Why Your Body Fights Back Against Weight Loss | Dr. Eric Ravussin & Mike Haney
In a recent episode of A Whole New Level, Levels editorial director Mike Haney sits down with Dr. Eric Ravussin, professor and associate executive director for clinical science at Pennington Biomedical Research Center in Baton Rouge, Louisiana. One of the world's foremost experts on human energy metabolism, Ravussin has spent more than four decades studying how the body burns and stores energy — including pioneering work with the Pima Indians, the construction of the first metabolic chamber in the United States, landmark research on caloric restriction and longevity, and his involvement in the Biggest Loser study. He is a member of the Lancet commission that recently proposed a new clinical framework for diagnosing obesity.
The conversation covers how the body's daily energy budget breaks down into its various components, what metabolic adaptation is and why the body fights so hard to return to its previous weight, what the Biggest Loser and CALERIE studies revealed about the persistence of that adaptation, why the environment — not personal failure — is the real driver of the obesity epidemic, and how GLP-1 drugs fit into a picture that metabolic science has been building for decades.
Humankind was evolved to protect ourselves from starvation — not to protect us against abundance. We have a much stronger defense for caloric restriction than we have for excess calories.
— Dr. Eric Ravussin
Pennington and the science of energy metabolism
Mike Haney: Well, Dr. Eric Ravussin, thanks so much for joining us today.
Eric Ravussin: It's a pleasure.
Mike Haney: So, by way of introduction, we could spend a whole hour just on your background. You've been at this for 40 years studying obesity, and any one of the landmark studies you've done — the CALERIE study, the Biggest Loser study, your work in the metabolic chamber — we could dive deep into. I thought maybe by way of introduction, let's just jump ahead to Pennington, where I think you've been for the last 25 years. Can you just describe what Pennington does and what kind of research you're doing there now?
Eric Ravussin: Pennington Biomedical Research Center is a center which was created as a consequence of a gift from Dr. Pennington — he was a rich oil man and he gave $125 million in the mid-70s to the LSU system. He said only one condition, and it's written on a piece of paper: I want you to build the best nutrition research center in the world. And of course it takes time to reach this level, but at least it was the aspiration. The first director came in the mid-80s and it's been running now for more than 30 years.
I'm involved in two large NIH studies. One is called MOTOR — molecular transducers of physical activity. Those are discovery studies. They are multi-center, with clinical centers, a coordinating center, and a data center. It's really to assess what are the determinants or the predictors of a successful outcome when you engage in resistance training or endurance training. Another one is called Nutrition for Precision Health, powered by All of Us — it's an ancillary study of a larger initiative targeting a million Americans to understand the intersection between their usual nutrition and their health in general. We have sub-studies, a little bit smaller, to look at the impact of three different diets on markers of health.
I'm still doing studies of energy metabolism, metabolic adaptation in response to weight loss and in response to weight gain. Those are still ongoing, but they are not the newest kids on the block.
Mike Haney: I'm very excited about that study and I definitely want to have you or other folks on as that progresses to talk specifically about that study, because I think the potential for precision here is very high — because of all the things we're going to talk about in terms of individuality around energy intake and energy expenditure.
Redefining obesity: clinical versus preclinical, and why BMI isn't enough
Mike Haney: I thought maybe by way of starting on the obesity big-picture side, we'd talk a little bit about the statement you were a part of in The Lancet last year around redefining how we diagnose obesity. Can you talk a little bit about what your group was aiming for with that paper — and maybe specifically this notion of clinical versus preclinical obesity, and what the utility is of this new definition at this moment in the obesity epidemic?
Eric Ravussin: BMI — the body mass index, which is basically based on your height and weight in a metric system — has been used since the late 70s or early 80s. But everybody knows that this is not a faithful index of how much fat you have on the body. A football player with 5% fat and high weight and very muscular would be obese by the BMI standard. BMI does not truly reflect body fat and doesn't give you any indication about the distribution of fat — and we need something better. Ideally I would like a measure of your body fat, and we're getting there. The technology is improving. I mean, I worked a long time with the Pima Indians and we were drawing blood to measure blood sugar, and then we had sticking the end of the finger to measure blood sugar, and then we started to have CGM — and those progressions are happening. For example, now there are digital methods using your camera and turning around to measure your circumferences and measure something which is better than BMI.
The Lancet commission was really tasked with giving a new definition of obesity, and second, distinguishing between clinical obesity and preclinical obesity. To have confirmed obesity, we need not only BMI but a confirmation. It can be waist circumference, it can be waist-to-hip, it can be waist-to-height. But the best would be percent body fat. Now, there are methods — the DEXA — but of course people cannot afford to have a DEXA machine in their medical office. There's bio-impedance, which is becoming cheaper and cheaper, and there are developments of digital anthropometry like I mentioned. You need two measures to characterize what we call confirmed obesity.
After that, when you have confirmed obesity, we need to know more about your medical history, your family history, your health and disease state, the medications that you take, and all of that. The distinction of clinical obesity is that this confirmed obesity is associated with one of 18 conditions — which are basically tissue and organs impacted by excess body fat. Let me give you the example of the liver: if you have a fatty liver and you have some fibrosis in the liver, it becomes a problem. We need the BMI confirmation, and then we go through these 18 different characterizations of organs and tissues to ask: are they impacted negatively by this excess body fat?
If the answer is no for all 18 parameters, you have preclinical obesity — excess body fat, but you are not yet suffering the impact of that excess. That doesn't mean you don't treat it. You still have to reduce the risk and indicate lifestyle interventions. But maybe we won't use drugs unless the excess body fat is too large.
If you have any of those 18 conditions — going from cognitive function to sleep apnea to obstructive breathing to problems with your lungs to problems with your joints, going from top to bottom — that is called clinical obesity. Here you need to target first the tissue which is affected, and also the excess body fat itself. It's a little bit more the treatment of an illness when you have clinical obesity, whereas with preclinical obesity it's basically reducing the risk of developing clinical obesity.
What energy expenditure actually is — and its many components
Mike Haney: I want folks to take away from this episode that energy balance isn't just a model or a theory — it is physics, it is physiology, it is just the way the body works. And there are two sides to it: energy intake and energy expenditure, where you've spent much of your career. People might think energy expenditure is just metabolism — fast or slow — or maybe exercise. Can you walk us through what energy expenditure actually is and all the different ways the body is burning energy in normal life?
Eric Ravussin: Energy expenditure is the oxidative production of ATP — of energy — and there is a byproduct to that which is heat. That's why you can measure energy expenditure by heat losses or by oxygen consumption. We measure the amount of oxygen which is basically taken in and the CO2 which is given out, and according to this you can calculate how much carbohydrate or fat or protein are oxidized to generate this ATP.
This overall energy expenditure over, let's say, a day can be broken down into different components. You have the sleeping energy expenditure, which is your lowest basically energy requirement — it's when you are sleeping. When you are awake, you have already 5 to 10% more energy even still being on a bed not moving, because your brain is thinking, you are watching things, you are smelling things, and so on. We go from sleeping metabolic rate to basal metabolic rate — very few people measure basal metabolic rate because there are so many rules around it. We measure usually resting metabolic rate, which is about 5 to 10% more than sleeping metabolic rate.
On top of that, you need to eat to provide these calories that you oxidize to generate ATP, and there is a cost to eat. You basically have to ingest food, transit it through your esophagus and stomach and gut, and then you have the absorption of these nutrients through the gut membrane, and then this goes into your circulation, and then it's stored — because we burn energy 24 hours a day but we may eat one, two, or three meals a day, and therefore there is storage. It costs energy, and it's called the thermic effect of food.
Then on top of that you have energy expenditure related to what I call spontaneous physical activity. We used the word "fidgeting" one time in one of our publications and it was berserk — there were cartoons saying "oh fidget and you're going to lose weight." But anyway, it costs energy, something between 200 and 300 calories a day, not doing anything but being moving — like I am now, you moving your head and your hands and so on. That's called spontaneous physical activity. And then you have voluntary physical activity — you walk to the other office, you go on your treadmill, or you go for a jog or a bicycle ride — and this is also an important part of the energy expenditure budget during a day.
Mike Haney: That's really helpful to understand the various pieces of it. And I think it's interesting — the point about the way that the fidgeting discussion got misinterpreted speaks to what we're going to talk about next, which is how this energy expenditure intersects with obesity and with weight maintenance and weight loss.
Metabolic adaptation: why the body defends its previous weight
Mike Haney: Let's talk about metabolic adaptation, because that's really what we're talking about here — the body's ability to change that energy expenditure level across those different components as our weight changes. Maybe define metabolic adaptation just to start and talk about some of the basic mechanisms that are at play.
Eric Ravussin: Metabolic adaptation is, just as you said, in response to a weight change — and it can be weight loss or it can be weight gain. There is a mechanism which kind of defends the previous weight. I don't like the word "set point," because a set point to me is something which is constant in physiology. It's your body temperature of 36.5°. It's your fasting blood glucose between 85 and 95. Those are the same for everyone. Whereas weight can be 120 kilos versus 70 kilos. That's why I like the word "settling point." You tend, for your biology or your genetics in a given environment, to gravitate around a weight.
Now if you disturb from this weight, there are mechanisms which tend to defend it and return to this weight. Basically, if you lose weight, there's a drop in energy expenditure which is larger than what you would predict on the basis of the loss of weight — or better, on the basis of the loss of fat-free mass and fat mass. Or even better: we have measured in response to weight loss the organ and tissue size. You can take the loss of skeletal muscle, the loss of adipose tissue, the loss of size of the liver — and still you find that your energy expenditure is decreasing more than what you would predict on the changes in body size. And the same thing when you gain weight, but in the other direction: basically your energy expenditure is increasing more than what you would expect on the basis of the new body size.
I don't like the word 'set point' because a set point to me is something which is constant in physiology. I like the word 'settling point' — you tend, for your biology or your genetics in a given environment, to gravitate around a weight.
— Dr. Eric Ravussin
Mike Haney: Just to unpack a little bit of what you just said — because I think it's often unintuitive. People will talk about a fast or slow metabolism. They'll look at somebody who's genetically thin and say, "you must have a really fast metabolism, you must burn a lot of energy naturally." But in fact, the bigger your body is — just more tissue, fat mass or non-fat mass — you're going to burn more energy. Is that right?
Eric Ravussin: Absolutely. The reason I came to this country was that I was invited by the NIH to build the first metabolic chamber in the US, and it was done in Phoenix, Arizona, because of the studies in the Pima Indians. My first publication was taking people with normal weight, with overweight, and with obesity, and we found that in a metabolic chamber doing nothing, the energy expenditure — or the oxygen consumption — of those living with obesity was much higher than those at a lower weight.
I remember reading Lavoisier — he said the flame for some animals is larger than for others. He was equating energy expenditure to a candle: you burn energy, you produce heat, you use oxygen and produce CO2. He was studying rodents and said the flame in some mice is larger than in others. And it was true. Body size is the major determinant of your energy expenditure — and not only your weight, but really the weight of your brain, the weight of your liver, the weight of all the organs and tissues. As a simplification we take fat-free mass and fat mass and adjust for that. And indeed there is some variability between people. At the exact same body composition and weight, some people may burn in resting or sleeping conditions more energy than others.
Mike Haney: So there is individual variability. Just as a kind of basic — when you talked about the idea of metabolic adaptation being that bodies will burn more energy than you would expect given the change in tissue — that's because those tissues are burning energy. If we just extrapolate "I gained 20 pounds so I'll burn this much more," it's not a perfectly linear equation. You're going to burn more energy than one would expect just given that change in tissue.
Eric Ravussin: Absolutely. And there are physiological mechanisms behind that. In response to weight gain you have an increase in what we call sympathetic nervous activity, which is a determinant of your energy expenditure. You also have a change in the thyroid axis — thyroid hormones which are important for your metabolism. And the same thing in reverse when you lose weight. I think we have some good biomarkers or physiological mechanisms to explain this change in energy expenditure which is larger than what you would just predict on the basis of size.
Mike Haney: I want to come back briefly — before we get into more of those mechanisms — to this idea of a settling point of weight. Obviously folks are built differently. Some people are just naturally by genetics bigger, smaller, more muscular, maybe carry more fat mass, have different size adipose tissue cells to store more or less fat. But we're also dynamic creatures who change over time. As I watch my cohorts — a lot of the friends I grew up with who were built like me when we were 18 — a lot of them are now a lot bigger. Does our resting metabolic rate or the natural energy expenditure we have just change over time with age or with small fluctuations? How much wiggle room is there in that settling point?
Eric Ravussin: First of all, that's why I call it settling point and not set point — because with a set point you'd like to go to this weight and there's no room. There is some wiggling room. And what's really important is to understand that the resistance to weight gain or weight loss is not all due to metabolic adaptation. You have the other side of the energy balance equation — food intake. If you starve yourself or go on a low-calorie diet, you're going to be hungry and driven more towards food and your appetite is going to be higher. It means there are the two sides of the energy balance equation which are in play, and we have to understand the interaction between these two sides.
But yes, there is wiggling room. And yes, at the exact same age, same sex, same body composition, you have plus or minus 200 or 250 calories between people. That's important on the long term. For example, smokers are about 3 kilograms lighter. Nicotine is shown to increase metabolic rate and to decrease food intake and appetite — and you always have these two things going together. The increase in energy expenditure and the decrease in appetite is going to bring you to a lower weight.
These new drugs — the GLP-1s — are mostly targeting food intake, but now we have this problem of metabolic adaptation. If you want to be more successful at losing weight and then maintaining weight loss, it's good to have also a pharmacological agent which would stimulate slightly your energy expenditure.
The Biggest Loser study: when extreme weight loss leaves a permanent mark
Mike Haney: So the way this intersects with people sort of living their life and trying to lose weight — and maybe this brings us around to the Biggest Loser study — is basically an explanation of why it's just so hard to keep weight off. The traditional narrative is people can't keep the weight off because they're lazy, because diets are hard, they can't stick to it, exercising is hard. And what the metabolic adaptation reveals is that there are real physiological mechanisms going on — whether that's the thyroid, other things controlling those rates, or on the hormonal side which is affecting our intake and literally making us hungrier and decreasing our satiety. So what did you learn in that Biggest Loser study — the sort of extreme example of this? I know that was Kevin Hall's study but you worked on it as well. These people that lost a ton of weight — as I understand it, the metabolic adaptation persisted even six years in, was still something on the order of 500 calories of delta. Why did that happen, and what did that teach us about the persistence of this metabolic adaptation?
Eric Ravussin: I was personally also surprised when Kevin Hall got these people back to measure their resting metabolic rate. They were so low that reviewers when we submitted the paper challenged us — was it the same exact equipment? We shipped our equipment to Bethesda and all that. But I'm convinced that basically you have an imprinting from this drastic weight loss which basically perpetuates a higher energy efficiency. Even though some of these people had regained — not all their weight, but maybe 70% of their weight on average — they were still more energy efficient for their new body size.
What are the mechanisms? I wish we could do more studies. This is not the kind of study we can do in humans because it would become very invasive, but in rodents or better in monkeys which are closer to humans — to try to really look at all the different mechanisms underlying the variability in energy expenditure.
Mike Haney: Have you seen anything in other studies you've done where the intervention hasn't been as drastic? This is obviously a very strange kind of natural experiment — you've got this show existing that's putting these people through this insane process. Something like 40% of their mass they lost in a relatively short period of time, something like six months — a lot of exercise-driven, a lot of calorie restriction. One notion is that the drastic nature — a very rapid kind of weight loss — is what essentially locked the body almost by accident into this different energy expenditure model that it just couldn't escape even when people started putting that weight back on. Have we seen anything equivalent? Do we have a sense that there is a kind of linear notion — if I'm not quite so drastic in the weight loss, is there a point at which the body will adapt in the way you would expect, or do we see this persistence even in subtler weight loss situations?
Eric Ravussin: Unfortunately we have not designed very careful studies to address your question. There is the magnitude of the weight loss. There is the speed or the rate of the weight loss — to reach let's say 10% weight loss, some reach that in two months and some in six months. You obviously have less of a negative energy balance in those who lose over six months, but they get there. And it would require designing studies to exactly answer your question — what are really the consequences of the rate of weight loss and the magnitude of the weight loss?
The magnitude we can do some calculations on, because the Biggest Loser "winner" lost almost 50% of his weight and the "losers" of the Biggest Loser lost about 30% — and we can do some calculations, but it's not a proper study. The only thing is that it was six months for everyone, but the rate of weight loss was quite different from one to another — and does the metabolic adaptation increase with time, because the body feels more of a threat as it continues? Unfortunately I cannot answer your question and it would require designing specific studies to address that.
Mike Haney: Because as you say, even within that relatively small cohort of people — I think it was something like 15 or 16 people — even from the most to the least, you're still talking about people undertaking a drastic weight loss. Thirty percent weight loss even in six months is pretty extreme. Maybe it's a good place to talk about the CALERIE study.
CALERIE: two years of caloric restriction and what it revealed about aging and efficiency
Mike Haney: CALERIE was a very large study that you did over two years — probably the best study out there in terms of thoroughness on caloric restriction. What did we learn about energy expenditure through the folks who participated in that two-year caloric restriction study?
Eric Ravussin: Let me first state what was the reason to do the study. We cannot do a longevity study in humans because it would take 150 years to conduct a study like that. And that's why we looked at biomarkers. There is anecdotal evidence — first in insects, fish, rodents, and monkeys — of an expansion of the maximum lifespan with caloric restriction. The study was designed to look at biomarkers of aging: your strength decreasing with aging, your vital capacity, your VO2 max, physical fitness — we looked at all these things. And personally, because of my experience, I was interested in one of the drivers of aging which is oxidative stress — totally linked to the oxidation of substrate. When you transform glucose into ATP using oxygen, one of the byproducts if the reaction is not perfectly efficient is what we call reactive oxygen species. We were interested in: do people who have the best advantage show a bigger drop in energy expenditure and become more efficient and therefore have less oxidative stress? That's why we linked energy expenditure to aging here.
There are some interesting studies showing — and they were not very well controlled — that the Baltimore Longitudinal Study on Aging showed that those who had lower metabolic rate, measured in the 70s and 80s, had less mortality at a younger age than others. A low metabolic rate is a risk factor for obesity, and obesity is not good for longevity — so it's still difficult to totally understand the whole story.
Mike Haney: Just so folks are connecting that — a low metabolic rate basically means your body is more efficient, but that also means it's easier for your body to essentially pack on extra weight, because it's not burning through that substrate as freely as a less efficient person might.
Eric Ravussin: Yeah.
Mike Haney: How did those folks' energy expenditure change over time? As I understand it, one of the hallmarks of that study was that you had really good adherence — one of the challenges obviously with any kind of caloric restriction is that it's really hard to do, for all the reasons we just talked about. Your body pushes back. Your body wants you to put that weight back on, get back to your settling point. You're going to get hormonal signals that tell you to eat more. Your energy expenditure is going to change. But you had really good adherence over quite a long time of people taking in something like 20 to 25% fewer calories.
Eric Ravussin: 318 starting the study and maybe 180 finishing the two years — which is quite amazing. And to be honest, some of the dropouts were more in the control group, because they were disappointed. They were kind of selected as doing something good for their health even though they had no obesity to begin with — it was just normal weight and some overweight, from a BMI of 22.5 to 27.5. Some people came in and said, "I'm going to benefit from this help to eat less," and ended up in the control group. I remember our first participant — she came into my office and she was crying. "I'm in the control group. That's not what I came for." But anyway, there was very good retention. There was a lot of hands-on over these two years with visits and support. I remember one of our participants here — the first three months they came to take a lot of their meals with us here. His daughter was asked in school or preschool where her dad was working, and she said, "My dad is working at Pennington, because he was always with us."
But to answer your question: yes, we had very good retention. Yes, there was variability in metabolic adaptation, and some of this variability was associated with some of these indices of oxidative stress — we measured lipid peroxidation, we measured by what is called the comet assay damage to your DNA — and they were all consistent, if not significantly improved.
Mike Haney: So was one of the takeaways that the reason these folks were able to maintain that calorie deficit for so long — despite their body pushing back, despite metabolic adaptation at work — was just the support they got? It was just an environment that was helping them do that.
Eric Ravussin: Absolutely. But to be honest — we have a study now ongoing which is called CALERIE Legacy. At our site, and there were three sites — Washington University in St. Louis, Tufts in Boston, and LSU — I had a follow-up two years after and we published a few papers on that. But now there's an official study from NIH getting these people 20 years later. And surprisingly, quite a few of these people have learned from the experience and have continued to impose on themselves some caloric restriction and are being cognizant of the benefits. It's amazing to think that 20 years later they are still applying some of the things that they learned during those two years. The prescription was 25% caloric restriction. What we achieved as measured by doubly labeled water was about 14%. But now they are still — I'm going to say "behave" — they are still imposing themselves some caloric restriction.
It's amazing to think that 20 years later they are still applying some of the things that they learned during those two years.
— Dr. Eric Ravussin
Mike Haney: I guess what I'm getting at is contrasting a little bit that Biggest Loser group — an extreme form of weight change — where the body has this somewhat unexpected response that persists. A lesson out of that is probably that crashing your weight 40% over six months, going crazy on an exercise bike until you're almost killing yourself, is probably not the best way to long-term lose weight. Whereas we look at this CALERIE group who did a simpler caloric restriction — not easy, 14% effective even targeting 25% is a pretty significant change in day-to-day habits — but that they were able to persist. Are there lessons in these studies for folks who are trying to lose weight, knowing that these processes are happening in their body in the background and they can't get rid of them — it's just physiology — about how you can change your weight in a way that will stick?
Eric Ravussin: I really don't know. But I should say — at the end of the Biggest Loser, the end of the six months, the metabolic adaptation average was about 350 calories. Six years later it was close to 500. There was this question of different equipment and so on. But the metabolic adaptation in our subset of CALERIE people measured in our chamber here was on the order of 100 calories — 90 to 100 calories. It means it's less to begin with, with this 14% caloric restriction and about 10% weight loss in non-obese people. And I think the magnitude of the weight loss is a factor playing an important role in this metabolic adaptation, and as we discussed earlier, the rate of the weight loss is also important.
Diet composition and the calorie versus carbohydrate debate
Mike Haney: On the energy intake side — do we know anything from the work you've done or other work about the difference in macronutrients? Low-carb versus low-fat. Those things are oxidized a little bit differently in the body. Do we know anything about how that side of the intake equation might change the energy expenditure side?
Eric Ravussin: We have done a lot of studies manipulating the composition of the diet. The extreme study we did was with Peter Attia and Gary Taubes — for NuSI — and their hypothesis was that the low-carb diet was better than a low-fat diet for weight management. They hypothesized that the low-carb diet, by decreasing insulin, is really a situation in which the body would feel that there is a lack of calories, and therefore — if you have too much carbohydrate — it increases food intake and decreases energy expenditure. We could barely confirm something like that. There was a very small impact of a ketogenic diet — because it really was ketogenic — on increasing energy expenditure by about 60 calories per day. Really minimal. Kind of a disappointing result.
I was happy myself because I still believe in the low-fat diet for the management of obesity rather than low-carbohydrate diet. And I hate to be a scientist and say "I believe" — but there's a lot of data showing that during the weight loss phase it's the calories which count. Whatever you can manage to decrease your amount of calorie intake. After the weight loss, maintenance is a different story. And a low-carbohydrate high-fat diet is not ideal for sure.
Mike Haney: Let's talk about that a little bit more — both the point of weight loss versus weight maintenance and how the body's machinery is working differently in each of those situations. And maybe tie it into the idea of these other theories around obesity. We just talked to Gary Taubes — he can defend the carb-insulin model. We've had Rick Johnson on talking about his fructose-mediated model. We've talked to Rob Lustig about an obesogenic model. What I think is interesting is that what you see are these so-called debates — Gary Taubes yelling at Kevin Hall that energy balance is completely wrong and forget the calories and it's all carbs. But it strikes me that energy balance is the set of constraints under which our bodies are operating, and these other theories — whether it's carbs, fructose, or obesogens — are all contributors potentially to that machinery. They're all affecting it. But none of them are a monocausal explanation for obesity or weight gain. How do you think about those mechanisms, particularly around weight maintenance versus weight loss?
Eric Ravussin: NIH finally had an RFA for the study of weight loss maintenance, and there is an ongoing study called POWERS. We'll learn quite a bit from that. But there's no question that there is a different physiology during weight loss, because you are in negative energy balance — and therefore you have this lowering of your thyroid axis, this lowering of autonomic nervous sympathetic activity, and these orexigenic hormones — ghrelin and others — pushing you to eat more. I don't think it's the same case when you have reached an energy balance at a lower weight. Here it's really your physiology and your genetic makeup which should make a difference.
If you take the National Weight Control Registry from Jim Hill and Rena Wing, there are some characteristics of these long-lasting weight loss people: they all become almost obsessive about exercise. The question of whether they skip breakfast or not I'm a little less sure about, but there are characteristics of these people. In general, it all depends on the interaction of your genetic makeup with the environment. To avoid the relapse, one thing is to modify your own environment. Some of these successful weight maintainers really change what's in their fridge. They really change the way they park when they go to the grocery store. They really start to use the stairs. I'm giving you simple examples that people understand, but they change their own environment. And I think this is a strategy — if your genes are driving you back to regain.
The Pima Indians: the same genes, two completely different environments
Mike Haney: My experience with the Pima Indians — that's the epitome of what you're describing. They have among the highest rates of obesity and diabetes in the world. You had one population in the US in a more typical American food environment, and then a closely related population in Mexico that, when you first started studying them, had less of that. Can you talk about what comparing those two populations taught you?
Eric Ravussin: All of us developed mostly genes to protect ourselves against famine and not to protect us against abundance. And I think that we have a much stronger defense for caloric restriction than we have for excess calories. That's why I think the distribution of BMI — and I can take the example of Pima Indians living in the mountains in northern Mexico, in Sonora state near the border, versus the Pima Indians in Arizona — you have a distribution of BMI that is the same but not as wide in the Mexican Pimas. It's much wider in the American Pimas. And now they have changed their environment — they have running water, they have electricity. We had a follow-up ten years after our first survey and they had already gained three or four units of BMI. The environment is really the driver, and the variability in the response is associated with your genes or your learned behavior in protecting yourself in this obesogenic environment.
Mike Haney: And it's interesting that you talk about the separation, because I know there's a question about how long ago those populations separated — but at least there's a kind of baseline genetic susceptibility in terms of natural settling point and how they would adapt, and then really what difference does the environment make.
Eric Ravussin: We have genetic typing of these people. The language — they can understand each other, the Pimas in Sacaton or the Gila River reservation versus the ones in Mexico — and the separation is anything between 450 years ago to 750 depending on the approach you use to look at it.
Mike Haney: Just to bring this back to the kind of lived experience of people — when we're attempting to lose weight, we are putting ourselves in an energy deficit situation. Our body is going to fight back to some degree. But the notion is that once we reach a new level, our body can adapt down to that new level — but not completely. We're still going to have to control the environment, do all the things you talked about, to maintain that lower point. And if we don't, the body is naturally going to want to rise back up to whatever point we started from. Is that a fair summary?
Eric Ravussin: Yeah, it is. But the question is — if it was a set point, which I don't believe it is, it's a settling point — can you reset it? It's easy on a thermostat in your house. But here, after changing your body size, can you dial down the mechanism of energy balance to mean maintaining a higher energy expenditure and having less of an appetite? I don't think we are there yet.
GLP-1 drugs: a revolution with real concerns
Mike Haney: Well, that's probably a good bridge to one way we are now experimenting with how we change this — through the GLP-1s, through drugs. We talked about the two ways energy balance shifts: one is the mechanisms of the body, the other is what people might call the hormone conspiracy — leptin and ghrelin acting within your body to make you hungry or more or less satiated. Now we've got drugs like GLP-1s that are essentially messing with that. How do you see the GLP-1s intersecting with this idea of metabolic adaptation and sustained weight loss?
Eric Ravussin: The major concerns with GLP-1s right now are two. The first is metabolic adaptation — that's why we're doing quite a few studies now with pharma about metabolic adaptation with different combinations of GLP-1 with something else. The public data from Eli Lilly involves glucagon, which we know increases energy expenditure, and therefore it would be a plus to have a combination they call the "triple G": GLP-1, GIP, and glucagon. Novo Nordisk is publishing a lot on their combination of GLP-1 and amylin or pramlintide. The hope is that you can associate the GLP-1 with something that would decrease this drop in energy expenditure.
The second concern — and I think it's kind of misleading — is the belief that we lose a lot of skeletal muscle. When you look at, say, 27% weight loss on average with the amylin combination, there is about two-thirds of the weight loss as fat mass and one-third as fat-free mass. And people unfamiliar with the methods imply that there is a lot of skeletal muscle mass loss — but it's not measured. That's why now we need MRI data, really measuring the volume of the skeletal muscle in the arm and legs. And actually, physical functionality is improved. I just gave a talk at the Obesity Society showing that in response to the GLP-1 and amylin combination from Novo Nordisk, there was an improvement in physical functionality because they lose so much weight — it makes sense, you are more mobile — but also a slight improvement in strength, despite what people are claiming about muscle loss.
So yes, these GLP-1s have been a revolution — to see the magnitude of the weight loss. But it comes with concerns: metabolic adaptation, regain of weight, and this potential loss of skeletal muscle. And of course — if you take hypertension drugs and you stop them, your blood pressure comes back. The whole deal now is: do you have another drug to maintain the weight loss, or do you just taper down the drug until you can titrate and keep the weight loss? But to say that you've lost your 20% in one year and we can stop the drug and you're not going to regain it — that's a total aberration to me.
To say that you have lost your 20% in one year and we can stop the drug and you are not going to regain it — that's a total aberration to me.
— Dr. Eric Ravussin
Exercise: essential for health, but not the weight loss tool most people think
Mike Haney: One of the loose headlines I put on this podcast is "why you can't exercise your way to weight loss." How do you think about the role of exercise both within weight loss and then also weight maintenance? Obviously it's one of the best interventions you can do for long-term health for all kinds of reasons. But it would still seem, given these mechanisms we're talking about, that extra caloric burn through exercise would help with weight loss and would help with weight maintenance over time.
Eric Ravussin: I have been an exerciser all my life and I like to exercise — I have a good feeling from exercising. But exercise is not burning a lot of calories. One mile, depending on your weight, is 120 to 150 calories. Are you going to ask people to run two miles or jog two miles a day to burn 300 calories when they can just cut down with the GLP-1 by 500 to 600 calories a day? It's difficult.
I was fortunate to work with a British physiologist called John Garrow, who did a study in the late 70s and early 80s on three intensities of exercise. The moderate and medium intensities were stimulating food intake — after doing that exercise acutely, or even over a week or two, you have an increase in food intake and appetite. It's only the higher intensity which was really cutting down on appetite — the anorectic effect of the exercise. And most people, when it comes to weight management, there's no way they can do high-intensity exercise. We had Tim Church here who did a study called E-MECHANIC to look at the compensation, and it's mostly a compensation on food intake — the fact that you really don't lose weight with exercise alone. It is helping for weight maintenance, though.
Mike Haney: Is the helping on the weight maintenance side because adding skeletal muscle tissue has its own benefits — whether that's increased glucose uptake, or just that more tissue burns more energy, and skeletal muscle is a good efficient user of substrate as opposed to fat tissue?
Eric Ravussin: I think it's possibly why it's helpful. But again, now because of GLP-1s and this concern about skeletal muscle loss, there is a lot of push toward higher protein ingestion and adding some exercise to maintain skeletal muscle mass. I think it makes sense. But the question is — are people ready to include exercise? You talk to people and see a lot of volunteers for studies say "I don't have the time to do that" — that's usually the answer. Whereas people take the time to eat, and if you eat less, that's okay. So the GLP-1 route has a certain practical logic.
The core misunderstanding — and why it's not your fault
Mike Haney: The last couple of questions I just want to ask on the communication side, because that's sort of my role in this — I'm a professional explainer of these things. What's a key misunderstanding about obesity that's out there in the public narrative that you wish you could correct?
Eric Ravussin: I'm not going to tell you anything new, but it's still out there at large: there is this concept that obesity is due to you eating too much and not exercising enough. We have been failing for 50 years by listening to that. To me, what we need to accept is that humankind was evolved to protect ourselves from starvation — to allow the Pima Indians to be reproductively successful despite periods of feast and famine, to enable survival of the fattest babies. There is natural selection for a thrifty genotype, not for a spendthrift genotype.
I like to show this curve that really took off in the early 80s. The prevalence of obesity was kind of flat after the war until the late 70s, and then it took off — and it's mostly because of the change in the environment, acting on a genetic pool which has not changed. The misconception is that people still think: I eat too much, I don't exercise enough. Maybe true. But is it your fault?
When I did the first visit of the Pima Indians in Mexico, I came back and was invited to present the data to the tribal council of the Pima Indian tribe in Sacaton, southeast of Phoenix. At the end there was a long silence, and the chair of the tribe said, "Eric, do you think I'm not going to buy a bicycle for my son because I know that he's at risk of gaining weight and developing diabetes?" It was fatalism. We have a genetic pool which is deleterious in this environment of abundance. We have been aspiring to have a pickup truck. We have been aspiring to work less in the field. And this is where we are. How do you argue against that? I don't.
Mike Haney: So we're sort of victims of an intersection of having that thrifty genotype — our bodies want to maintain our adipose tissue, want to maintain our weight — but we're living in an environment that just makes it way too easy to do. Too abundant an environment. And so we have to be aware of that energy balance physiology as we fight against the environment, whether that's exercising or controlling what we eat or eating different kinds of foods.
Eric Ravussin: Yep.
Mike Haney: Perfect. Well, I think I'll leave it there then. Thanks so much for joining us today. This has been a super useful conversation.
Eric Ravussin: Thank you for the interview — and I'm impressed by how informed you are in the first place.
This article is based on insights from Dr. Eric Ravussin, a professor and researcher at the Pennington Biomedical Research Center at Louisiana State University, where he has studied energy metabolism and obesity for more than 40 years.