really really good at honing in on what the underlying biology of a condition is. So, in cases where we already know really clearly what the underlying biology is. These studies are really effectively identifying that. So we know that these kinds of studies work really well at identifying underlying biology. And in obesity, they're saying the underlying biology revolves around the brain, not insulin or fat cells.

Dr. Stephan Guyenet: 39:28

And furthermore, I want to say, like you know, we're having this replicability crisis in science where a lot of studies aren't replicating right Like and we're saying what's going on?

Dr. Stephan Guyenet: 39:39

Or, you know, is this information rigorous? Well, these types of studies genome-wide association studies are some of the most rigorous replicable studies in all of biomedical science. This is not just another type of study design. These are highly reliable studies and they've done these over and over again and the same thing keeps coming out over and over again. And, furthermore, these are unbiased, because researchers aren't going into it with the hypothesis and saying we think obesity is all about the brain, so we're looking for brain genes. That's not how this works. It picks up whatever genetics is associated with body fatness and then after that they see what is showing up more often than by random chance. So they're not looking for brain genes, they're not looking for insulin genes, they're just seeing what pops up, and what pops up is the brain. In my view, anyone who has a hypothesis about what causes obesity that is inconsistent with what these genome-wide association studies are finding needs to find a new hypothesis, because this is the most rigorous evidence we currently have.

Philip Pape: 40:57

Excellent, excellent, yeah, and I wanted to bring that up just so that people know you're one of the experts in this area especially contrasting the genetics and the brain research with some of these hypotheses. So folks want to go find you out in the whole low carb claim. When you ask somebody, hey, what did you cut out to cut out your carbs? It's often things like pizza and ice cream and donuts and you're like, well, that's actually highly balanced fats and carbs. So is it the palatability that led to that peak fatness? Because they're just eating more calories? Is it as simple as that?

Dr. Stephan Guyenet: 41:40

That's a really good question. I would say that that is my leading hypothesis for it. I'll say that I don't think we really know, but I think that's the most compelling possibility. It is true that the reward value of food in other words, what kind of eating drive it stimulates, kind of pleasure response it generates is higher when you're mixing fats and carbs than when you're keeping those separate. So this has been shown in a variety of different ways and I mean we understand it right.

Dr. Stephan Guyenet: 42:12

Like what are the foods that get people going the most? They're usually combinations of fat and carbohydrate. You know whether we're talking about pizza, ice cream, chocolate and depending on what kind of a, you know whether we're talking about pizza, ice cream, chocolate and depending on what kind of a. You know cultural period we're in, we'll call those things like back in the 90s pizza was a fatty food and today we call it a carby food. So but if you look at the actual macros it's got lots of both, but we just interpret that through the, you know, current cultural lens, whatever macronutrient we're demonizing at the time.

Dr. Stephan Guyenet: 42:46

But I do want to say that I think low-carb and low-fat diets, I think there is something restricting carbs per se and restricting fat per se. So I do think that macronutrient restriction itself is kind of a time-tested strategy that can help people control their calorie intake independent of other things. So even if you were like keeping your food pretty simple, keeping it low, low calorie density, I still think if you cut back on the carbs or you cut back on the fat, it would give even on top of that, it would give it probably a boost.

Philip Pape: 43:31

And I think you're right, because when we let's say, take it from the other direction. If you, let's say, you are tracking calories and macros which, like my clients might do and we talk about a lot on the show just as a way to learn about what you're eating and how much you're eating, if you follow the palatability and the nutrient density kind of guidelines we talked about, you're going to eat leaner meats, you're going to eat lower fat forms of, say, dairy, you're going to eat more fruits and vegetables Guess what it's going to look like Fairly lower fat and carbs, high protein, and now your calories are where they need to be without being miserable Like you're. You're cutting things to be on a diet. So, yeah, it all makes sense, stefan.

Philip Pape: 44:07

Okay, so I mean we talked a little bit about the environment, and I don't know if the environment and epigenetics can can be combined here, but assuming we have the environment we have, which is very different than our ancestors, who just didn't have a choice, really, they couldn't go to the grocery store, and we can't really change it, at least not at the individual level when does lifestyle come into this? Where does choice come into this, and is there a way to do it. That feels more frictionless, especially for people who are predispositioned to just be at a higher body fat.

Dr. Stephan Guyenet: 44:37

Yeah, I think the frictionlessness aspect is really the key to zero in on right, Because anyone is physically capable of eating less and losing fat. If you had a gun to your head, you could do it, but the problem is, are you going to do it when you're fighting these non-conscious brain regions that are telling you to eat more day in and day out, and day in and day out? That's a struggle that most people are just not going to win on an ongoing basis, and so I think the question is how do you make it more frictionless, how do you make it easier to maintain those changes? And so I'll start off by saying that I think environment is really important. So, obviously, genetics is very important, but genetics is not what created the obesity epidemic, right, Because the obesity epidemic has been happening around the world and people of all different genetic backgrounds, so you can't really explain it by changes in genetics. What's changed is the environment. So the environment is obviously very powerful, and I think the most powerful part of it is our food environment Not necessarily the only part, but that's probably the biggest part.

Dr. Stephan Guyenet: 45:55

If you want to make an animal or a human fat, modifying what they're eating is the fastest and easiest way, and vice versa. If you want to get them to lose weight, modifying their food is also the most powerful lever. So I'm going to put a little brain spin on this, because that's what I do, and so I think a good way to make body composition control easier and more frictionless is to work with the non-conscious parts of your brain that regulate your body, fat and synaptic, rather than struggling against them. And so, you know, I think the typical weight loss scenario that might come to mind for someone is one in which they're pitted against these systems. So you're experiencing hunger and you're choosing not to eat. In the face of that, that might be, you know, an image that comes to mind for someone who's considering dieting In that way. You know, you can think about that. There's a brain region that is automatically and intuitively generating that hunger response. And then there's the you part of your brain that is the rational, conscious part, that is inhibiting that behavior that wants to happen. And that's an internal conflict, right, and that's a struggle. It doesn't feel good to be struggling against yourself like that, especially in the long run.

Dr. Stephan Guyenet: 47:20

You can do it for a day, you can do it for a few days. It's going to be hard to do it for a month, a year, 10 years, and for people who haven't experienced that, just consider, think about it like you're feeling thirsty. Let's say you're feeling thirsty all the time and you're not letting yourself drink. You could probably do that for a day. You could do it for a week. Could you do that for a year? I doubt it, and so I think what we want to do is we want to recruit those systems so they're not generating those responses that we have to struggle against, and I'll talk about two ways to do that.

Dr. Stephan Guyenet: 47:58

One of them we already talked about a little bit, which is working with the brainstem to create more satiety per calorie. So satiety is technically. Satiation is that feeling that you get that causes you to terminate a meal, that causes you to feel like you've had enough, you're satisfied and you push away from the table. You can reach that feeling with 700 calories. You could reach it with 1500 calories and get to the same place in terms of satisfaction, but having eaten more than twice as many calories. That's why selecting food for higher satiety, I think, is one of the most important things you can do to control your body composition. So, as I said before higher protein, lower calorie density, not going really high in palatability and tending toward higher fiber. Those are some important variables.

Dr. Stephan Guyenet: 48:56

The other thing I often focus on is controlling food cues in your personal food environment. So the reward regions of your brain that generate cravings, generate motivational response towards specific foods and to some extent generate hunger, those are taking cues from your surroundings. So cravings are activated when your brain gets a signal that a desired food is available in your environment. So you smell brownies in the oven or you walk by that bakery and you smell that baking bread, or you're hanging out with the friends that you always have a beer with or there's cookies on the counter and you see those cookies. That visual cue. Those are the things that get your dopamine spiking, that trigger the motivational response for you to engage. They energize, they behaviorally energize you to engage in that eating behavior.

Dr. Stephan Guyenet: 49:55

And so you know I'm going to use a little analogy here for cigarette smoking.

Dr. Stephan Guyenet: 50:02

It's a similar process, even though food is not a drug.

Dr. Stephan Guyenet: 50:05

It's a similar type of reward association. If you want to stop smoking, the main thing you need to do is stop exposing yourself to those cues that remind your brain to generate that motivational response to smoke. So you don't leave cigarettes on the counter, you don't go to the bar where you usually smoke, you don't go to the convenience store where you usually buy cigarettes, etc. You cut those cues totally out and then you're not going to have as much of that reward getting triggered in your brain, triggering that motivational response, dopamine spiking, and then that will make it easier and then over time you lose that association and you don't even want to smoke anymore, even if you see those cues. And so controlling your personal food environment in terms of not having foods readily visible that you can readily smell, putting in little effort barriers so that you might have to unscrew a jar or peel an orange or do something like just a small effort barrier those are little things you can do to kind of shut down those motivational responses that can arise.

Philip Pape: 51:18

Yeah, those are two really good strategies. And the whole controlling food cues thing reminds me of a question I got from a listener recently, which was what if my family isn't quite on board with my goals for food? And that's another kind of area of friction for you, because now you have to add in the social element of having conversations with people and seeing that other people are engaged with you for that support, even if they don't buy into what you're doing a hundred percent. So I just wanted to add that in there because it came to mind. So those are really good stuff and I know, in the interest of time, I do have one more question, if you can hang out for a couple of minutes, and that is have there been any studies on specifically on naturally lean people, like as an independent population? Uh, when we look at body fatness and body fat percentage, yeah, there have.

Dr. Stephan Guyenet: 52:07

Yeah, there have been genetic studies on lean people and what they've shown is that a lot of the genes are actually the same as the ones that have been identified in obesity, and they're just acting in the opposite direction. So, whatever the variant, the gene variant is that causes some people to be fatter well, the opposite variant causes them to be leaner in many cases.

Philip Pape: 52:38

Do you see genetic like CRISPR or some genetic manipulation down the road with some of these genes, or is that you know far off?

Dr. Stephan Guyenet: 52:45

I mean, it's not far off at all. I mean, technically it's already possible and in fact, the easiest way to do it wouldn't be by CRISPR, it would just be by selection, so you could create a bunch of embryos and then select the ones that have the best profile of whatever genetics you're looking for. And yeah, it's already technically possible and we do it already. Actually, we do it in a limited way in prenatal genetic diagnosis. So if you have parents who have propensity for some really bad genetic disease, they can create embryos from those parents and then they screen them and make sure that the one that gets implanted is one that doesn't carry that disease Through IVF.

Dr. Stephan Guyenet: 53:32

And so yeah, yeah, through IVF. So we're already doing it for genetic diseases. You could, in theory, do it for complex traits like the ones that have been studied, like BMI, and I think the only thing that's limiting us right now from doing that is potentially thorny ethics. I think a lot of people have ethical questions about that, about whether it's a good idea, and then also just kind of like financial and technical capacity. Like do we have, even though we have the knowledge and the technical capacity to do that? Do we have, you know, enough lab capacity to meet the demand that would be there for for parents actually wanting to do this.

Philip Pape: 54:15

Yeah. Yeah, it's very interesting. I was just curious about that. All right, so I guess, within the scope of what we've discussed, is there anything you wish I had asked or touched upon?

Dr. Stephan Guyenet: 54:24

No, nothing I can think of off the top of my head.

Philip Pape: 54:27

I only have about 20 other questions I could have asked you. That's why I phrased it that way. Well, Stefan, it's a pleasure talking to you today. I do want people to be able to find you and your work at the best place you want to send them to. So where would that be?

Dr. Stephan Guyenet: 54:44

Yeah, to send them to. So where would that be? Yeah, I'm most active on Twitter, sgna. I also have a website, stephangeanaorg. I don't update that much these days though.

Philip Pape: 54:49

No problem. Yeah, I mean your picture still looks the same, so it's all good. You kept in shape all these years, all right? Well, thank you so much, stephan, for being here. It was a lot of fun, and I know the listeners are going to take away a lot from this today, so appreciate it.

Dr. Stephan Guyenet: 55:01

Great my pleasure Phillip.