Bonus – Dr. Stephan Guyenet: The Proven Neurobiology of Your Set-Point Weight

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Jonathan: Hey, everyone! Jonathan Bailor back with another bonus, Smarter Science of Slim Podcast. Folks, I know that I am always saying that I am excited about this podcast but I am uniquely excited about this podcast because we have the good fortune of being joined by one of the researchers whose work and related works is just so seminal, to, not only in my life, but the Smarter Science of Slim work, everything we talk about with the homeostatic regulation of weight, the set point of fixing our biology, rather than fighting against it.

That is none other than Stephan Guyenet with the University of Washington, the proprietor of Stephan will inform us of wonderful research he’s done but, suffice to say, he’s a brilliant man. He’s got a PhD. in Neurobiology, from our backyard here, at the University of Washington, and has authored some of my favorite papers on the Homeostatic Regulation of Weight or The Set Point.

Our goal is make this show the place where, if you are interested in the technical ins and out of what we mean by the body works to balance itself out, as long as we don’t break our brain, where you can get that definition. So, Stephan, welcome to the show.

Stephan: Thanks, Jonathan.

Jonathan: Well, Stephen, I am so thrilled again to have you sharing your time with us. As I mentioned, part of the show, I am hoping in as meticulous fashion as we can, I just want to geek out because, while it is widely accepted that, for example, blood sugar is homeostatically regulated and blood pressure is homeostatically regulated, and it’s just a given that for some reason, there still seems this “woo woo” vibe in some people’s minds about the homeostatic regulation of weight. What is that, and let’s just break down why that is false?

Stephan: You mean, why is there resistance to that idea?

Jonathan: Exactly!

Stephan: I think the reason why there is resistance to that idea is because there are both homeostatic and non-homeostatic influences on body weight. You can take a person and deliberately overfeed them. You can take someone and say, “We are going to feed you a thousand extra calories today,” and that person will gain fat due to that deliberate overfeeding.

So, there can be influences that are not homeostatically regulated that can influence body fatness but that does not take away the fact that we have this sophisticated system in the brain that regulates a variety of factors pertaining to body fatness.

Jonathan: Stephan, just real quick, I love what you said there. I often think to myself, though, people don’t question the homeostatic regulation of blood sugar, yet we have diabetics. They don’t question the homeopathic regulation of blood pressure, yet you can have hypertension. What confuses me a bit is, just because we can overwhelm the homeostatic system clearly does not disprove its existence.

Stephan: Yeah, that’s right. There are a lot of studies that show that a variety of environmental conditions, things like plate size and calorie density of the food and atmosphere of the eating environment, things like that, can influence meal intake, calorie intake at a meal.

People will say, if there is this homeostatic regulation going on, why are all these things that have nothing to do with calories influencing the balance of energy in and energy out and potentially influencing body fatness? I think, not to diminish the importance of those observations, but that does not rule out the fact that there’s also a guiding force that nudges us in a homeostatic direction on a long term basis.

Jonathan: Stephan, correct me I’m wrong, which I am hope you would do anyway, because you really are the expert here. I am just a mouthpiece for researchers, such as yourself and Dr. Schwartz, for example. In my simplistic mind, if you have studies which show that, for example, if I overfeed a person 1,000 calories a day, and they consistently, dare I say, in hundreds of studies gain less than would predicted by calorie math, as is traditionally presented to us. Then if you underfeed people in a separate study 1,000 calories and they gained less than would be predicted by calorie math, doesn’t that in and of itself show that the body is not some passive vehicle that just adheres to calorie math, but plays a role in this?

Stephan: Yeah. The body is obviously defending body fatness to a certain degree. My view on this, frankly, is that people who don’t think that there is any defense on body fatness is simply not aware of the research. We have research going back to the mid 1800’s, demonstrating that centers in the brain regulate body fatness. There is an entire sophisticated network of brain regions whose main function or at least one of the most important function of those brain networks, is homeostatically regulating body fatness.

If there is no homeostatic regulation of body fatness, why do we have this sophisticated network of brain regions we have already identified, in rodents and in humans that do exactly what they are not supposed to do? I think frankly it’s the people that aren’t quite connecting on the research level. Maybe some of the studies, influences on food intake that aren’t related to homeostasis might not think that homeostasis is an important variable in the equation.

Jonathan: I think that is a great point, Stephan, and I think that if we look at, for example, your formal training, it is in neurobiology, which traditionally, if someone were to think about nutrition or diet or weight loss, they wouldn’t necessarily be, like, “Ah, yes! I should ask the neurobiologist what I should do,” but, in fact, that is obviously a hugely important field when we talk about this area. Might that have something to do with it? People just aren’t opening their neurobiology textbooks when they think about this?

Stephan: Yeah, I think so. Neurobiology is a field unto itself, and it’s complicated and most people don’t have a background in it. The fact is that energy homeostasis relates in large parts in behaviors, behavior such as food intake, and behavior such as how much you move your body, either actively or passively, consciously or unconsciously. There is, of course, an influence of the basic metabolic rate that is independent of those things but, compared to the behaviors of food intake and physical activity, together, it is not as large, it can’t be varied as much as physical activity and food intake. Therefore, it is not a large determinant.

The point is that behavior is generated by the brain. I don’t think anyone would deny that, it’s just common sense. The brain obviously plays an important role, and the factors that determine the brain’s selection of behavioral outcomes are the factors that, in large part, are going to determine energy and body fatness, so that’s the part of it. To take a step back and take even broader approach, the brain is basically the driver’s seat for the body.

It is the command center that regulates virtually every large scale homeostatic process in the body, if you’re talking about body temperature, the brain. If you’re talking about blood pressure, the brain. There are a variety of other things that are homeostatic variables that are regulated by the brain, blood glucose, for example. That does not mean that the brain is the only thing that’s regulating these processes, but the brain plays a high level regulatory role to nudge those things back into the optimal range, when they are exiting the optimal range. So, it makes sense, since the brain is the command center of the body, that it also plays a role in regulating body fatness.

Jonathan: It seems, Stephan, that it is such an important distinction because if we leave the brain out of the equation, which again, like you said, the brain is everything. Your brain is you, in a sense, and if we leave it out of the equation, there are factors. For example, if eating certain types of foods or engaging in certain types of behaviors, for lack of better terms, break our brain, it may have nothing to do with caloric intake.

I know you have some research which I want to get into about, substances which may cause inflammation in the brain, which, if you break your brain, and you think the solution to that is just to starve yourself, if you do not acknowledge the existence of the brain in this process and the problem is fundamentally rooted in the brain, then you really have no hope of ever solving the problem, right?

Stephan: Well, you can lose weight by restricting calories. We know that. Regardless of where the calories are coming from, if you sufficiently restrict calories, you’re going to lose body fats. So, it’s not that you can’t do it without engaging the homeostatic pathways. It’s just that if you do it without engaging the homeostatic pathways, without working the homeostatic pathways, you’re going to be doing it in a more difficult manner.

It is going to be essentially your conscious mind, your conscious long-term goals, your conscious self fighting against your unconscious self. This homeostatic regulation that’s making you hungry, that’s making you feel lethargic, that’s making you have increased thoughts and desire for food, particularly calorie dense, highly palatable foods. These are all things that have been documented to occur with calorie restriction. It’s part of the brain’s program to try to regain lost body fat.

If a lean person, such as you or myself, were to lose body fat, that’s probably not a good thing. That’s not a good thing for survival, in a natural context, because you need a certain amount of fat tissue. Fat is an endocrine organ that’s an important for the overall functioning of the body and critically, it’s also a very important energy reserve. The brain is going to react negatively to that. It’s going to do what it can to enact this broad program to try to restore that lost fat, in a variety of different ways.

That being said, I’m sure we’re get into this more later, but basically, the same thing happens in an obese person. Their brain doesn’t really see them as obese; it sees them as the same as a lean person’s brain does, as having the right amount of fat mass. When they try to lose, their brain enacts that very same program and opposes the lost of fat. That’s not to say they can’t lose the fat by eating a low calorie diet of pizza and doughnuts, and going to the gym for two hours a day, not to say that doesn’t work. It does work if you stick to it, in terms of producing body fat, but it’s not going to be very pleasant.

For the average person, it’s not going to be very effective because you are essentially fighting yourself and those unconscious drives that are engaged, those are designed to wear you down. You are not supposed to be able to override those. If you have an iron will, maybe you can for a while but they’re designed to essentially wear you down, so that you do not hurt yourself. That’s what they are there for.

There’s another point I want to make, just really briefly, before we move on. You mentioned that if you break the homeostatic system, then you have to address the homeostatic system. I prefer to think about it in different terms than breaking it. I see where you’re coming from, but what I’d like to think about is more of a mismatch between, not necessarily that it is broken, but that there is a mismatch between the environment and the environment that your brain is kind of hard wired to deal with. When that occurs, you get maladaptive outcomes, basically.

Jonathan: I like that distinction, Stephan, and I also like what you said earlier about, it’s not that the traditional “just work harder, eat less, exercise more” doesn’t cause you to lose weight. Obviously, it does. The question is sustainability and it reminds me of, while you were talking, I just thought of the analogy of, if you’re on the first floor of Sears and you want to get to the second floor of Sears, you could walk the down escalator.

You could get to the second floor by trying to walk up the down escalator. It’s just that much harder. Why not just take the up escalator, and why not work with the escalator rather than working against it? Is that somewhat of a fair analogy of what we’re trying to talk about here?

Stephan: Yeah, I think that’s absolutely true. It’s not a matter of efficacy under calorie controlled conditions, or it’s not a major matter of efficacy under calorie controlled conditions, it’s a matter of efficacy under real life conditions, where we have people engaging in normal behaviors, people who are human, and people who want the most sustainable route.

They don’t want to be fighting themselves, they don’t want to do something that has 80-90% chance of being unsustainable at the one year time point. They want something that feels natural, where they can just engage in natural eating behaviors, not obsessed about food, not counting calories but engage in natural eating behaviors, feel good about it, and also maintain an amount of body fatness that they would prefer.

Jonathan: Well, Stephan, let’s dig into and let’s geek out a bit and again, I want to invite the listener s to embrace the geeking out that we will do, because, I think it’s actually very, very powerful. Stephan, for me, at least, the more I understood the actual homeostatic system, the more you dig into it, the more real it becomes because you understand it. For me, that’s actually very freeing because there’s like, “Oh, yeah, Jonathan and Stephan are saying that there is a set point and that’s neat. They seem to be credible guys.”

That’s one thing but to really get it and understand why it works, I think can be very empowering, when you hear constantly from the media, just eat 100 calorie snack packs, this can help give you an alternate mindset. If you don’t mind, Stephan, I don’t know how to best describe this because it is quite complicated but can we just step through a little bit, what this homeostatic system is, the brain components, the adipose tissue components, all that kind of fun stuff?

Stephan: Yeah, sure. So, at the broadest level, the brain is basically an organ that, in large part, gathers information about your environment: where you are, what’s going on outside of you using the senses, and then it also gathers a lot of information that’s internal. It’s gauging the internal state. Then it’s integrates all that information into other brain regions that basically decide on what action to take, either behaviors outside your body or actions inside your body, like, metabolic change, insulin secretion, release of fatty acids from fat tissue, glycogen synthesis, et cetera, et cetera, heart rate.

That’s basically the over arching idea of what the brain is doing. It does all that to promote, essentially, survival and reproduction. That’s the over arching goal of the organism. One of the aspects of that is maintaining adequate energy stores. You need to have adequate energy stores, if you want to survive periods of low food availability or if you have big things you have to do, like have a baby, for example. You have to have a certain amount of fat to protect yourself from variability in your food supply and in your calorie expenditure.

Actually, let me take a little step back. There are basically two systems that we can identify that are involved in energy homeostasis. So maintaining , somewhat stable, energy stores. There’s one that operates in the short term, meal to meal basis, and that machine is located, primarily, in the brain stem. Then there’s one that operates on a longer term scale and regulates body fatness, and that one’s located primarily in the hypothalamus.

I am simplifying because there are elements, the parts of the brain that does the primary areas for each of those. I’ll start off with the meal to meal homeostasis, because it is easiest to understand. It is very intuitive, really. There are negative consequences associated with eating too little, and there are also negative consequences associated with eating too much. For example, if you eat too little, you might not have enough energy to do what you want to do for the day.

If you eat too much, you can stress the digestive system, you can stress the metabolism, you can stress your digestive organs, et cetera. It turns out that your stomach has a much larger capacity for food than almost anyone ever feels. You see a guy like, what was the swimming champion in the Olympics? Michael Phelps. What was he eating? 12,000 calories a day? Can you imagine the size of that guy’s meals? I’m sure he ate multiple meals but that’s more than four times the number of calories that most people eat. I’m an active person. I eat a fair amount number of calories.

That’s more than four times the number o calories that I eat, which is just insane to think about. The point is that the stomach can hold a lot of food. It can hold a lot more food than we habitually put into it. Why does it feel like your stomach is about to explode when you eat an amount of food that’s only filling up your stomach halfway? The reason is that this short term meal to meal energy homeostasis called the sytadin system.

Basically, when your body senses that you’ve had enough food to fulfill your metabolic needs, based on your habitual meal pattern, then it sends signals to the brain via stretch receptors in the stomach and via a variety of gut hormones that communicate to the brain. A lot of it is going through the vagus nerve. Some of it is going through circulation and directly impacting on the brain stem and that says, basically, we just ate X number of calories and the composition of those calories was roughly xyz.

It’s not a perfect system. It’s not perfectly accurate about how it reports these things. That’s something we can use to our advantage, to manipulate sytadin per calorie. However, that is the basic function of the system. That’s the short term things. Basically, it’s a negative feedback that’s limiting meal size so you aren’t going to overeat. Basically, you’re hungry as the default state and then as you continue to eat, the sytadin system kicks in and limits meal size. So you have, basically, limits. The hunger is setting your lower limit, and the sytadin is setting the upper limit of food intake. That’s the short term homeostatic regulation system.

The long term homeostatic system is, again, in the same way that the brain is measuring the internal state of the body by monitoring the digestive track after you eat a meal, the brain, and this time it is primarily the hypothalamus, is monitoring the size of your body fat stores. Like any negative feedback system, just like the thermostat in your house, you have to have a signal that’s travelling from body fat to get to your censor. So that signal, in this case, is primarily the hormone Leptin.

Leptin is a peptide hormone that’s produced in proportion to body fatness, travels through the circulation and gets to the brain, where it… Oh, sorry, I forgot to mention, Leptin is secreted into the circulation into proportion to fat tissue size. That’s how the brain measures body fatness; the more Leptin there is, the more fat it thinks you have.

Leptin is also responsive to the amount of food you have eaten over a two or three day period. If you ate a lot for a couple of days, you would also have a disproportionately high Leptin freer level of body fatness.

Leptin sets the tone, among other things, on the sytadin system. If you haven’t eaten as much as you usually eaten for a few days, your Leptin is going to be lower, your body fat’s going to have dropped a little bit. Your Leptin is also going to be lower because you have not eaten over the last few days and that, basically, decreases the responsiveness of your brain stem to sytadin signals. It takes more food to allow you to achieve sytadin, because your body is enacting a program to regain that energy deficit.

Leptin acts in the brain in a variety of ways to manipulate, to influence, to regulate body fatness. It influences energy expenditure, including the basal metabolic rate and that’s just the amount of energy your body burns just doing housekeeping. Regular DNA synthesis, protein synthesis, keeping your neurons polarized, et cetera, that also takes a lot of energy. A large decrease in Leptin can modestly decrease the amount of energy that’s being used for that. The more important thing, and it does that, in part through effecting thyroids. Basically, the hypothalamus controls the thyroid, indirectly, controls the thyroid hormone.

If it detects an energy deficit, it can shut down your metabolic rate to some degree, through reduction of thyroid hormone. Conversely, if you’re eating more, it works in the opposite direction, too. If you’re eating more, your brain can increase your metabolic rate to a limited degree. In rodents, that effect is really well documented, it’s very consistent. In humans, it’s a little more squirrelly. The effect on basal metabolic rate, specifically, are a little bit more squirrelly and part of the reason, is humans really don’t have nearly as much brown fat as rodents. That’s the type of fat that burns fatty acids to produce energy.

Rodents have a ton of it, they are small mammals. They are very threatened by the possibility of hypothermia, so they have a lot of brown fat. Humans have a little bit between the shoulder blades, around the neck area. Anyway, the main point I want to make is that the brain can, homeostatically, regulate energy expenditure but it is mostly via the efficiency of muscular contraction and via something called non-exercise-activity thermogenesis. That’s basically, involuntary fidgeting, people tap their feet, move their hands, change their posture, et cetera.

That, studies have shown, is capable of dissipating several hundred calories a day during deliberate overfeeding. It’s a major mechanism of calorie dissipation that’s under, presumably… it’s under unconscious control, presumably, under the control of that energy homeostasis system, and conversely. Leptin controls the amount of energy going out of your body. If you are not eating as much, it can reduce energy out. If you are eating more, it can increase energy out but it also has a major impact the amount of energy that is going into the body by controlling hunger.

There is this really interesting phenomenon in humans, whereby, if you overeat today you probably won’t under eat the next day but studies have shown that you probably will under eat two days from now or three days from now. There’s this kind of long-term delayed compensation that occurs. I think that’s actually, interestingly, one of the main things that prevents people from seeing these homeostatic effects, as they are so long-term and many of the studies that we are looking at food intake are very short, so, it is really hard to pick up if these things that might have a major impact in the long term.

That’s basically an overview. I want to mention, too, before we get off this topic, that, it’s not just Leptin. There are a variety of signals impacting on the brain. Leptin is the major one that represents body fatness, but there are a variety of signals that participate in this homeostatic regulation process. So, that’s a summary of how the systems work.

Jonathan: Stephan, thank you so much. It is wonderful to get that level of depth and understanding, because, again, it really grounds us and helps us. The more we can see this beautiful complexity, that is our body and our body weight, really, our physiology, the more statements like; “just eat less, or you’re just lazy, you’re just a glutton,” start to be like… if someone’s unhappy, you don’t just say, “Smile more! Be happy!” Human psychology is complicated. We need to kind of dig below the surface, dig below the sound bites, and understand what’s going on.

You just can’t say, “Well, smile more and frown less then you’ll be happier.” It’s the same thing when we understand our biology is as complicated as our psychology, we start to appreciate that a little bit more. Stephan, the question, though, then becomes, what are the ways you’ve seen and I know this is an area where there is conclusive evidence that, X, so we have to do the best we can with what we have. What do you see as the most promising approaches to re-regulating, maybe for lack of better terms, this homeostatic system, such that, it does not think we’re slim, when actually we’re not slim, and works to defend a slim weight, like many of us currently are defending a non-slim weight?

Stephan: Yeah, my take is that if we’re going to make an attempt at sustainably reducing body fatness, then I should be an attempt that tries to address both homeostatic and non-homeostatic influences on food intake and energy expenditure. It is true that there are non-homeostatic influences on food intake and I think those are meaningful, like just having tempting food available all the time is going to tend people to want to eat more. I really focus a lot on trying to get people to improve their food environment, create an environment that consistently favors positive choices and makes negative choices more difficult.

You can’t eat something that’s not there, and you probably cannot be tempted by something that’s not there, if there’s no cue around that reminds you of that thing, that’s one part of it. If we’re going to address the homeostatic system, there are a variety of things that are known or suspected to influence the homeostatic regulation of body fatness that we can use to leverage the system that we’ve been talking about. I think one of the more important ones is protein. There’s been a lot of research on protein over the last couple of decades, and it’s only accelerating.

Protein works on a couple of different levels. It works on the sytadin system, because protein is the most satiating macro-nutrient among the protein-carbohydrate and fat, per unit calorie that is. Also, elements of protein, particularly the Leucine, have been shown to act directly on energy balance centers in the hypothalamus. Leucine particularly impacts a pathway called the MTOR pathway. It’s one of intercellular energy sensing pathways of the body.

Leptin is the whole body energy sensor, MTOR and another protein, Mp Kinase are the major cellular energy sensors and MTOR is particularly responsive to amino acids, particularly the amino acid Leucine. When you eat a high protein diet, you’re increasing signaling through this pathway and, potentially, that plays a role in homeostatically re-regulating to a lower level and you see this a lot. You see people who [Inaudible 00:34:08]… increase the protein intake and suddenly they’re spontaneously eating fewer calories. Yup, can you hear me? Oh, sorry. Hello?

Jonathan: Got you back! Got you back!

Stephan: Okay. Alright.

Jonathan: Spontaneous caloric reduction is what you were saying.

Stephan: Yeah, yeah. Okay. When you do study and you put people on a certain diet regimen, and suddenly they are eating several hundred calories fewer, even though they weren’t being asked to restrict calories, they are losing a significant amount of body fat without trying, without feeling hungry, et cetera, then I think that’s pretty compelling evidence. At least it’s strongly suggestive, that you’re having effects on the energy homeostasis system to reduce the defended level of body fatness and protein certainly qualifies for that in human studies.

It’s been shown, as I said, that it directly acts on hypothalamus in rodent studies. It’s also been shown that when someone loses weight on a high protein diet, you don’t see the expected disproportionate reduction in metabolic rate that would occur with calorie restriction, normally on a non-high protein diet. Basically, all signs point to protein, actually, acting directly on those energy homeostasis circuits and re-regulating them to a lower level in conditions of overweight and obesity.

Jonathan: Stephan, just a quick question, just to get your expert opinion here. You know I love me some protein. I am a big, big fan of that. I just kind of wondered, this is more, totally theoretical, but I just wondered why does that happen? Obviously, we are talking about MTOR, but I’m saying more meta evolutionary level. Do you think, and this is obviously just hypothesis, but it seems like maybe an abundance of protein seems to signal an abundant food environment. Protein is a major structural component and historically, relatively scarce substance for us to get.

When our body is presented with an abundance of, let’s call it, the gold standard of structural components, it needs to stay alive. 200 calories of protein is going to be perceived, for lack of better terms, much differently than 200 calories of carbohydrates. It’s a more valuable commodity, for lack of better terms, in the body’s mind. Did that make any sense or seem reasonable at all?

Stephan: Yeah, I understand what you are saying. I have given this some thought as well. The fact is, you can come up with a variety of teleological arguments about why protein is satiating but, personally, I don’t feel sufficiently compelled by any of them to speculate. What I will say, so there is this idea that protein leverage hypothesis, have you heard of this?

Jonathan: Oh, the listeners would love to hear! Go ahead.

Stephan: Okay. So protein leverage hypothesis is basically the idea that our bodies want to obtain a certain absolute quantity of protein. If you’re eating a diet that’s more concentrated in protein, you have to eat less pure calories to obtain that, so you’ll eat less. This hypothesis would predict also that if you eat a low protein diet you would eat more to be able to maintain a consistent protein intake. The problem is that it does not happen.

When you reduce protein intake, calorie intake does not go up. It remains approximately the same when you go from normal to low protein. I think this is really an effect that is specific to elevated protein intakes. I really don’t know, teleologically, what evolutionary function it would have had. I have thought about this, and I have to say that I’m rather stumped about it.

Jonathan: Well, that’s fair and most importantly, we’ve got the research that points to, it seems to work, so, why? At least, give me the placebo. If it’s going to make me feel better. This isn’t a placebo, in this case but if the results are there, I’ll take it, even if we can’t necessarily explain why. So that’s all good for me!

Stephan: Yeah, and the results are there. Protein, I would say, is one of the more compelling approaches that have been identified to date.

Jonathan: Alright, so we’ve got protein. You also mentioned, of course, just general satiety signals in the digestive organs, which food size plays a role there. Water and fiber must also play a role. If that’s incorrect, please correct me if I’m wrong. Assuming they are correct, what else can we do to potentially manipulate the system?

Stephan: Certainly. What you said, water and fiber, these are major factors in sytadin per unit calorie of food, to a point. You can eat zero calorie, high fiber, high water foods and feel satisfied. To a point, things that are higher in water and higher in fiber are going to be filling per unit calorie. That’s something that probably acts primarily in the short-term energy homeostasis pathways, the sytadin system. Not necessarily going to have much impact on the homeostatic regulation of body fat in the longer term. Let me rephrase that.

I think it can impact body fat to some degree but it’s can’t necessarily impact homeostatic regulation of body fat, in a way that’s going to make you lose a large amount of body weight. That’s my opinion. But that being said, there’s another that’s related to fiber and that’s the health of the digestive flora. I’m not going to take this too far. I’ve done quite a reading on this. My AHS 2012 talk was on this topic,

There’s a lot of hype about the gut flora. I’m not going to take it too far, because I don’t think the evidence is there yet to be making grand claims. That being said, I think there is enough evidence to strongly suspect that the gut flora do have an impact on body fatness and that may be through homeostatic influences. It’s hard to say for sure, at this point. We do know that, for example, certain types for antibiotic used can be associated with weight gain. We know that C-sections are associated with childhood obesity in the offspring, not clear whether these are causal relationships but the association has been noted.

In animal models, it’s very clear. In rodent models it’s very clear that the gut flora can have a strong impact on body fatness. For example, you can take an animal, you can feed it a fattening diet, animal will get fat. You can take its gut flora and transfer it to a sterile mouse, an animal that does not have any gut flora, and it will actually make that animal fat that received that gut flora. Whereas when you get the gut flora of a lean animal and give it to a sterile animal, it will not make that animal fat.

There is a certain amount of information that seems to be carried in the composition of the gut flora as well and the point of my bringing this up now is bring a background to the fiber content of the diet, because gut flora are very strongly influenced by the fermentable fiber content of the diet. If you’re eating a diet that is rich in a variety of fermentable fibers, then you’re more likely to have a large and diverse and thriving community of gut flora that are helping you maintain a healthy weight, rather than hindering it.

Jonathan: I love it, Steph. I love it! What do you think is next? Do you see anything on the horizon for where the research is headed in the homeostatic regulation arena? What are the key questions are we trying to answer right now?

Stephan: Well, one of the really big questions is, what exactly is the mechanism the defended level of body fatness to increase? We know how to do it, empirically. We can put animals on a fattening diet, certain types of fattening diets. We can make them obese readily, and that’s associated with the defense of increased body fatness. You can make an animal obese on these diets. I can tell you what’s in the diet. It’s composed entirely of refined ingredients. It’s 60% calories from fat, 20% from protein, and 20% from refined carbohydrate, with some vitamins and minerals and a little bit of fiber added in and rodents will become markedly obese in just one or two months on this stuff.

In fact, in my own hands, rats will double in body fatness in as little as two weeks, their body fatness will double. They eat it voraciously, at least at first. They are very efficiently pack on fat tissue. We know when that happens. We don’t know what exactly in these diets that cause that to happen. We don’t know whether it’s the fat content, we don’t know if it’s the lack of fermentable fibers, fatty acid composition, the type of protein. I say, we don’t know. Actually, there are quite a number of clues. In one of them, frankly, it’s just that, animals just really, really like the food. It’s highly palatable, highly rewarding.

When you fist expose it to them, they literally eat double the number of calories than they would normally eat, for approximately the first week and then they start to level off in calorie intake but it’s basically like cookie dough. You can look at it, you can play with it. It’s not very appealing to me or you. It’s not something you would want to sit there and eat a plateful off but to a rat, that spent its entire life eating this high fiber whole foods, hard pellets, that’s about 14% fat, 70% carbohydrate, that tastes awesome. When that’s all the rats has ever eaten in its entire life, is this one food.

This is like the potato diet. You entire this one food for your entire life, and then you get another food that tastes better and you’re going to like it, you’re going to eat more. This touches on something else, too, that I’ll just take a brief ten in here. When you give them this food, it’s novel, they really like the taste, so they eat a bunch. Eventually, after 7 to 10 days, their calorie intake actually drops back to normal even they continue to gain weight.

Interestingly, there are ways to keep them eating calories so they won’t level off. Basically, the way you do that you send them with a variety of highly palatable foods is you present them with a variety of junk foods, it’s called the cafeteria diet, somewhat commonly used fattening diet in our field. It’s extremely fattening. You just put a variety of junk food in their cage and just giving them that choice, that variety keeps their food intake high, and so, they’ll continue to gorge themselves. They’ll continue to keep their calorie intake high, and they’ll gain fat at a more rapid rate than an animal that’s just eating this high fat pellet that we give them.

Anyway, that’s a tangent but the point I want to circle back around to is, we don’t know exactly what it is about this food that is causing them to be obese. What I would really want to have is a complete map of the mechanism from the food, not even going into their mouth, from them seeing the food, from them smelling the food, then entering the mouth, being digested, metabolic signals going to the brain, nutrients, fatty acids, amino acids, etc., going into the brain, going through the digestive tract and getting metabolized by bad bacteria, bacterial components potentially translocating into the blood, all of that.

How is that resulting in, not just in animals eating and gaining more fat, but actually, becoming fat and resisting fat loss when you try and put them on a diet? This is the same thing we see in humans, very easy to replicate in animals. If you give them this fattening diet, they will gain a remarkable amount of fat, and then you can restrict them. You can restrict their calories but not switch them off the diet. You keep giving the same diet, and restrict their calories, and their bodies will fight it; they’ll fight it hard.

They’ll reduce their energy expenditure, they will increase their food seeking activity and if you give them access to as much food as they want after dieting them, they’ll immediately regain back to the same place that they would have been if you have never had dieted them. It’s exactly the same thing. Obviously, humans are a lot more complex, and we have a lot of things going on, like, goals, social stuff, and all that. It’s not a perfect analogy but the basic fact of homeostatic regulation is there.

Interestingly, this is something that’s been shown previously and also in my own hands, is that, the defended level amount of body fat is very specific to these specific conditions animals are in that time. If you take that diet, that very fattening diet, and give them half as much, they’ll lose weight and they’ll initiate this program to try to regain weight. But, if instead of doing that, you just switch them back on to their regular chow, this is the thing they are on prior to their fattening diet, it’s a whole food based diet that works pretty well with rodent physiology.

They will spontaneously eat less, and they will spontaneously lose that fat, even they have access to a ton of food. It’s very much dependent on the context. It’s the same thing if you give them a running wheel. If you give them a running wheel or of you given them an enriched environment where they can socialize with other animals, toys et cetera, they will be more resistant to gaining fat than if they don’t have these thing, even if you let them have as much food as they want.

Jonathan: It’s fascinating! I love animal models in some ways, because you can eliminate all the…when you get humans involved, it gets a little sticky quickly. When you just use rats you can do this cool stuff, and you’re like, there’s no emotional eating going on there. It’s so cool because you can see what you are doing; you are try to emulate this human-like environment. I think that’s really neat. That always makes me happy.

Well, Stephan, I really could, frankly, listen to this all day. This is what I live for and I just wanted to thank you for the research you’ve done in this arena, and hope will continue to do because I do think, well, hopefully, it doesn’t take this long, but in a few decades we’re going to look back on weight, just like we look back on blood sugar now.

This is what the body is designed here to do, it doesn’t mean that we can deregulate the system but it means there is a system. If want to walk up the down the escalator, we can, but why? Why not just walk down the down escalator. Stephan, if I may understand correctly, you do actually have a program, which for lack of better terms, may help people to walk down the down escalator, rather than up the down escalator. Can you just tell us briefly about that?

Stephan: Sure. It’s called the Ideal Weight Program and it’s a body fat loss program that I designed along with Dan Party, with some support from a few other people. Basically, it is a comprehensive diet and lifestyle program that’s designed to work with bodies to promote fat loss in a sustainable way.

There are a couple of things that are really unique about it that I’ll just say really briefly. One of them is that it really comes from the position of knowledge on homeostatic body fat, and focuses on not counting calories but living your life in a way that naturally promotes a reduced level of body fatness, which many people find that strategy works well for them.
The other thing that’s really unique about it is it incorporates some very simple and very effective tracking software, so you can track your physical activity and your sleep and your body weight and get objective feedback on those things so you can meet the goals that you set through the program. We feel that sort of objective feedback, that’s made it easy as possible is really very critical for evaluating your progress and meeting your goals and motivating you as well.

Jonathan: Well, Stephen, certainly! For all my listeners here, if you don’t realize it, you have been influenced by Stephan’s work even before you listened to this podcast, because, like I said, his work… Michael Schwartz, is it fair to say, he’s your mentor or do you just work with him? How close do you work with him?

Stephan: Yeah, he’s my mentor. I’m a post-doc in Mike Schwartz’s lab, so it’s fair to say he is my mentor.

Jonathan: Folks, if you are interested in this kind of stuff, please look up for Stephan’s work, not only “regular internet at” I’m going to define it as the regular internet and then the non-regular internet, let’s call that pub med. If you really want to get at it, search for Stephan’s work and also his mentor Michael Schwartz, just look up their names at the University of Washington and check out their work over there.

Obviously, I got that Washington Pride because it’s over here at the backyard. It’s kind of nice that you got the premier obesity researchers in the world, right here in Washington. You wouldn’t that, but it’s pretty awesome! Watch out, Washington, first we brought out Michael Moore, then we brought out Stephan. Excuse me, Stephan Guyenet, so you’re going to be the next big star at out of Washington, right?

Stephan: I think I’m going to need to get a new haircut.

Jonathan: I love it! Well, Stephan, thank you so much for joining us. Folks, again, if you want to learn more, Stephan’s got truly an amazing amount of information in his blog. I have no idea what his word count is but there’s lots! So please check out and again the name of Stephan’s homeostatic regulation friendly weight program is called the Ideal Weight Program. You can find more information for that on his website. Stephan, thank you for joining us, it’s absolutely a pleasure.

Stephan: Thanks, Jonathan.

Jonathan: Listeners, I hope you enjoyed today’s show as much as I did and remember, this week and every week after, eat smarter, exercise smarter, and the better. Talk with you soon.