The Obesity Debate: Breaking Down the Science | Dr. Faidon Magkos

00:05 - Gabrielle (Host)

Faidon Magkos, we go way back. And you laughed at me and I said, Faidon we've been friends for over 10 years. Yeah, that's about right. That is about right. You are a professor in obesity and metabolism at the Department of Nutrition, exercise and Sports at the University of Copenhagen in Denmark, which, by the way, your flat looks amazing. Oh, thank you I you know it's really interesting because I met you at WashU. You were a professor at WashU. You, let's see, there's Harvard Medical School here.

00:46

You have published over 200 papers, with their impact factor of an average of 6.3. Each index is 54. For those who are not academics. Basically, I'm talking to a genius.

01:03 - Faidon (Guest)

Thank you Probably those who are not a genius. Thank you Probably those who are not academics. They believe you.

01:10 - Gabrielle (Host)

But you know, you said something to me that really struck me and I'm sure you don't remember this.

01:21 - Faidon (Guest)

I would normally say this would embarrass you, but it's not going to embarrass you, because most things don't. You said to me something that.

01:27 - Gabrielle (Host)

I've taken with me for over 10 years. You said when you are average or mediocre, nobody cares about what you do, do you remember saying that? But when you are great, people have these expectations. People have these expectations. So how I took that was basically, if you're functioning at a level and not producing and not providing, you know, it's kind of like great, whatever. But when you are exceptional, uh, there's a lot of criticism and there's a lot of focus on your work. Do you remember telling me that? Is that a fundamental?

02:04

I don't, but it sounds about right, and you do not have a Instagram YouTube channel or probably not even a Twitter account. I do not.

02:15 - Faidon (Guest)

Yeah, I do not. I typically don't disseminate my research in those channels, so this is an exception my research in those channels, so this is an exception.

02:26 - Gabrielle (Host)

Well, I feel very special and you didn't really have a choice but to say yes, there was no choice, and if someone were to Google your name, they will find a ton of citations, they will find a ton of papers.

02:42 - Faidon (Guest)

But I do want to mention that the quality of these papers, these are hallmark papers.

02:50 - Gabrielle (Host)

They are literature that has moved the field of obesity in ways that is so meaningful, and I don't know if anyone has ever said thank you.

03:06 - Faidon (Guest)

Thank you so much. I mean I think that you're too kind, but thank you so much for your kind words. I mean some papers are better than others. I mean that's the reality, right.

03:14 - Gabrielle (Host)

And this was published August: 2024

03:42 - Faidon (Guest)

There are really juggernauts.

03:43 - Gabrielle (Host)

We've got Kevin Hall, we have, you know, arnie Astroff. The list goes on and basically I want to know why you wrote it. I mean, why did you take this beast of a perspective on? And what was the perspective? And, by the way, I know it, but hearing it from you is way more interesting.

04:07 - Faidon (Guest)

of a background. Um, back in: 2023

04:58

It was about 15 or 16 people, pretty much as many authors, as you see in that paper and during these two days we had a lot of interesting discussions. Some of them were more heated than others. There was a lot of agreement, much more disagreement. So at the end of that workshop, we kind of thought that it would be a good idea to summarize. You know, what came out of this. I mean, did we spend those days in a meaningful way? Did we manage to achieve anything, or did we just go to to a very nice place that noble foundation kind of rented for us and we just wasted our time pretty much, you know, because generally speaking, scientists tend to support their hypothesis quite a lot. So it's always difficult to have people with very different perspectives and ideas to kind of get together and discuss in a way that is also very open, easygoing and transparent. Right, because that was not a conference so nobody really had to defend anything.

06:10 - Gabrielle (Host)

And I have to say to interject.

06:13 - Faidon (Guest)

You've played a huge role in the way that I think.

06:15 - Gabrielle (Host)

I don't know if you know that, but I'm sure you do, because I do call you freaking out on numerous occasions. Call you freaking out on numerous occasions and you always say to me number one, science is a science of uncertainty. Yes, absolutely. And you always challenge me why muscle, why this?

06:38 - Faidon (Guest)

Yeah, you're absolutely correct. When we say in science and now research that something is happening, we always say that with a certain level of being uncertain, which means that it might not always happen this way and it might not always happen for everybody in the same way, right? I consider myself relatively I mean, nobody can really be completely neutral right in this debate but I'm one of the people who kind of understand the arguments from both ends. And then I took on the task of putting all these discussions into a paper that everybody would agree on and then getting it out there for the public to kind of read.

07:34 - Gabrielle (Host)

And what are? Oh sorry, go ahead. I'm sure you're going to tell us the arguments and why.

07:40 - Faidon (Guest)

Well, I was about to tell you the process. So it took us many, many months and drafts and back and forth, because everybody needs to agree on the final version of the paper and all the actual words, not just the meaning. But we had back and forth in terms of trying to find the correct words to portray what these people believe and agree on, back and forth in terms of trying to find the correct words to portray what these people believe and agree on. So that task was not particularly easy. So it was one of the more difficult papers for me in terms of getting together all the authors to agree on writing a paragraph, and sometimes it took us forever to write the paragraphs but, thankfully, agree on writing a paragraph.

08:24 - Gabrielle (Host)

and sometimes it took us forever to write a paragraph but thankfully it all culminated in a nice paper that was published well, and now it's out there and give us the overarching themes of what people disagree on, what people agree on, and this really was what is the cause of what people disagree on, what people agree on it, and this really was what is the cause of is this a energy balance issue?

08:50

Is this a carbohydrate insulin issue? And I have to say, looking at the authors, when I saw this I couldn't believe it. As you'd mentioned, you have Kevin Hall, you have David Ludwig. There are people that have drastically different views.

09:07 - Faidon (Guest)

Correct.

09:08 - Gabrielle (Host)

And they're all very well respected.

09:12 - Faidon (Guest)

Absolutely, yes, absolutely. There's no question about this. And if you look individually at you know in the literature there is evidence to support arguments on both ends. Right, I mean, that's the reality of human research.

09:25

But going back to the two different ideas, or two different models, let's say that these two camps represent. One of them is, I would say, the most, the one that we were all pretty much brought up with and the one that we are more or less familiar with, which is the energy balance model. And what this hypothesis states is that obesity generally develops as a result of people eating more food, more calories, than the amount of calories that they burn. Right, and the main reason why this happens is that the modern food environment, predominantly the modern food environment, and the characteristics of the modern food supply, what they do is that they facilitate overeating below the level of your conscious awareness. So you eat more without even realizing it, right? So that's the general idea.

10:26

It so that's the general idea. So the excess calories, regardless of whether you eat more carbs or more fat or more protein, when you do not burn them, the body typically eventually tends to convert them and store them as fat. So you have an expansion of adipose tissue. So in the energy balance model overeating or positive energy balance precedes the adipose tissue expansion and the development of obesity. So that's what I would say most textbooks on dietetics and nutrition and obesity kind of portray as well.

10:58 - Gabrielle (Host)

And that's what we've all been taught, correct?

11:01 - Faidon (Guest)

So, to try to give you an analogy, right, right, correct, correct. So to try to give you an analogy, right, imagine that you go, let's say, on a Monday morning, you go with your car to the gas station and you put 10 gallons of gas Right, and then you take your car around, and as you go around, of course, you burn some of this gas, right? So at the end of the week, by Sunday night, you pretty much are empty. So the next Monday morning you put again 10 gallons of gas, and that goes on and on, but on every Sunday night you are always at zero, you are always empty, right. So you are in an energy balance in this case.

11:37

But imagine now that you decide to change gas station right, and this new pump that they are using, it kind of works a little bit in your favor, meaning that it reads that you are dispensing 10 gallons, but in reality you are dispensing 11. Okay, so now that you go around your daily life and do whatever you do during the course of the week, but now, at the end of the week, on Sunday night, you are left with one gallon in the tank. Right Now you think, however, that you are left with nothing. So next morning you put again another 10 gallons of gas, as you think, but in reality another 11. So if this goes on, you accumulate one gallon of gas every week.

12:26 - Gabrielle (Host)

And this gallon is fat, or this gallon we're talking about fat. Are we talking about calories, correct?

12:32 - Faidon (Guest)

If you do not, let's say, strive to do something with physical activity, most of the excess calories are being stored as fat. Nonetheless, as the time goes on and your weight increases, imagine this as a form of passive training. So obesity is also associated with an increase in lean mass and muscle mass, because you need the additional muscle to carry the much more weight of your body right. So most of the weight gain is fat, but part of it is lean mass and muscle.

13:06 - Gabrielle (Host)

Lean mass and muscle and I'm just going to mention this and you and I certainly discussed this it doesn't necessarily reflect the health of that tissue.

13:16 - Faidon (Guest)

Absolutely, but I will get back to that. We can get back to that. So this is the energy balance model and the idea is that, because of the food supply has changed and now we have these ultra-processed foods which are calorie dense and they have a lot of other ingredients in them, that kind of mask or saturate the ability of our brain to understand how much we eat. That's the general idea. So it all starts with eating more than what you need in the energy balance model and then the end result is an expansion of adipose tissue and obesity and muscle Correct and muscle to some extent. So also energy expenditure goes up along these lines, right. So the total energy expenditure of the body goes up simply because you have a larger body right now. So for any sort of activity you do, you burn more calories right Now.

14:11

The other model, that is, let's say, the contender, is the carbohydrate-insulin model of obesity, right, and that model suggests that the primary defect is not really the brain that does not understand how much you eat, but it's something that happens in your body, the peripheral organs, say in the liver or in the adipose tissue or the skeletal muscle. So the handling of the incoming nutrients and the incoming food is changed, and it's changed in the way that you cannot utilize all the calories that you ingest for doing all sorts of things that you want to do. Right? To put it back in the analogy of the car, let's assume now that the pump is functioning correctly, so you're putting 10 gallons, but the tubes that transfer the gas or the fuel from your tank to the engine, they have leaks, so you cannot take advantage of all the fuel that you entered in your car, right, does it make sense?

15:11 - Gabrielle (Host)

The chicken or the egg? What came first Is it? Are we over-consuming food and then getting an adipose tissue right? It would be considered hyperplasia. Would that be considered hyperplasia, or?

15:27 - Faidon (Guest)

consider hyperplasia. Would that be considered hyperplasia? Well, hyperplasia and hypertrophy refer to two characteristics ways by which tissues typically increase and grow. Hyperplasia is that I am making more cells, and if we are talking about adipose tissue hyperplasia, then you would make more adipocytes, so the number of cells increases.

15:44 - Gabrielle (Host)

Hypertrophy means that the cells themselves grow bigger right, and is that what happens when someone… Typically, both.

15:53 - Faidon (Guest)

Typically both happen in obesity, although hypertrophy is more pronounced.

16:00

So, typically you develop larger adipocytes rather than more cells when you develop obesity in your adult life. But going back now to the carbohydrate-insulin model, so what this suggests is that since your body cannot, let's say, take advantage of all the calories that you just ate, it signals to the brain and it tells your brain that you know what I need more food, right, even if you have it in your body but you just can't utilize it. So the brain, then what it does, is that it tells you that you either need to burn less so it will make you make your energy expenditure lower to match what you have or what you think you have or, most commonly, it will make you overeat. So in the carbohydrate-insulin model, the causal chain is reversed, meaning that you start first from depositing more of the ingested calories into fat and then this leads you to overeat. I see, I see. So in the carbohydrate-insulin model, it's something that happens in your periphery, that then signals the brain to eat more, whereas in the energy balance model it's quite the opposite the first eat more and then you deposit those calories into fat.

17:26

I see, and as you mentioned, the chicken and the egg, that's something that is extremely difficult to dissect in humans right, because we would have to take people who have normal body weight and then perhaps overfeed them for a prolonged period of time until they become obese and see what comes first. But this is not possible in humans to do. The best model that we have so far for weight gain and obesity is these overfeeding studies where we experimentally feed people more than what they need. But this is typically a very large extent of overfeeding. So let's say we feed them 1,000 or 2,000 calories per day more than what they need for a few weeks. Right, that's not typically how obesity develops. Nobody goes to bed being lean and wakes up the next morning being obese. Typically, obesity develops by at least that's what we think is by eating a few more calories than what you need on a daily basis for years. So we do not have really a very good model for human obesity in research.

18:36 - Gabrielle (Host)

We don't. I want to restate that because many of us who are not academics and, as you know well, you might not know because you're not on the social media circuit or sphere, but there's a lot of information out there and the discussion is stated in ways that it seems as if these are absolutes. Yeah, this is we'll review literature and then you'll have influencers or scientific educators, then speak to the public, and a fundamental concept is that I think it's important to highlight is we don't actually have a good model of obesity to study, and the foundation of the work is built on the best that we could do is is that fair to say yes and I would say you know all the.

19:37 - Faidon (Guest)

So one thing with the, with the social media and the influencers and all these arena is that you know you have to always defend or try to convince people why things are not necessarily as stated in the social media. You know what I mean and that's a little bit tiring.

19:59 - Gabrielle (Host)

Explain to me a little bit more. I agree.

20:02 - Faidon (Guest)

So you know there is a lot of the new trends in the fads and the diets that come up from time to time stem, for instance, from studies in animals or from a single study in humans, and their results are very good because they are very good to make a headline, but nobody really digs deeply to understand the limitations of the study. What does one study mean? Nothing really, right. There is no definitive study, research in humans at least or, generally speaking, science. You have to consider every study as a little brick and we are trying to build a building. So if you take a brick and you focus on that brick and you tell me, look the story, that brick tells you it's really relevant for the whole building, right. So that's kind of the analogy that I try to give to my students as well, when it comes to a single study versus understanding what the whole literature shows.

21:04

Now, coming back to obesity in humans, for instance, right, to give you an example, in the overfeeding studies we are very successful. We take people in the lab, we can overfeed them. We can make them gain 5, 10 kilos, right. But remarkably, when we send them home and the study is finished, the majority of them, within a, a few months, lose that additional excess weight effortlessly, without even doing anything, according to their you know testimonials. So this is completely different to the model, to the real obesity that we have in real life, where people struggle to lose weight Right, yes. So how good of a model. That is Probably not so good. And of course, you know, there is not even a point in discussing the animal studies, because it ends up with different species right Completely different.

21:56 - Gabrielle (Host)

And whether you're ad libitum feeding them, it is, so it's very easy to pick up the results.

22:02 - Faidon (Guest)

You know to cherry pick and make a story. That's not a difficult thing to cherry pick different findings and make a story. What is difficult is to say that, ok, if all of these let's say, magical diets or reasons why we get obese and why we lose weight and don't lose weight, if these were true, we would have solved the problem already, we wouldn't have obesity. But we still do have obesity and we are very much unsuccessful in treating it.

22:31 - Gabrielle (Host)

I want to ask you a question and I want your opinion.

22:37 - Faidon (Guest)

Now notice, I said your opinion, or maybe your informed opinion.

22:42 - Gabrielle (Host)

Why do you think we have obesity?

22:50 - Faidon (Guest)

Well, you know I would say that, as neutral as I try to be, I think that the major factor is that you know food is nice and eating is really it's an enjoyable activity right For you For pretty much everybody I would say and you know the fact that the modern food supply helps you overeat. So you eat a slice of pizza or a hummigan and that's 500 calories. If you eat it in vegetables and fruit, that will be a bucket of fruit right, or vegetables and volume. So energy density is a major factor. But there is a lot of other reasons why we eat food. So eating hummus is not just a homeostatic response, meaning that it's not just when my brain understands that I don't have enough energy and I go and eat. I mean in Copenhagen, to give you an idea, I'm running in the mornings and in the mornings all the bakeries are baking their you know croissants and bread and da-da-da. You know I love carbs.

23:54 - Gabrielle (Host)

Yeah.

23:56 - Faidon (Guest)

I struggle to not stop and just not go in and just eat something right. Yes, I know better and just eat something right. Yes, I know better. But what I'm trying to say with this example is that there is a whole lot of other sociocultural factors that drive eating behavior in humans.

24:15 - Gabrielle (Host)

And let's say we were to take that out, though, and for those of you listening, I'm really hoping you get to watch this because I've never seen Faidon wear a suit ever. I've seen him wear lots of t-shirts and running shorts.

24:30

He will run for hours and then go to a the store Straub's and get an entire baguette and I would call him and he would be sitting there eating the entire huge loaf of bread and him. And I would go him and he would be sitting there eating the entire huge loaf of bread and him and I would go back and forth about do you need carbohydrates? Could someone just eat protein? And you know, one of the other things is, and I don't want to get too off track, but I do want to have you be humanized. You are an incredible researcher and even you with all of this knowledge, it's not so cut and dry. And when I think about these two competing ideas, this energy balance or carbohydrate insulin model, I wonder when did these first? You know, when was there an idea that perhaps there was an emergence of two models?

25:30 - Faidon (Guest)

o we're talking about back to: 1910

26:13 - Gabrielle (Host)

This is irrespective of Well.

26:15 - Faidon (Guest)

I would say. I mean, of course, going back and looking at what happened historically. The quality of the data that we have is not so good, but I would say that the majority of evidence would suggest that up until maybe the 60s 70s, there has been decreases in activity levels simply because of the industrialization and the changing in the type of jobs that we do. From the 60s 70s onwards, I don't think that there has been so much change, because focus also has been put on having people do more leisure time, physical activity, and you have to also remember that it depends on so if you are bigger, you burn more calories. So maybe the reduction in the level of activity is counterbalanced to some extent by the increase in our body weight, which bears more calories. Right, but what I want to say by that is that there is evidence that our metabolism has been changing way before the obesogenic transformation of society where we start blaming the you know modern food for all the bads and all the obesity and all the diseases that have been happening.

27:29 - Gabrielle (Host)

Is it possible then, if we were to think about and expand a larger view, the carbohydrate-insulin model, energy balance model? These are the ones that are most robustly discussed. You mentioned environmental contaminants. We do see this in my clinical practice.

27:47 - Faidon (Guest)

We do see environmental contaminants?

27:50 - Gabrielle (Host)

To what degree? Do these environmental contaminants play a role.

27:54 - Faidon (Guest)

I can speculate. There seems to be a disruption in potentially thyroid regulation.

28:01 - Gabrielle (Host)

We do see these contaminants and to what the mechanism is.

28:05 - Faidon (Guest)

I remember that.

28:07 - Gabrielle (Host)

I'll just give you an example is that I had a military family, a commander who was living on a golf course and his dog dramatically gained weight and it was over. I mean, we are talking about this dog went from a normal lean animal to a very obese dog in a matter of two months and it wasn't that he was changing anything. It was that he had actually gotten into some of the pesticides Okay.

28:44 - Faidon (Guest)

So he was not eating more. You mean he was being fed the same amount of food.

28:48 - Gabrielle (Host)

He was being fed the same amount of food and it turned out that he had been exposed to all of these chemicals. He also lost vision and eye.

28:59 - Faidon (Guest)

There were other things that happened, yeah. So one thing that is very, very possible is that all of these factors can operate in tandem, right or at the same time, meaning that some individuals may be more prone to the, you know, energy balance type of obesity, meaning that they tend to overeat. Some individuals, maybe because of genetics or other factors, or where they live, as you say, may have problems with their peripheral metabolism and handling of the ingested food. And then, you know, the SIM-like model may be more relevant. It is possible that you know more than one factors or model or contributing pathways accounts for obesity in different individuals.

29:51 - Gabrielle (Host)

And would you say that there are other models before we go back to this? You know this perspective paper that maybe we're going to begin to hear more about.

30:00 - Faidon (Guest)

Well about the fact that you can. Even if you identify the cause of obesity, removing that cause doesn't mean that you're going to treat obesity right.

30:10

That is a challenging way to think about it though, because if, for example, if excess calories, if that was the cause of obesity, and then you remove the excess calories, one should be able to treat it no Well you know, not necessarily, because if, let's say, the alterations or the adaptations that have happened in the body in the obese state are resistant to change, then this does not necessarily mean that you will be able to treat obesity effectively, meaning that physiology is not linear, right, that's something that happens in pretty much all physiological responses. Our body doesn't respond linearly to increases or decreases in a stimulus such as calorie intake.

30:59 - Gabrielle (Host)

Where do you think the divergent pathways came from? People historically focused on this energy balance model, then somebody must have had an opposing view.

31:11 - Faidon (Guest)

dates back maybe to the early: 1900

32:04

Yes, yes. So you know, in randomized control trials you can have people lose weight for the first maybe, you know three, six, nine months. Then they reach a plateau and then they just start to be gaining weight, even though you're still supposedly trying to calorie restrict them. So you know, the body is very, very good in defending that obesity. We don't lose weight so easily. So the body perceives that as a threat, I would say. But you know, starting from that realization, that if energy balance is correct, then by removing the excess calories we should lose weight. Right, and if this doesn't work, then something else must be happening, and that something else is what eventually led to the formulation of the carbohydrate-insulin model. At least some indication that calories may not be the culprit dates back to the 40s, 50s or something like that, but as a model, the carbohydrate insulin model was formulated relatively recently maybe the past 20 years or so and that still, you know, it's interesting when you speak to some scientists.

33:29 - Gabrielle (Host)

So if you look at these two groups that were there, these two groups that were curated I'm assuming it was intentional it was intentional to bring experts in both perspectives together.

33:41 - Faidon (Guest)

Of course, yes, yes, absolutely perspectives together.

33:43 - Gabrielle (Host)

Of course yes yes absolutely. And you'll hear many scientists say well, the carbohydrate insulin model that's been disproven.

33:58 - Faidon (Guest)

And what would you say to that? Well, as I said, it's very difficult to prove or disprove something in humans, right?

34:06 - Gabrielle (Host)

So how do you prove the energy?

34:08 - Faidon (Guest)

balance model Are there. So we should take people who have normal body weight, put them somewhere in a hotel, isolated, right. Then try to have or to mimic the normal food environment where there's all these ultra-processed foods and all those things, and then keep them there for years, right, yes, then see what happens and then have another control group where they would be in another hotel, where the food resembles the minimally perhaps, or low little processed food that we had in the beginning of the previous century. So these studies are impossible to do. And, of course, when I say isolated, you know you have to think, as I mentioned, obesity has a very strong sociocultural component, right? Because you know, I remember when we were doing studies, you remember at WSU, that we had some TVs in these rooms.

35:03 - Gabrielle (Host)

I was just having flashbacks to the metabolic ward, the unit.

35:09 - Faidon (Guest)

You remember that all these people were watching the Food Network? I?

35:14 - Gabrielle (Host)

know, did you guys do that on purpose?

35:16 - Faidon (Guest)

So what I mean is that you know the influencers, the amount of advertisements, what you see, this is impossible to replicate in a controlled environment and see what is the effect of that on eating, right?

35:35

So in the same way that I cannot answer you whether the carbohydrate insulin model has been disproven, I can also not answer whether the energy balance model has been proven right. Because what does disproving mean? I mean people would say that let's say, if you give people a low-carb, low-gi diet and they don't lose weight, that that kind of disproves the carbohydrate-insulin model, that that kind of disproves the carbohydrate-insulin model. But the reality is that all our diet intervention studies are either too short or they have too little intensity right, and the reason, of course, is feasibility and funding. Just to give you an idea, when you test weight loss drugs, for each person that we recruit in a study we spend about $40,000, $50,000. In weight loss studies with diet, exercise and these lifestyle behaviors, we spend about $2,000. So we just can't do these studies so far, at least in humans, in a way that it will be a definitive answer to whether this works or the other thing works.

36:48 - Gabrielle (Host)

Have there been particular hallmark studies that we can pull information from? I think it was the ABC trial In humans you mean?

37:02 - Faidon (Guest)

Yes, I think that on the energy balance side right, the Kevin Hall's group they have this setup where they actually have some sort of a hotel-like clinical research center where they can actually control the food supply with vending machines and they keep people isolated.

37:29

And they have compared in a randomized design what happens when you put people in vending machines that offer only ultra-processed food versus vending machines that offer only minim-processed food versus vending machines that offer only minimally processed food or stuff like that. And they have generally seen that under agglutin conditions, meaning that people were allowed to do and eat whatever they wanted, on the ultra processed food, they tended to eat a little bit more right and then they tended to eat a little bit more right and then they tended to gain weight. Of course, these are like two-week studies, right? So what can two weeks tell you about obesity that develops over a timeframe or a timescale of decades? It's very difficult to answer this question, unfortunately. So even the very well-p publicized studies, in reality they tell us very little. They give us an indication, but they tell us very little in terms of definitive proof.

38:29 - Gabrielle (Host)

And if you look at this paper that you wrote the key differences between the energy balance model and the carbohydrate insulin model, energy balance is the energy balance model. The causal direction is the energy balance model. The causal direction is positive. Energy balance results in net fat deposition and then the carbohydrate insulin model is altered.

38:52 - Faidon (Guest)

Fuel partitioning results in net fat deposition and then subsequently positive energy balance correct because, in the latter case, because you actually store more of the ingested nutrients as fat and you don't utilize them, let's say, to fuel your movement your brain tells you that you need to eat more. I don't have enough energy to do what you want to do in your life, so that's why you overeat.

39:18 - Gabrielle (Host)

In that case, and it's interesting because, if I were to think, what are the components that these two models have in common? The primary dietary driver for both. For the energy balance model is increased availability, which is clear, and marketing of a wide variety of inexpensive these are the highly palatable foods that are high in portion size, fat, salt, sugar, low in protein and fiber. And then the carbohydrate insulin model. It really points to carbohydrate rich foods with a high glycemic index and fructose rich beverages. The energy balance model point of entry into the regulatory system is the brain, versus the carbohydrate insulin model being the periphery and really the brain's response which you had mentioned. For the energy balance is that there's an impaired appetite is not the right word, but an impaired response in the brain, and the carbohydrate insulin model seems to not have anything to do with the brain.

40:27 - Faidon (Guest)

Yes, so in the energy balance model the brain is really tricked right to not see how much you eat or to not understand how much food and energy you need. Yeah, so that's why the brain has a central focus in that model, because the characteristics of the food themselves or something else in the food environment or the non-food environment either saturates the ability of your brain to sense how much you eat and how much you need, or it kind of impairs it. Right, on the other hand, the brain, the carbohydrate insulin model, is functioning very well. It's just that the brain in that case cannot see all the nutrients that you just ate, so it actually correctly tells you that you need to get something more, because I I cannot see it go back. Going back to the analogy with the tank right, if you have a leak in the tubing that transports the fuel from your tank to your engine, then you will still have that fuel somewhere in your car, but you would not be able to use it, so you will be forced to actually put more gas next time.

41:42 - Gabrielle (Host)

Right, and you continue to eat.

41:45

And then the final difference, the final area in which this discussion rounds out, is that the predicted changes in energy expenditure. For the energy balance model, it's increased at the whole body level, unaltered if adjusted for changes in body composition. So predicted change in energy expenditure meaning how much energy you're going to burn, the energy balance model is it's increased at the whole body level. Carbohydrate, insulin model and obviously please, please, correct me where I state this incorrectly is decreased. Energy expenditure is decreased if food intake does not increase. It's unchanged or even increased if food intake increases. Correct.

42:34 - Faidon (Guest)

Let me just take a step back, right, thank you. So, in humans, there is a lot of evidence suggesting that our total energy expenditure, meaning the amount of calories that we burn right on a daily basis for maintaining, you know, our basic metabolic and physiological functions. So, our hearts pumping blood, our lungs exchanging oxygen and carbon dioxide, all of those things that maintain us alive are a function of body weight. The same thing is true for the calories that we burn with all sorts of weight-bearing activities, which for all intents and purposes, are all sorts of exercises and physical activities that we do right, unless you are in space, for instance, but at least you know running, cycling, walking the amount of calories that we burn are a direct function of body weight. Okay, so the more body weight you carry with you, the more calories you burn.

43:34

To understand that, think how easy it is to walk around in the gym and then grab two 20-pound dumbbells and walk around again. You can understand that it's a little bit more difficult. You are burning more calories as you carry more weight. So this is what the energy balance model tells you that as you gain body fat and your weight becomes greater, then you start burning more calories. That's why the total energy expenditure for the whole body goes up. However, if you take a piece of muscle tissue or a piece of liver tissue or a piece of adipose tissue, then the metabolic activity of that tissue per unit of mass is not altered. It's just that you have more of that tissue in your whole body. That makes a greater energy expansion, does it make?

44:28 - Gabrielle (Host)

sense? Yes, that makes sense. Would one be able to argue, looking at the commonalities between this, that if we had a low energy environment, that would solve the problem? Energy environment that would solve the problem If we had limited access to food, right Versus, let's say, someone has a virus but no access or environmental contaminants, clearly, yes, I will get back to that.

44:54 - Faidon (Guest)

That's a very good point and I will get back to it. But just now to explain to you what happens with energy expansion in the carbohydrate-insulin model. So, in the carbohydrate-insulin model. So what the carbohydrate-insulin model tells you, remember, is that, since your brain cannot see all the calories that you just ate, right, it tells you that you need to eat more. That's what it tells you. It drives you to eat more. If you do not act on that drive and you do not eat more, then the second option for the brain is to shut down your energy expenditure, so it will make you feel more tired, for example, so you will not go for a run, so that it will decrease your energy expenditure in order to match with the amount of calories or the amount of energy that your brain thinks you have available. That's why it decreases if you do not eat, but, of course, in the modern environment, most people would eat. That's why, most commonly, the end result of the carbohydrate-insulin model is also overeating or positive energy balance.

45:54

Let's put it this way and going back, I'm sorry. No, let me now go back to what you just said. So there is no question, this is something that, of course, needs to be clear. No matter whether we are talking about genes, environments, type of food, amount of food, whether I am feeling good or bad, or sad or happy All of these factors that affect my drive to eat, they must manifest by a known biological mechanism that affects either energy intake or how I handle the food that I just ate. And you are correct If I take people in the lab and I just remove their access to food, they lose weight as expected, right Like textbooks. So there is no magic there, but that is not something that we can do in humans and it does not really prove that either model is correct.

46:55 - Gabrielle (Host)

Were there any surprising points during this conversation? Would you call?

47:04 - Faidon (Guest)

it a debate? Yes, to some extent I would. I think what was surprising, actually satisfying to me, was to see these very good scientists come in the same room and during, let's say, breakfast on day one you could actually cut the tension with a knife. But I think that as the day progressed and then as we had the second day at the end of the workshop, everybody was so much better and the environment and the client was so much better. So, for me that was satisfying to see that we can achieve that Because, as I said, as humans, as scientists, we also have our egos and these are not easy to kind of put on the side.

47:57 - Gabrielle (Host)

Were there any insights from either party, Because really this debate between the energy balance model and carbohydrate insulin model has really been robust within the scientific community. That we have any kind of mental flexibility is if we're willing to acknowledge or hear from the other side. Do you think? And also, is there a place where these two models work in tandem, versus it's this or that?

48:33 - Faidon (Guest)

Yeah. So I think that you know, if you also read the paper, a lot of how the normal physiology and the normal regulation of energy intake and expenditure is regulated in humans. Both models agree to that right. So there's a lot of overlap and a lot of agreement. It's just that it's not highlighted anywhere. But again, both camps and everybody, I guess, no matter what kind of model they back you have to agree that it will operate under known mechanisms of energy intake, energy expenditure, peripheral metabolism and all the things that we know that operate in humans as a species. It's unlikely that you will find someone that will suggest something different. I think that the realization that they have actually a lot of points where the two models converge is something that the two camps also realized during the workshop and that was a pleasure to see as well.

49:40 - Gabrielle (Host)

And what was their big takeaway? That we need also longer human trials.

49:47 - Faidon (Guest)

Yeah, what were the big takeaways? So my feeling first of all is that, even though they acknowledge that there is a possibility that I may be wrong or something else may be happening, they went back home and they're still believing what they believe, and we did not expect that something else would happen. But something that emerged from that workshop is that, now that we started having collaborative ideas and perhaps designing projects in common right to try to test some aspects of these models or some predictions of these models. There is no way that you can have a single study, as I said, that can prove or disprove one or the other, but at least now they are open to the possibilities and that's a wonderful thing to see that it happens, even at that level of science, which you would think that this is the norm, but it is not really the norm.

50:48 - Gabrielle (Host)

And you actually mentioned this in the paper. The paper mentions that the debate has often led to controversial discussions in both parties, in both scientific and popular media, and you are a phenomenal scientist. I could speak with you for hours, which I do, but for the podcast particularly. I was so excited that you wrote this paper because again and I do want to touch on what you have seen in randomized control trials and some of the work that you have done in effective ways to lose weight I do. I want to discuss diet exercise. I know we didn't really decide that we were going to do that before, but I do want to make sure that we have tangible items that people can take away, and you've done a tremendous amount of research.

51:45 - Faidon (Guest)

So of course I mean that's the reason why we are really interested in that. In what sense? No matter how obesity develops, right? People or let's say the majority of individuals right now are interested in trying to figure out ways to effectively lose weight, right? So it doesn't really matter how you put that weight on Now, you're interested in losing that weight, it doesn't?

52:08 - Gabrielle (Host)

It doesn't matter the speed, if we were to think about and I just want to pause there, it's an interesting mental exercise when it comes to obesity, does it matter the swiftness at what's at which someone puts on weight and the reason? I ask this because in my mind, I think that the distribution of fat would be variable over time, For example, if someone has been obese for an extended period of time. Now you're not looking at just peripheral adiposity, but you're looking at intra-organ adiposity, and perhaps that might take longer to then course correct metabolic outcomes.

52:50 - Faidon (Guest)

Yes. So one thing that I'm not sure how much known it is to the wider public is that perhaps during the past 20, 30 years we have had a lot of evidence and we realize that obesity or having excess weight and total body fat is not necessarily associated with metabolic abnormalities and metabolic disease and increased risk of diabetes and cardiovascular disease. Right, and vice versa. I have to push back on that. I'm sorry.

53:25 - Gabrielle (Host)

So your students would never push back on that. So what you are mentioning here is a phenotype of obesity that would be metabolically healthy.

53:38 - Faidon (Guest)

It's metabolically healthy relative to the majority of obesity. It's not the same as being lean and metabolically healthy, right Okay?

53:46 - Gabrielle (Host)

I just definitely wanted to say that.

53:51 - Faidon (Guest)

Right. So if you just focus on body weight and total body fat, that doesn't tell you much in terms of risk of disease. That's the point that I want to get across. And vice versa, you can have a normal body weight and a normal total body fat, but if you have accumulation of fat in specific locations around the body, then you can have increased risk of metabolic abnormalities.

54:14

And this is the fat that typically people refer to as visceral fat, which is the fat that we have, let's say, around our bellies, but also fat that we can store in our muscle or in our livers or in our pancreas, and then that fat really affects the function of those organs which are critical for metabolic homeostasis.

54:35

And it is remarkable, if you think that you can have you can be a person with obesity, right, and a BMI of 40 or 50, so you can have 50 kilograms of extra fat in your body, but that doesn't necessarily tell you much, as if you accumulate only, let's say, 5 kilograms as visceral adipose tissue or 200 grams of fat in your liver, this is remarkable. So the location of where you store that fat seems to be way more important for your metabolic health rather than the total amount of fat you have in your body. Now why people tend to accumulate fat in this or that or in the third organ, it's something that we do not really know. Genes definitely affect or play a reason, but there are probably other reasons as well. So diet would be a reason. Exercise and physical activity habits definitely have a reason on body fat distribution and they have a big role. So generally, yes, obesity itself is not necessarily associated with increased risk for disease.

55:45 - Gabrielle (Host)

And I think that there's a bit of a spectrum on that. Again, just to take it back, I was reading another paper and one of the things is, potentially it's on a continuum we might not be identifying, it's almost on a spectrum. So we might see an obese quote metabolically healthy person, but it's at that point in time and I would argue that obesity is never going to be healthy. We might just not have the science yet to put into words. We might just not have the science yet to put into words. And you know, potentially it's just that the body is able to manage and mitigate negative outcomes for a period of time. Or let's say, we're not measuring the myokines appropriately, or the inflammatory markers.

56:35 - Faidon (Guest)

We just are not identifying it from a clinical, you are totally correct, because one of the commonest things about metabolically healthy obesity is that these individuals tend to be younger, right, and we know for a fact that as we age, the chances that we are staying metabolically healthy are diminishing almost linearly, even if your weight does not increase so definitely it seems to be. It is not a shield against the metabolic abnormalities. That is a permanent shield, right, it's just a temporary shield. That it's exactly what you said. Your body, because of your age or your other functional capacities, has the ability to kind of withstand or mask the metabolic complications of excess weight and fat.

57:26 - Gabrielle (Host)

But let me touch up.

57:27 - Faidon (Guest)

I'm sorry, I just remember you mentioned also the rapidity at which we put gain or the period yes, the period in which you gain.

57:35 - Gabrielle (Host)

So we don't really have a very good.

57:36 - Faidon (Guest)

we don't have good studies that made people gain the same amount of weight with different rates, right? Because in a study like that, in order to be able to get a good answer to your question, you would have to have the same amount of weight gain with different rates, so at different time frames right, but we do not have studies like that. What we do have, however, is the opposite. So not have studies like that. What we do have, however, is the opposite. So we have studies that compared what happens if you lose the same amount of weight with different rates. So lose it fast or lose it slow, right?

58:12

Yes, and generally, these studies suggest that if you look acutely, so if you look on the day that you reach the target weight loss, then losing it slow is generally better. Right, but this is a little bit of a confounding interpretation of the data, because you do not allow the body to stabilize at that new lower body weight. If you do that, so if you do the measurements after one month of stabilization at that new lower body weight, then it doesn't really matter whether you lose it fast or slow. For all intents and purposes, all the metabolic effects of weight loss are the same, no matter how fast or slow you lost it. And, if anything, just as a last point to this point, we have data to suggest that people who, for some reason, lose weight initially at a faster rate are those who are more successful in long-term weight loss. Whether it's biological, whether it's something else, we do not know the mechanisms, but this observation comes again and again, that rapid initial weight loss predicts longer success.

59:28 - Gabrielle (Host)

I was so hoping you were going to say that and remind me that came out of. Was that the ABC? I think?

59:37 - Faidon (Guest)

so and also the Look Ahead trial had the same it.

59:40

it was the look ahead trial several others, I think you know it is remarkable to say that the rate at which you lose weight in the first one month or two months of a diet predicts what you do four and eight years later. But because what I mean is that in the first month or two months of a diet, everybody is excited, right, so there is no issue of compliance over there, because you can easily say that compliance is a major factor that predicts weight loss success, and that's true. Two of the main predictors of weight loss success is compliance with the diet and then the initial rate of weight loss.

:: 00:17

So the initial rate of weight loss must be something that has to do with the biology, right, because everybody's excited and they're very compliant with the diet in the first few weeks, and this is all without medication, because when you use GLP-1s or GIP, some of these dual agonists and I'm sure that I know that they will have multiple generations of these agents coming out, you know I wonder where that plays a role, because the recidivism rate, the regain weight of individuals, just in general, who struggle with obesity is, I mean, it's over 80%, right.

:: 00:55

It's higher than that. Yes, it varies, but generally it's not satisfactory because, if it were, we would have treated the problem right. Yeah, it varies, but generally it's not satisfactory because, if it were, we would have treated the problem right. So clearly, weight loss drugs, and especially these GLP-1 agonists and the dual agonists kind of help quite a lot and actually results for these dual agonists suggest that you can reach bariatric surgery levels of weight loss. Really, the point is that you need to get these drugs forever, meaning that if you stop taking these drugs, you go back to your initial weight trajectory. And I think that there is some studies published recently on clinical practice and real-life effectiveness and it seems that, like with most other medications, the majority of patients are just not compliant to their medications, even if it has to do with these GLP-1 and GLP agonists. And, of course, you have to take into account the costs, right?

:: 01:55

Yes, which brings also.

:: 01:57

Then the other question of insurance and politics, because if we consider obesity as a disease, globally speaking, and then these medications need to be reimbursed by the insurance companies, then this would bring most national economies to their knees. We have 1.8 billion people who struggle with excess weight globally right. 1.8 billion people who struggle with excess weight globally right. So there are a lot of other factors involved when you talk about how to treat obesity medically.

:: 02:26

Yes, and if one of the other things that we haven't spoken about is the quality of the weight loss, rapid weight loss typically seems to be lower quality. Rapid weight loss typically seems to be lower quality. It is lean tissue as well as fat tissue, and I'm curious from your work and some of the things that you've been involved in. Ideally, if you were to think, ok, based on evidence, how would I personally design a diet? How would you do that? Based on evidence, how would I personally design a diet?

:: 03:03

How would you do that? Yeah, so let me just say something about the composition of weight loss. Right, when we lose weight, generally speaking, it's about 75% fat and 25% lean mass. What this means is that if you lose 10 kilos, about 7.5 kilos is fat mass and about 2.5 is lean mass. Kilos about 7.5 kilos is fat mass and about 2.5 is lean mass. Out of those 2.5, most, but not all, is muscle, but not all. Okay. So when we say lean mass is not just muscle, lean mass is everything else other than fat and water and bone. Now, in terms of rapid weight loss, you're right. When we lose weight rapidly, it seems that we tend to lose more lean mass. But this is what happens. If you measure people's body composition acutely, if you allow them to stabilize it at that new lower body weight, then these differences are actually minimized, and I'm not sure if they are clinically significant anymore.

:: 04:00

Say that again. That's a very important point.

:: 04:04

If you do your body composition measurements at the end of the weight loss treatment, where people are just coming out of their negative energy balance, a lot of the changes in body composition that you see also have to do with water fluxes around the body, so they are not really true. When you repeat those measurements one month later, when you have stabilized those people at their new, lower body weight, then the composition of lost tissue doesn't differ that much between slow and fast weight loss tissue doesn't differ that much between slow and fast weight loss.

:: 04:51

It's just interesting because oftentimes, even in the literature, we think about rapid weight loss being extremely negative for muscle.

:: 04:55

Well, correct, but that's what I mentioned, that this probably is not true.

:: 04:59

Which is incredible to think about. The next obvious question is how good at actually measuring skeletal muscle and differentiating between lean mass are we?

:: 05:12

Yeah, we don't really have that good of methods. If you really want to be very specific about muscle, you would probably have to resolve the methods including either CT, like computer tomography, or magnetic resonance imaging, and you would have to do it at the whole body level. Right, so you have to scan head to toe Because you know muscles we have. Muscle is an organ that is not anatomically defined like your heart, right? Muscle is a tissue that is interspersed in various parts of our bodies, right, so you would have to scan the whole body and that would give is a good insulator, whereas the rest of the body is a better insulator, so it kind of gives you a guesstimate of body composition. We also use another type of scanning with dual x-ray absorptiometry, which gives you fat mass and lean mass, but it cannot separate muscle mass. So I would say that the majority of the studies that we see out there they do not use a particularly robust method for muscle mass.

:: 06:44

What do you see as the problem in that?

:: 06:50

Of not being able to quantify muscle mass. You mean, yeah, well, clearly you could argue that if I cannot get a good measurement of muscle mass, then I do not get a good estimate of what is the effect of weight loss on body composition. And it goes back to what you said, right the quality of the weight loss. Because if you lose more muscle, theoretically your resting metabolic rate would go down, you would have alteration in the amount of all these myokines that you have circulating in your bloodstream and this could of course affect metabolic function. But of course we have some, let's say, indirect ways that we can probe that, meaning that you can actually measure myokines in the bloodstream. Are you guys doing that a lot in Copenhagen?

:: 07:38

Which, first of all, I?

:: 07:39

know, that you are and, if I could, maybe you'll put in a good word for me. Bente Penderson's lab yeah, yeah, but over here we Bente does though. Yeah, yes, she does. I was actually trying to set you up for a softball. I was trying to pitch you a ball. I was going to see if you were going to bite on this. I don't even know what softball is, and quantifying skeletal muscle mass loss as well as gain in my mind it stands to reason. This has been a huge disservice. I know that that is not scientific, but then we will fail to see number one the potential importance and the potential impact the loss or gain of muscle is in overall health in general. The you and I were talking about about something else, and 10 years ago, when I was in fellowship, it was just the start of getting better at identifying and measuring skeletal muscle mass with CT MRI and that was 10 years ago.

:: 09:07

Yeah, but you know these pieces of instruments are very expensive. I mean, I understand what you're saying, but generally we do the best we can do. Generally we do the best we can do and you know the majority of studies, I would say that focus on the dietary treatment of obesity. They are not so muscle-centric, to put it this way. So you know you have to allocate your resources in a way that is equitable for the outcomes that you want to measure, right?

:: 09:39

I'm guessing that you would have to do a specific study that focuses on the amount of muscle mass in order to engage and utilize those techniques that are more accurate. Still, muscle mass in itself doesn't necessarily tell you everything, right, because you have muscle function on top of muscle mass, you have fiber composition, right, so you can have the same amount of muscle, but depending on the composition of these myocytes, the function and their metabolic effects might be different. So I mean, we see that in professional athletes, right, whether they are endurance trained or resistance trained, they have different metabolic profiles and they have different changes in their metabolism during their training. So, clearly, mass is an important factor. It's definitely not the only thing that matters, I would say, for health, right, you have to take into account how that mass functions.

:: 10:40

Do you think the oversight in skeletal muscle or the lack of skeletal muscle is in part due to its complexity, because it is heterogeneous versus adipose tissue, which is homogeneous, and I'm just referring to circle back to what Faidon was saying about muscle mass. No two people have the same fiber type composition. Intramuscular fat. It's a very complex tissue and the composition of the fiber throughout the body potentially can be different.

:: 11:15

Yeah, not potentially. We know that. Different fibers You're the one who taught me to speak like this, to not speak in absolutes.

:: 11:21

This is your fault.

:: 11:23

But this we know because we have actually taken biopsies from different tissues around the body of the same individuals and you see that there are differences, let's say, between the fiber composition of your cellulose versus glute, versus gastrocnemius versus so on and so forth. There is also differences in the rates of protein synthesis and all those things. Whether or not these are clinically significant we do not know, but statistically you can see differences anyway.

:: 11:49

And maybe we're just too early. I think that we're just too early in the research.

:: 11:57

Yes, the other thing is, as you said on Aves, you're right that adipose tissue at least white adipose tissue, subcutaneous white adipose tissue is a more homogeneous tissue compared to muscle, right? But you know, you have visceral adipose tissue, you have adipose tissue or fat inside organs. So what it means is that, yes, probably, probably on average. The remark that muscle is much more complex is true. Now, the the. You know, if you approach the diet right, which you have to approach the whole body, you cannot really approach the diet in an organ specific way. Typically people get obese and this affects all organs. And the same thing as they lose weight, this affects all organs.

:: 12:48

So, you know, if you go back to the 30,000 feet view and try to see, you know what can we do? You know, for obesity, you know we have at least ideas about the characteristics of a healthy diet. And again, I'm using the term healthy because I think that obesity treatment has over-focused on the scale rather than on the outcomes. What I mean is that would we care about obesity if it were not for the increased risk of disease? No, obesity would not even be considered by the w health organization, right, because obesity is defined as the amount of excess fat accumulation that may impair health. If it was not for the complications for obesity, we would not mind so much. Nobody would care about aesthetics. Historically, if you see this, there was a time where obesity was considered a favorable trait in humans. We know that some characteristics of a diet that are conducive to good health are be prudent in calories, have variety, eat the mostly plant-based diet.

:: 14:05

But with enough protein, not vegan, I'm just kidding, so the.

:: 14:08

Mediterranean diet. You know, I'm from Greece, right? We like the Mediterranean diet. So the Mediterranean diet is mostly plant-based diet, but we eat meat, we eat protein, we eat dairy. So you know, I would say, eat everything in moderation is the trick here, right? So we know most of the characteristics of a healthy diet, but yet it's very difficult to adhere to that diet because that requires that you go to the grocery shop. You know it's not convenient with everyday life to go to shop and cook and do all those things at home. It's much more easy to get ready-made food and heat it in the microwave and eat it. So it's really tricky. And of course, I know you're interested in exercise, right? We know that doing exercise or exercising, being active, is good. And what is the best exercise? Well, it's the one you do.

:: 15:01

That's very simple the answer to that question is very simple, not the one that Aidan does. This guy runs, he just runs, no not like me.

:: 15:07

No, I don't, yeah, but what I mean is that it doesn't matter if you lift, if you run, if you cycle, if you swim, as long as you do something. Right, dog? All these are behaviors that we know are healthy. We know that they help you maintain a healthy weight or reduce a little bit the excess weight that you may have. We definitely know that they will keep you healthy for longer, which is important, right? Because it doesn't really matter if you have one, two, three more kilos in your body. As long as this doesn't affect you, then you can still go around and do the things that you want to do with your life.

:: 15:42

I agree with you and, for history's sake you guys listening again Finn and I have known each other for over 10 years. When we think about the percentage of and we've worked together Actually, we've worked on multiple studies together he's much more published. I think. I have two papers and a book chapter published, but I did write a book that did well, which you, I think, pretty much Congratulations. I remember that. Yep, yes, because I think that you refused to review it because it was for general consumption and not in the white tower of academia. I'm totally kidding you guys. I am kidding.

:: 16:18

But our perspective on muscle, I think, is very similar, although I would say I tend to be very dogmatic in my thinking and I definitely recognize this. If I were to really think about, where does obesity, where do these problems begin? For me it's muscle. I appreciate my biases From a dietary perspective if one were to set up from a giving actual number perspective. And there is variation. For example, Faidon does a lot of endurance training. He does, he weightlifts two to three days a week At least he did, and he's a creature of habit. I'm assuming you still do that. Yeah, right, you go to the gym, you spend like three hours training and then you're ready to go to bed by. I mean, you train at night. It's a whole thing. The listener wants to know how do they design a diet? And let's say they're very prudent about protein. We know that 0.8 grams per kg is the minimum to prevent a deficiency. It's probably not enough to support aging. One probably requires more if they are in a catabolic condition or even with obesity. Correct, yeah.

:: 17:42

Yeah. So now let me just say, of course there is a lot of different ways that you can design a diet. So I believe that you know if you think about drugs versus food, right, drug is a very specific compound. It's one compound that targets one specific metabolic pathway. Let's say, in the body, diet or food has like thousands, if not millions, of compounds that act on everywhere and interact with each other right, so each one affects the effects of the other. So I like to think that there is no ideal diet. There is no perfect diet, and when I say that to people, most people get sad and disappointed. But I try to give it a positive spin, in what sense that there is so many degrees of freedom for you to go out, choose, experiment and find out the diet that works for you. As you said, I like pasta. My diet is 70% carbs. I've measured so I'm 70% carbs, 20% fat and 10% protein, but I cover my protein needs because of all this exercise that I do. I eat a lot of calories.

:: 18:53

Right, and you definitely have to to expand on that yeah, what I want to say is that I have found a diet that works for my lifestyle and your body type, though you're very lean, yeah, and I'm sure that there is a variation, just as some people do better on a higher protein diet, which I am one of them.

:: 19:15

Absolutely. Yeah, absolutely. You're absolutely correct. Some people do better on different diets and that's the positive spin.

:: 19:23

For me, that diet has a lot of degrees of freedom and you have to find a person who is a little bit knowledgeable like me, you or whoever, and and and help you identify what are, let's say, the, the mistakes that you may do, because you know, sometimes, when you know a lot of things, like on this, if you are on the academic side of things, you take some knowledge as granted and that's's not true.

:: 19:49

You know, I can see that. You know, whenever you have a new input of students, we also have to kind of deal with all the ideas that they come in the university, right, and then I get to remind myself of oh my God, how is it possible that you know you don't know this, but that's the reality out there for the general public. So you know, you have to find somebody who is a little bit knowledgeable and they can help you identify some errors that you may be doing, and then try to experiment. And you know trial and error. It's all about trial and error and finding something that works for you. That's how I managed to do it anyway.

:: 20:27

Well, you're also very evidence informedformed, Evidence-based and evidence. You're evidence-based, but you're evidence-informed For you to get 10% of your calories from protein. The reality is, you counterbalance that by your activities extreme. I think that you're also at a standing desk. You have enough.

:: 20:50

Well, everybody in Denmark has a standing desk. You have enough. Well, everybody in Denmark has a standing desk that goes up and down.

:: 20:53

yes, we don't have that here in the studio. Denmark, everybody moves around, by the way.

:: 21:01

Let me just correct you. In Copenhagen everybody moves around because bicycles is so much into the culture. I bike to work every day right Back and forth, in addition to the other stuff. But everybody does that, Everyone does that, but rural.

:: 21:14

Denmark is not the same, but again, from a larger view, copenhagen is really the Mecca. It's like the Harvard outside of the US, especially for anything metabolic exercise related and skeletal muscle and just really this nutritional perspective. However, one thing that you have to take into account is their lifestyle is not an American lifestyle.

:: 21:49

Of course, absolutely.

:: 21:50

So the perspective is you know, that is what the exposure is the individuals could get away with a lower protein diet because they counterbalance with a way of life that is extraordinarily active.

:: 22:06

Yeah, but, as I mentioned you know, if you think 10% of calories over 3 or 3,500 calories on a daily basis, this is about 300 calories from protein. Divide that by four, right, you get about 90-something, which is low, right.

:: 22:24

From my perspective, it's low.

:: 22:27

But I'm weighing 70 kilos, so I'm eating about 1.3. You know what I mean. I do, I do so. The percent of the calories seems or sounds low, but the actual amount is not low, is not low. And I'm lifting for maintaining right. I'm not weight lifting to be a bodybuilder.

:: 22:48

You could be if you decide not to be a bodybuilder. You could be If you decide not to be a bodybuilder.

:: 22:50

Clearly, If your target is that, then yes, of course you need much more protein.

:: 22:54

There's no question about it. If someone wants to build muscle, how much protein?

:: 22:59

Well, I think that you should go up of 1.6, but definitely no, I don't think there's any need for more than 2.2, 2.3. I think that that's where you saturate the system, and all the studies that we have so far where they measure muscle protein synthesis in response to, you know, different types of exercise and different forms of feeding, amino acids, insulin and all those things the response is always the same you have a linear increase and then a plateau. So there is definitely a point where you saturate the system and then any more than that, you will obviously either burn it for energy or store it as fat.

:: 23:39

So you should not overdo it. That's what I mean, and I want to pause there and interject. What he's saying is that from a, if your goal is muscle hypertrophy or repair skeletal muscle repair, anything above 2.2 grams per kg might not be necessary. Right, and that's definitely the upper limit from a overall calorie perspective and an overall intake overall intake. There's no downside, and Finn and I may disagree here. But one gram per pound ideal body weight I find is safe. I think it's easy to do.

:: 24:23

So two grams per kilo approximately.

:: 24:24

yeah, At the upper limit. I haven't seen any evidence to suggest that.

:: 24:32

Oh no, there is no downside. As long as your total energy intake is kept under control, no problem at all. There are no side effects, really, if you're healthy and you don't have any sort of kidney problems.

:: 24:43

Correct and you had mentioned insulin and these other hormones. Where do you think that that plays a role from a obesity perspective? Because if insulin and other hormonal responses to food play a role in the carbohydrate insulin model, do you think that, say, having a diet high in carbohydrates would be obesogenic, or is it a genetic and activity related?

:: 25:17

question. So I mean, I obviously don't have the exact answer to your question, but but let me just say that you know we are talking now about building muscle. But if you are talking about building muscle in the context of losing weight so losing weight and building muscle but if you are talking about building muscle in the context of losing weight so losing weight and building muscle then that is very difficult to do. So you have to actually be going to the gym almost daily for like 15 hours a week. I only know one or two studies in the literature with professional athletes where they were losing weight because they were trying to make to make competition weight right and they were training about 15 hours a week. And only in this population, under this condition, do they manage to gain muscle while they are losing weight.

:: 26:03

For all intents and purposes, for the average person, I would say that when you lose weight, you cannot avoid losing muscle. You can minimize that muscle loss by exercising anything more protein, but you will not be able to avoid a complete loss of muscle. And now then the protein that you have in your diet as a percentage of your calories should go up if you are calorie restrictedrestricting yourself, right? So maybe because I'm eating 3,500 calories a day, I can get away with 10% protein. The person who is actively in calorie restriction and eating 1,000 calories a day to lose weight, the percent protein should be 20 or 30. If it was higher.

:: 26:51

Remember the protein sparing fast. Do you remember those modified protein sparing fasts?

:: 26:56

Yeah, so now the commercial VLCD products, the very low energy diet products like the Nupo and I don't know what you have in the States, but all these now are about 50% protein. Right, because you eat only 800 calories a day, then protein is the most important nutrient to match and to meet your body's needs. So, as a percent of calories, the less you eat, the more you need.

:: 27:22

And then aging as well.

:: 27:25

Yes, with aging as well, and that's true. So aging has been associated with a little bit of an anabolic resistance, as we call it. Meaning that and going back to your insulin question, right? So the main effect of insulin is that it kind of stops muscle breakdown. So when you exercise you increase muscle breakdown. Really that's the effect of resistance, exercise or weight lifting on muscle. But then when you eat after that exercise, the insulin, what it does is that it stops muscle breakdown and then the additional protein that you have eaten is being used to stimulate protein synthesis. So your balance becomes positive, right? So it seems that aging is associated with a little bit of anabolic resistance, meaning that for the same amount of protein people who are older, they do not respond very robustly in terms of muscle protein synthesis. What you can do to circumvent that problem is to feed them a little bit more protein. So if you flood the system a little bit more, then you get the same response that you would get. So that's easily solvable with aging.

:: 28:37

When your students are coming in again. You're a full professor when your students are coming in. Are you seeing trends? Are you seeing trends of incorrect thinking or perspectives, and what are those?

:: 28:55

Well, you know, rather than incorrect thinking because, again, I would say that I can never be 100% sure in research, right, but there is definitely thinking that is not supported by the weight of the evidence. Right? Things like eating both carbs and protein in the same meal. Things about what the effects of exercise are, things about when you should eat, like the time of the day, tell me.

:: 29:27

We all want to hear. We're all dying to hear. I just want to hear the highlights where it's not supported by evidence.

:: 29:35

Well, I wouldn't say it's not supported by evidence. But for instance, there is this idea that, let's say, eating earlier or breakfast skipping, or breakfast eating is associated with more or less body weight and obesity. Right? So generally, if you go out in the population, you will see that people who typically habitually tend to avoid breakfast, they are more obese or they have greater body weight. So this has led to the assumption that breakfast is important to kind of treat obesity. However, if you take people who are habitual, not breakfast eaters, like myself, and you put them in a study and you tell them now start eating breakfast, we gain weight, we don't lose weight. So breakfast is bad in that scenario.

:: 30:22

Right so complicated? Yeah, so that's what I mean. So observation in the population is very difficult to different from what happens when you actually put it to the test, because there's a lot of other factors that that could be responsible for that relationship. If so, another thing is that you know.

:: 30:41

We know also that people who tend to eat or to spread their calories around the day have better weight body weight than those who pack more of their calories in fewer meals, right? So that's why we say it's better to eat more meals rather than pack all your calories in a single meal or two meals.

:: 31:04

Right, you've heard that I guess I I'm trying to think where what I hear. I mean I have seen people try to. You know, I don't know, I don't know if I've heard that some people try to do one meal a day, or Okay, yeah, I'm not sure.

:: 31:23

Generally, however, I think that, at least in my students because that's who you asked about, that, at least in my students, because that's who you asked about the general perception is that eating fewer calories spread out even throughout the day is better for body weight homeostasis. But again, when we put this to the test and we bring people and we randomize them on one month to eat one meal, all calories of the day in one meal, versus spread out in six meals, we do not see any differences. Again, kind of new right.

:: 31:52

Yeah, and I just want to put a little caveat on here. What he's talking about is really thinking about things in population base. This would not be, for example, that would not be a strategy. A one meal a day kind of a thing would not be a strategy I would use for an older person, someone who's trying to build muscle, someone who's trying to protect muscle. But again, this circles back to the beginning of the conversation that I had with Faidon is, there are population studies.

:: 32:21

We're doing the best we can, but when it comes to individuals, there's variation, Clearly, and it also will depend on the characteristics of the person, right? Because we know that even if you prescribe the same diet and exercise regimen for a group of 100 people, you will get 100 different responses, right? Depending on your outcome. These responses may vary from, you know, a little improvement to a lot of improvement, but for some outcomes they may vary from improvement to getting worse. So you know, the variability between people to the same diet and exercise is humongous. Some of it could be genetic, Some of it could be compliance to your instructions, right? Because people also are not particularly compliant, and we see that when we bring people in the lab and we actually house them in the lab, so we are responsible for feeding them, for telling them, you know, now rest, now hop on the treadmill, now rest, now eat. The variability is much less than what we see in real life, right?

:: 33:30

I didn't know that the variability is much less when we study that. You mean their response to exercise, because there's some data out there that talks about exercise non-responders.

:: 33:41

Yeah, yeah, yeah. What I mean is that of course you see that in the lab as well. It's just the range of response is smaller because you take the compliance part out of the equation. Response is smaller because you take the compliance part out of the equation. Clearly, if you just prescribe an exercise treatment in real life, then compliance to that exercise regimen will be a big factor in mediating the individual differences in response. But when we take that out of the equation we still see some level of individual responses, right.

:: 34:16

What about exercise? That you are seeing your younger students come in, thinking that is potentially not following the literature?

:: 34:23

Well, you know, unfortunately most of my teaching is in the nutrition field, so my students don't feel strong about exercise, and that's I think it's a pity, because you know me, I mean, I always I'm 50% diet, 50% exercise, and I think that you know these are two sides of the coin, that you cannot consider the effects of exercise without knowing what you are eating and vice versa, you cannot evaluate the effects of eating without knowing whether or not they exercise.

:: 34:51

Yeah, from a nutrition perspective, I'm sure you get ketogenic diet questions, and even with the energy balance model and the carbohydrate insulin model, where does a ketogenic diet play a role and does it prove or disprove one or the other? Where does a ketogenic diet play a role and does it prove or disprove?

:: 35:10

one or the other. Yeah, so ketogenic diet and if you mean by strictly ketogenic, so I eat less than 20 or 50 grams of carbs per day these are very, very effective diets in inducing weight loss. So, actually, if you do a real, true ketogenic diet, even if you feed people, you cannot maintain their weight because they tend to lose weight. Of course, the majority of this initial weight loss is more water rather than fat, for instance. Right, but the point is that these diets, they are not diets that you can maintain in the long term, and by long term I mean years, for the rest of your life, and that is a problem whenever we talk about diets. So it is not difficult to make people lose weight in short term. What is difficult is to change their habits so that they can do that effortlessly for the rest of their lives. That's the big obstacle that we have with the treatment of obesity. Right, you mentioned that before. If we take food away, people lose weight. Thank you very much, but this is not life right?

:: 36:19

Yeah, it certainly. When everyone was together, was there a discussion about muscle, about exercise? I know that this is you know, and I bring this up because you said diet is 50% and exercise is 50%, but you know they are tackling the pathogenesis of obesity, but where was the conversation about muscle and exercise?

:: 36:51

Well, back then, you know, I think, that again, where we both were, we were mainly focusing on diet and weight loss and obesity in regards to diet rather than exercise. But you know, to put it this way, you cannot overexercise yourself out of a bad diet in the same way that you cannot, um, you know, eat your way out of being sedentary. Um, there is no question, that's a let's say that again, that that's fascinating.

:: 37:22

I don't think we've ever heard anyone say that. That you cannot eat your way out of being sedentary. Yeah, meaning that if you are, sedentary.

:: 37:29

It doesn't mean that you cannot eat your way out of being sedentary, yeah, meaning that if you are sedentary, it doesn't mean that you can follow a prudent diet and then be in optimal health Right, that's what I meant by that In the same way that you cannot eat whatever you want to and then just exercise yourself out of it. So you have to pay attention to both. Clearly, there is no question that being active helps you stay healthier for longer, and that's important, I think, as a message because, outside from what the scale says and all those things you know, as we grow older, we realize that you know, we want to know, we want to be healthy, we want to be functional and we want to be independent, and exercise and being physically active is a critical component of functional independence as you age.

:: 38:20

There is no question about it will tell me it's whatever anyone will do, and that's the kind of exercise. How do you place the importance of endurance, resistance, high-intensity interval training?

:: 38:43

Where do you think about that from a health, longevity, obesity prevention standpoint? Well, all of these things that you mentioned are probably different because from the let's see from the energy balance perspective, clearly endurance exercise predominates simply because, uh, for the amount of time that you spend during exercise, you burn more calories. With endurance and resistance exercise right, at least acutely during the exercise session, uh, which again is not that much, meaning that if you see how many calories you burn by running for an hour, it's 500 calories. If you run at a moderate to high pace, 500 calories is, you know, a slice of pizza, so, or a danis. So it's really disappointing to see how many calories you.

:: 39:27

But the point with exercise is that it puts you in a positive mindset, right, and in a positive feedback circle that you know you exercise, you feel better, you pay attention to what you eat and then you keep this going and then you enter a healthier way of living. I think that's the main value of exercise. Now, again, if your main focus is calories, then I would focus predominantly on endurance type of exercises. If your main focus is to build muscle or to maintain functional capacity, then definitely resistance training is important. So for aging I would say I would put more emphasis on weightlifting and resistance training rather than endurance training, because this is mostly what you need to maintain your functional capacity.

:: 40:21

And that's ultimately what people want. They want to age well, yeah.

:: 40:25

I think so too. Of course I think so too, and you also mentioned the high-density interval exercise, which is a great way to exercise, as long as you can do it, of course. It's a way that you can reach your goals at a smaller amount of time. So it depends. Some people have more time to spend in the gym, some people have less time to spend in the gym. So with high-intensity interval exercise, you do not increase your biological ceiling, you just reach it faster. Interval exercise you do not increase your biological ceiling.

:: 40:51

You just reach it faster.

:: 40:55

Do you think that there is a biological ceiling? Well, I think so If you are trying to maintain all other parameters, the same meaning that if you do not want to increase your weight, then yes, of course there is a biological ceiling in terms of what you can achieve, and we can see that even in, as you said, in the response to exercise. Right, we see some people who double or triple in capacity and some of them who increase only by 10 or 20% and they do the same amount of exercise. So there's definitely some sort of ceiling in all of their responses. The human body is not endless.

:: 41:33

I absolutely agree with you, and there are foundational principles that everyone, from my perspective, should be doing. I agree, and we know most of that stuff, right? Yes, we know most of that stuff when you were in this room and you're seeing researchers and I'm not sure if there were any clinicians in there, but obviously, if the smartest people in the world are struggling to have these conversations, how do you suggest that we, as science communicators, as academics, as clinicians, as trainers, as coaches, communicate the complexities to the public?

:: 42:20

Well, I'm sorry, let me just mute my phone, because it just told me that I need to get my medicine.

:: 42:28

Also, by the way, we're wrapping up anyway, you want me to ask you that again. No, I remember that. Okay, medicine, okay, I'll talk about that later.

:: 42:41

Well, I didn't tell you. I was in Beijing and then I was running like crazy and exercising like crazy and I got an exercise-induced asthma attack. So I was hospitalized in China. You didn't tell me that. Yeah, that was a surreal experience. So I had to stay, like I had to go to the hospital like for six consecutive days. Oh my God, yeah, yeah, yeah, but the Chinese were really detailed about how to treat it. Anyway, so now I have been prescribed an inhaler, oh, like, inhaled the brohold dilators for like three months. Oh my god, uh, okay.

:: 43:17

So, going going back to how do we communicate, I think that what is important is to avoid being absolute and to avoid placing focusing on a single topic, a single finding, a single food, a single finding, a single food ingredient, a single diet, because you know, focusing on a leaf or a leaf it makes you lose the tree, let alone the forest, because that's what you know, the public discussions typically take the form of right. We focus on just a small, tiny little thing and then we forget the whole idea of the forest behind that leaf. So I think that, taking a perspective, that is trial and error, and we know basic things about healthy diet and healthy lifestyle. But we tend to not even doing those because we are focused on other things.

:: 44:16

That makes sense. And I have one last question, and that is where do you think the future is going, the future of obesity research?

:: 44:27

Well, I wish I knew, because, had I known, I would be very successful in getting new grants in the future. Right, yeah, but you know, I, hopefully you know. Now we are entering an era where we have big data. So, because you have huge studies around the world with thousands of people which are deeply phenotype and genotype and you, you know, now, with the advent of AI and all these artificial intelligence systems, we might be able to mine this data in a more effective way that can possibly give us some ideas, or some better ideas about, you know, possible causative factors or possible ways to treat obesity.

:: 45:12

But it's not that I will see that this will go away relatively fast, simply because, again, obesity is so multifactorial that it's very difficult to kind of understand all of these factors in a comprehensive way. So, on one side, that's good for me because I will have work to do in the future. Again, on the other side, I don't want this to sound as pessimistic, in a sense that, again, we know a lot about what you can do right now already to be healthy, even if you maintain one, two, three more excess kilos. So you should not be focusing on the scale so much. You should be focusing on your health and all those other aspects that make living worthwhile Right, so I think that that's an optimistic note to end this discussion with you, Gabrielle.

:: 46:11

Well Faidon, thank you so much for sharing time and your brilliance. You are an amazing human and a phenomenal, phenomenal academic, and thank you so much for coming on the show. Thank you so much for having me.

:: 46:28

And thank you for your kind words.