Unsolved Mysteries of Obesity Science with David Allison

Jim Hill:

Welcome to Weight Loss And, where we delve into the world of weight loss. I'm Jim Hill.

Holly Wyatt:

And I'm Holly Wyatt. We're both dedicated to helping you lose weight, keep it off, and live your best life while you're doing it.

Jim Hill:

Indeed, we now realize successful weight loss combines the science and art of medicine, knowing what to do and why you will do it.

Holly Wyatt:

Yes, the “And” allows us to talk about all the other stuff that makes your journey so much bigger, better, and exciting.

Jim Hill:

Ready for the “And” factor?

Holly Wyatt:

Let's dive in.

Jim Hill:

Here we go. Holly, did you know that since the 1980s, obesity rates in the U.S. have more than doubled? Even with all our advances in science, there are still critical mysteries about obesity that remain unsolved. Why do some people gain weight so easily while others don't? And could the epidemic get worse, or is there hope for a turning point? We're diving into 10 intriguing unanswered questions or mysteries that could redefine how we understand, treat, and prevent obesity.

Holly Wyatt:

Wow, Jim, I love this topic. You know, even with our advancements, there's definitely critical pieces of the obesity puzzle that are missing. There's lots of excitement around these new weight loss medications, but do they solve everything? Are they really truly the answer, Or is there a much deeper, more complex story about obesity that we haven't uncovered? And today, I'm eager that we're going to be able to go beyond the usual explanations and dive into some of these unknown, these unsolved mysteries. So what are some of the biggest mysteries that we can still talk about that have yet to be unsolved?

And what crucial questions are holding us back from real breakthroughs? Each of these questions can take us in an unexpected direction and lead to insights that only change the science field, which always excites me, but also transforms the lives of our patients.

Jim Hill:

Yeah, Holly, and we couldn't ask for a better guest to help us explore these unknowns than Dr. David Allison. Dr. Allison is a groundbreaking researcher in obesity, nutrition, and statistical methodology. He spent his career unraveling complexities of weight and health. David is clearly one of the top researchers in the world. And as an aside, he was the director of the Nutrition Obesity Research Center here at UAB before I came to UAB. And David, this is a podcast supported by the UAB NORC. So even though he's not a part of the NORC right now, he has a history of being part of the NORC. He went on from a center director to dean. So as dean of the Indiana University School of Public Health, Bloomington, he's published over 600 scientific papers, and he's renowned for his interdisciplinary approach that tackles both environmental and genetic factors influencing obesity. Dr. Allison's expertise offers a unique perspective on the questions we'll explore today, some of which may challenge what we think we know.

Holly Wyatt:

So, David, you've been an obesity researcher for many, many years, and now you're dean. This is exciting to really have you on the show. Tell us briefly how your academic career evolved. Just give us a little snapshot before we get into the questions.

David Allison:

Sure, absolutely. I would say that for me, my academic career and my life and personality and ethos as a human being are not separable. And so when I think of my academic career, my scientific career, I think of how Lee McIntyre in his book, The Scientific Attitude, defined a scientist. And he said, well, what scientists do is they look at the world or some aspect of it. They make some observations. They formulate ideas about how things work, how things are. Then they get more information and then they update their views. Yeah. And I've been doing that since I was a kid. So I feel like by that definition, I've been a scientist since as long as I probably could use language and remember asking questions. And I'm the kid in the backyard who picked up the rock and looked underneath and said, what is that? How did it get there? What does it eat? How does it live? And then I had the annoying habit when adults would give me answers saying, are you sure? And how do you know?

And to this day, I annoy some people with questions like, are you sure? And how do you know? But most people think that's a good scientist and like that. So I've, I've been a scientist all my life. It's, you know, when I get at the question of how did you choose to be a scientist? Like it wasn't a choice. It's who I am, but I love it. I have fun with it. And it's one part, you know, the strictness, the rigor, get it right. And it's one part, the joy, the wonder, the awe, the fun of puzzle making and puzzle solving and so on. I've been doing that all my life. I got to college, started studying psychology at Vassar, great university. While there, I took a course as a sophomore called Human Emotion and Motivation. And we studied the theories and the books of Stanley Schachtler. And I fell in love with this idea. And so I've been studying obesity since I was a sophomore in college. Got to be eventually a postdoc at the New York Obesity Research Center, which in 1991 was the first and only NIH-funded obesity research center. Thrilled to be there. It was the mecca of obesity.

Started learning about how to try for bigger targets of thinking and pushing back the boundaries of ignorance through science in the domain of obesity. And wanted to have more people around me. So got some postdocs around me. And suddenly, it was selfish initially. It was just I wanted help on my research. But soon, people seemed to value my mentorship and my leadership. And then over the years, I kept progressing into more leadership roles within academia. Eventually, becoming the dean at Indiana University, where I feel like I get to be close to the science, which I like. And close to the learning and the education and help other people experience the joy of wonder and awe and education they might not otherwise have, but also to promote good science.

And to be a leader in that. And that's both fun and challenging. This is the hardest job I've ever had, being the dean. It's very much a job that is all about, as I think many people think, it's a job about achievement and satisfaction and purpose and meaning, as opposed to other jobs, which are more immediate happiness. Being a center director is a lot more day-to-day fun. Being a dean is a lot more long-term pride in the ability to build something that lasts and has a big impact on so many people. So that's been my journey. And I love both aspects of the leadership.

Jim Hill:

Wow, Holly, this is great. So we're going to have some fun with David today. And again, we're going to jump into these mysteries and our goal isn't to solve it. We aren't going to answer the question. We're simply going to talk about why it's important and why it's important to learn more about it. So I'm going to start with the first one, because this is something that I've seen my whole career. And that's, what is the role of set point in body weight regulation? Do we have a dialed in number in our brain that determines our weight? David, what do you think about this?

David Allison:

Well, it's a very, very challenging question you're asking. It goes to almost philosophical, or not almost, it does go to philosophical and so-called ontological issues. There is no, if you dissect a human or any other animal, you will not find some physical object that's the set point. You will not find a thermostat, an apostat, a gravostat. You will not find a measurement device that measures the absolute amount of body fat or body energy stores or body weight, and then has a little dial on it that's set at a particular level, and your level is different than mine. The set point is...

What some people might call an emergent variable, or it's also, one could think of it as just a hypothetical descriptive device. So there's no physical set point that we can identify in any of us, but we can look at our behaviors, including our physiologic behaviors, and say we act as though there's a set point, as though there were a physical device in there. Question, is that a useful heuristic for us to actually give us increased knowledge? Were we better off just staying at the level of identifiable causes and effects and saying, this is the effect of ambient temperature. This is the effect of more carbohydrate, of more fat, of this molecule, that molecule, this drug, et cetera. And I don't think we know the answer to that.

It does appear that people behave to some extent like there's a set point, but there are so many challenges to it, both philosophically, as I mentioned, but also empirically. We know, for example, that populations have gotten heavier and fatter over the centuries, not just over the years, over the centuries. The obesity epidemic, so to speak, if we define it by increased body fatness and body weightiness, doesn't seem to have started in the 1980s, as some people pretend. It goes back hundreds of years. If there's really a set point, why is the set point seeming to get higher? Also throughout age, it changes. And so you can say there's a set point that's context specific, and that's okay. But then at some point, are you starting to say, well, then is there really a set point? Or are we better off just talking about all the different factors?

Holly Wyatt:

Yeah.

David Allison:

An alternative is called a settling point. And that's less of a smart system. Set point sort of implies a smart system. So for example, if my set point is, you know, whatever, 130 pounds and I, pull myself up or down five pounds from that, then there's something that tries to pull me back and there's an active reading of it and some sort of counter-regulatory system like there would be with a thermostat in the house. In contrast, you can imagine just a kitchen sink, not the thermostat in the house, whereby you start running the water and the sink starts filling a little bit and it keeps filling because the water's coming in faster than it's going out the bottom drain. But then the weight of the water starts to make the water go out faster from the drain as it fills. And eventually it starts going out faster through the drain until the amount of water going out of the drain and the amount of water coming in from the faucet are equal and then it stabilizes at that level of water content in the sink. But there's nothing smart, right? There's nothing reading anything and making decisions. Which one are we like or both neither? And it's tempting to think that the settling point is a better description.

And then you get into things like, well, if Jim takes in a mean energy intake of this with some variability from day to day, and it has some mean energy output of that, then eventually he'll settle at this point. And the same thing for David and the same thing for Holly. The problem as one of my colleagues, Harry Kissileff once said to me is David, a mean is not an explanation. It just moves the question further upstream. Well, you explained Jim or David or Holly's sort of tending to hover around a certain degree of body fatness or body weight. By reference to saying they tend to hover around a certain degree of energy intake or an energy expenditure. They have said, well, why do they hover around there? Is there a set point for that? And now we're back to where we started. So I don't know.

Jim Hill:

So really, this gets at the essence of how body weight's regulated, and we still don't totally understand that, which is the essence of our field. So big mystery there.

David Allison:

Is it regulated, and what does regulated mean?

Jim Hill:

Yeah, yeah. Is it regulated? Is it a byproduct of something? So many, many important questions here.

Holly Wyatt:

Yeah, and I think probably all of us have been in a debate before. Is there a set point or not a set point? Is it a set point? Is it a settling point? So my whole career, that has been a question that we keep talking about. So I do think it's probably kind of at the essence of body weight regulation, which how does the body regulate, especially energy balance? I'm always like, how does it stay in energy balance? That's kind of an amazing thing.

But this kind of goes to the second question. Let's go to a second unsolved mystery around obesity. And this is one that my patients talk a lot about because it's frustrating. So why do some people gain weight easily while others don't? And let me kind of explain what I think I mean by that. Two people basically eat similar, feel like they're exercising similar, doing similar behaviors, and yet can weigh two very different weights. And that can be very frustrating. You've got a partner who is eating pizza and not moving, and you're eating pizza and don't move, and you have two very different weights. So what about that mystery? Why has that happened?

David Allison:

I think there's three major reasons why this happens. One is that the premise is, you've offered and that other people state that they perceive it, they're offering it with honesty, but they're not accurate premises. So the facts of the question are not in evidence. And what I mean by that is I often hear things like this person, my spouse, for example, or my friend or whatever, they can eat huge amounts of food. They can eat anything they want and not gain weight. But if I eat just a little bit, I gain weight.

And we know that people are very poor at estimating and reporting how many calories they actually eat. And much of that is probably unintentional. It's just really hard. Even if you're really pro at it, I think I'm pretty good at it. And sometimes I weigh my food and yet I know there's a big error in there. I can't figure everything out, how much water loss, how much fat got left in the pan, who knows. So these things are different. And if you're not weighing all your food and measuring it and writing it down and remembering it accurately, you may think you are eating much less than the other person. You may feel like you are eating much less than the other person. You may be feeling that way, especially because the other person, yes, can eat as much as they want, but they just want to eat a lot less.

Whereas some of us want to eat a lot more and that may lead to an inaccurate perception. And so the real big difference may be the ease with which somebody eats less as opposed to how much they eat. It may not be that my counterpart who can seem to eat anything and not gain weight just doesn't eat that much, but they're comfortable with that. They're still eating what they want. So that's one. I think that's probably a lot of it. Now, the second thing is called nutrient partitioning. And that is the idea that two people can have the same degree of calorie excess. Let's say each of us, all three of us, we each expend on average, let's just say 2,500 calories a day. And then one day we eat 3,500 calories. And now we have an extra thousand calories. What does our body do with that? Well, Holly's body might stick 90% into fat-free tissues or sources and 10% into body fat.

Holly Wyatt:

Oh, no, no. You got it backwards.

David Allison:

Okay.

Holly Wyatt:

Mine would all go into fat.

David Allison:

All right.

Holly Wyatt:

Make this real.

David Allison:

Jim, maybe, it all goes into muscle and none goes into fat. And David, maybe it's 50-50. And that's called nutrient partitioning. And there are clear differences in that. And those can be affected by very subtle things or not so subtle things like diet composition, like drugs, like whether you're doing resistance training, age, and yet some other very subtle things we might want to get into about psychosocial signals that may be somehow affecting the body. And then the last thing is energy expenditure. It may be that, yes, you and I might eat the same thing, and yet your body is either ramping up or down energy expenditure through physical activity, right? You're becoming more or less active, whether you realize it or not, and or you are expending more or less energy than me through things other than physical activity, like body temperature and fetal substrate cycling. and so on. There are other little things like fecal and urinary losses, but unless you're doing something unusual, those are probably not the major players. They're not zero players, but they're not the major players.

Jim Hill:

Got it.

Holly Wyatt:

Yeah. I like that, yeah, there's some about the perception and I always say my patients remember the days that they didn't eat very much and you tend to maybe not remember the days where you ordered the pizza and extra servings of something. And so that can play a role. But I like it that you're also talking about the fact that there's other things that are involved because the whole reason I got into the field of obesity is because I knew as even in high school that what I could do and what I watched my friends do and the weight they could maintain and the weight I could maintain were different. It was just so frustrating. And so I think saying there are some other things going on in terms of body weight regulation is helpful to recognize for our patients.

Jim Hill:

Okay, great. So, David, this next one, everything I hear these days in obesity is about the microbiome, the microbiome this and that. And I think we clearly know the microbiome is playing a role, but could we one day treat or prevent obesity by adjusting the microbiome? What do we know here?

David Allison:

Well, I'm going to reiterate a sort point I made earlier, which is, I think first we need to question the premise. You said, we know the microbiome is important in obesity or something like that. I'm not sure we really know that. When we look at the model organism, the mouse, the rat studies, and so on, what we rarely see is clear replications, right? Of one person doing a study and then a separate lab doing the same study, or a very, very similar one, and getting very, very similar answers. In fact, Rob Knight published a paper years ago in which he looked at the consistency of the findings of microbiome studies with obese versus not obese organisms, and then with irritable bowel syndrome versus not. And he found that in the latter case, irritable bowel syndrome, there was a great deal of consistency from study to study in what was found. In contrast with obesity, each study seemed to find something different. Everybody found something, but there was very little consistency. Now, we know that with these high-level OMIC techniques, there is, as they say, many a slip twixt cup and lip.

And there are many opportunities for the data analysis to go wrong, for the study to go wrong, for people to do a lot of data dredging that's not always clearly reported and not realize the effects of that. Matthew Dalby did a terrific talk on this in 2022 at the Royal Society in an obesity meeting. Torkild Sorensen, Kevin Hall, John Speakman, and I co-hosted, and that video of his talk can be found online through the Royal Society or YouTube, and he shreds the microbiome literature for lack of consistency and rigor. It's well worth seeing.

Jim Hill:

Interesting.

David Allison:

So I would really say that on the gut microbiome, it is entirely reasonable, plausible, and conceivable that it has a huge, important role. I am not even close to convinced that it's been demonstrated as a huge important role, especially in humans with respect to obesity, not to say the gut microbiome doesn't matter for anything.

Jim Hill:

Wow. What a good mystery, Holly, that what is the role of the microbiome in obesity? So sounds like we don't really know. And that's something to pay attention to. Could turn out to be important. Maybe not.

David Allison:

I'd love to see two studies, two investigators agree up front to say, we're going to do these two studies, largely identical. Then we're going to do them independently, not tell each other results. We're going to call our shots, say what the analysis will be up front. We're going to make all the raw data publicly available. We're going to have the assessors be blinded. And then you show me a real consistent, enduring effect of gut microbiome on an obesity outcome, then let's talk.

Jim Hill:

Well, there's a challenge.

Holly Wyatt:

I think we're in its infancy of understanding this, but, you know, it wasn't that long ago that I didn't think microbiome played a role in much of anything. So I think we've moved forward in saying there's something going on here, but what is it? Is it playing a role in obesity? How does it work? I agree with all that. And people already are buying probiotics and prebiotics and all this trying to change their gut. And I'm always saying, I don't think we're there yet to know at all how to change it for sure. So I think it's like, stay tuned on this. It's something interesting, unsolved, but to be determined.

David Allison:

Absolutely. And when you look at the human randomized controlled trial literature on it, there have been some things with fecal transplants, which I don't know about you, but before I would take a fecal transplant, I'd sure want to know work as well as be safe. What other microbes am I going to be getting from someone else's non-sterilized feces injected into my body, or in some other way taken in? I'd like to know what works from rigorous randomized controlled trials. And right now, there are no rigorous randomized controlled trials showing that, manipulating the gut microbiome has an important outcome with respect to obesity.

Holly Wyatt:

Got it

David Allison:

And there are several null findings.

Holly Wyatt:

All right. Let's move on to another one because I got another exciting one here, Jim. I'm going to skip ahead a little bit. I want to talk about, do ultra-processed foods play a role in obesity? There's lots out there about that now.

Jim Hill:

Boy, there's so much controversy. The recent one is the dietary guidelines failed to call it out, and some people were real critical of that. Really interested, David, in how you see this one.

David Allison:

Well, the dietary guidelines, it's sort of like being a dean. You're guaranteed to have complaints about it, right? Whatever the dietary guidelines committee comes out and says, there will be a party to complain about it. But with respect to ultra processed foods, I'd like to offer a little bit of a sort of allegory here. And so let's imagine that some aliens come from outer space and by some miracle, they happen to speak English and they're very intelligent. And they like to do research and they understand how to make observations. They only have a modest understanding of our world and our culture and how we do things. And they say, “Tell us an interesting question.” And you say, “Okay, we want to know what seems to contribute to obesity.” They say, “What's obesity?” And you explain it. You show them how to identify which people are and are not obese.

And then you say, “We think there might be something to do with food intake. And most people buy their food in stores. And these are some of the characteristics. And you can sort of get a sense of what's in the food by looking at the label.” And they say, “Okay, we'll come back to you. Now we have enough knowledge.” So they come back and they say, “We took all the labels and we looked at the ink on the labels and we didn't really know what it all meant, but we just sort of categorized it. And we found that there were some labels that had a particular pattern of red and black ink on the packaging.

And there were others that didn't have that pattern of red and black ink on the packaging.” And they said, “We found that people who ate more of the red and black ink package stuff were fatter than people who didn't.” Oh, that's interesting. They said, “But we weren't sure it was causative”. So then being aliens, we had a lot of money and we ran a big randomized controlled trial and we fed half the people food. We only bought food that had the red and black ink in the packaging or not. And we fed half the people, the ones with the red and black ink, half without. We kept the calories the same.

And what we found was there was more weight gain, or we let people eat ad libitum and they ate more of the food with the packaging with red and black ink. So it's causal now. We've done a randomized controlled trial. And we've shown that there's something about red and black ink in food packaging. And so what we recommend is that you don't eat things packaged with red and black ink, and we get rid of all the red and black ink. And what you might say is, “Oh, can you show me this red and black ink example of the package?” They show you, “Oh, That's a brand.” It's a marker of a brand. What you were looking at was a cookie manufacturer. Everything in there was cookies pick your food, whatever it is.

What you were really looking at was people who eat cookies versus people who eat things other than cookies. And cookies may seem to matter and we can go and dig that up. And I think that's where we are with ultra processed foods. We've found a label and the label is associated with, we assume, some element of the molecules of the food, right we don't think it's the label there's a great line from Joe Fleiss who has a book. The book is titled A Fly in the Ointment. It's funny as all hades to read. I highly recommend it. And in it he says, “I have a mantra for you. Repeat after me. The effect of substances in the body depend on their molecular structure, not their ancestry.” So where the food comes from, whether it was ultra-processed or not, whether it was made in a lab or pulled off a tree, whether it came locally or not, whether it was something your grandmother would have eaten or not, are all irrelevant.

What is relevant is what is it you're eating now it may well be that things that get labeled ultra processed on average tend to have more of this and less of that and that and though this and that they have more or less of the substance maybe the driver from a clinical and public health point of view it can be a useful technique. Back to my alien allegory if you said, “David, you want to lose some weight, don't eat any foods that have black and red ink in the labels in this configuration.” It might make me lose weight because if I tend to eat a lot of cookies and that's keeping me heavy and this makes me not eat cookies anymore, it worked. But it wasn't the black and red ink. It was the cookies. So same thing with ultra processed. You know, protein shakes, meal replacement formulas. You guys know ‘cause you've studied these more than I have. People who go on them, they lose weight. Those are ultra processed. I think by almost any standard, as many of the things that are the darlings of folks, we hear recently that eating more ice cream may make people resist diabetes and so on.

Jim Hill:

Yeah. I heard that.

David Allison:

Dariush Mozaffarian went so far as to be quoted in a newspaper saying “it does”, not “it might”. It does prevent, okay? Dark chocolate came out last week, right? With news things saying this prevents diabetes and is associated, I think, with lower weight gain. Cinnamon, coffee. So what you should have is some cinnamon, dark chocolate, coffee ice cream.

Jim Hill:

Ooh, I like it.

David Allison:

And they're all ultra processed foods, right? Dark chocolate is an ultra processed food. Red wine is an ultra-processed food. Didn't come off the trees this way. Nice cheeses are ultra-processed foods. The cow didn't just drop some milk in the form of cheese. Had to be processed. So I think the whole ultra-processed thing, it may be fine if you say, “I'm a dietician, I'm giving you some advice, here's a heuristic.” It's just the same as saying, “Don't buy any of your food on the north side of town, only buying on the south side of town” if in fact all the better foods are on the south side of town.

Jim Hill:

Yeah, but David, this is another example in my mind of where we come up with these simple solutions to obesity that are usually wrong. But the thing that stays in my mind here is the idea of aliens doing randomized control trials. I love that.

Holly Wyatt:

Wait, I want to say one more thing. This reminds me, because this is the other thing people say all the time. If a food is natural, so not processed, they tend to use that word, natural, it's safe, right? Because it's natural, it's safe. And I say, “You know what? Some of the poison, some of the most toxic substances we know are natural in nature.” So we get into this idea of natural is safe and ultra processed is bad and all this kind of stuff. And I think what you're saying is, “Yeah, we've labeled it in a way that doesn't necessarily make sense or really have the power we think it does.”

David Allison:

You're exactly right. My hero Socrates died because he was forced to drink hemlock to kill him. Hemlock is a perfectly all-natural poison.

Holly Wyatt:

Yeah, that's what I say.

Jim Hill:

Okay. All right. I want to jump into one here that I've been dying to get David's opinion on, Holly.

Holly Wyatt:

Okay.

Jim Hill:

In the news now, the new GLP-1 medication, some people are saying, “What are you guys going to do now? You're out of a job. We've solved obesity. This thing is over. We've got the answer.” What do you think? What do we need to be concerned about here?

David Allison:

Well, it's interesting. I may in the next few weeks be having a very collegial, formal debate with another colleague on GLP-1 drugs and their appropriate usage or to whom should they be made available. Some people like Jeff Friedman, in a wonderful lecture he gave, which you can find on YouTube, he gave it about a month ago at Rockefeller University. He referred to where we are with GLP-1 agonist related drugs as the end of the beginning. Quoting Churchill, not the beginning of the end. And the idea is that we've been in the beginning phase of obesity treatment for until probably less than 10 years ago, until the GLP-1 drugs really took off. And by that, he means, and I would second, that we were dealing with a very limited understanding of how things work. And even more so, we were dealing with a very limited armamentarium of procedures to help.

The best drugs we had before the GLP-1 agonists, and I would also throw the SGLT-2 inhibitors in there, were mediocre. They had either very, very minimal side effects, but very, very minimal efficacy, or stronger effects, but very severe side effects. Right? So certain things like amphetamines were pretty effective but pretty dangerous. There are other things that make you lose weight very effectively but kill you. And then there are things that make you lose just a little weight like Orlistat and it has side effects and they're not dangerous, but it's not a big effect. Now, for the first time, we have drugs that cause big effects and appears reasonably safe, recognizing that safety is a social judgment, right? We don't show that things are safe or unsafe. We show their risk if we do good research. Risk is a scientific concept. Safety is a social concept. But they appear safe by most people's standards and by the FDA's standards. But safe for what and for whom? So should we put it in the water so that everybody's exposed? Metaphorically, or should we limit it to a very small number of people? And clearly we want to continue to get ever better ones that have even bigger effects and that have even better safety. And those are on the way.

People are now combining in research studies, the GLP-1 agonist related drugs with anabolic enhancers. That is drugs that would promote the growth and or maintenance of skeletal muscle, things like myostatin inhibitors. And one company just put out a press release in the last few days on a myostatin or inhibitor in early phase human trials that looks quite effective. So this is very exciting. Then we'd have much less concern about saying, well, I'm going to lose a lot of weight, lose a lot of muscle. And at some point, I think we do need to ask the question of, should these be made widely available? And I think there's one point of view which says, “These are drugs to treat a serious medical condition or medical conditions, obesity and diabetes. And those are the only people for whom they should be used, in part because that's where we know the risk benefit profile is a good one. That's what the FDA has approved them for.” We shouldn't use them for people who just, and I emphasize that word just, because I think when you hear that phrasing, you've now started to hear the pejorative stigma view about obesity, who just want to look a little better on the beach, as though looking better is not okay.

Holly Wyatt:

Right. I totally agree with that. Talk about judging. That to me is equally as saying something about someone who's overweight that, you know, wants it for other reasons. Yes.

Jim Hill:

And Holly, we know weight affects many aspects of quality of life independently of metabolic disease.

Holly Wyatt:

I'm so glad you said that. That's, I think, really interesting. A lot of people do not believe that. They believe that there's a right way to use these drugs. One way. Their way, usually.

David Allison:

Right. So I think that the most extreme position is the drugs are expensive. Society pays for them. They're in limited supply. People should not be allowed to take these for anything other than the medical indications of obesity and diabetes. And subjective non-medical motivations for taking them or losing weight. Like I'm a movie star and I want to get the next role. You think about people like Robert De Niro who gained all that weight to play Jake LaMotta in the movie raging bull. We didn't all say, how dare he do that? Right. We said, oh, that's cool that he did that. We understand it may or may not have been healthy, but that was his judgment of what was valuable to him. Who are we to set the values for people? I would take an opposite position. And I would say, obviously, I have very strong libertarian leanings. And I would say, let's put who pays aside. I'm not saying who should pay for the treatment.

Let's put aside shortages and say, you know, there's going to come a time when we've solved all the shortages. So let's hypothetically say shortages are all over and say, we're not saying anything about who's going to pay for it. You may have to pay for your treatment, but now it's about, it should be available to whom? And I would say certainly, of course, people with obesity and people with diabetes as the FDA has approved. But soon it's going to be people with, and in some cases is, heart disease, fatty liver, so many others. Then further spread the medical indications. There's very compelling and exciting emerging evidence to suggest, I don't know if I want to go so far as to say prove, but to suggest strongly that the GLP-1 agonist drugs may help in cancer prevention. They may help in resilience to infectious disease like COVID.

They may help in addictions, both addictions to substances like alcohol, but even addictions to gambling seem to be reduced by this. So we don't know how many other things they have, but if you have a patient who says I'm struggling with addiction, um, and I want to try this and I've tried other things, I think you and that patient should have the right to do that. Now, as a physician, you do have the right to prescribe off-label, but you may be looked down upon and you may be running some risk if you go too far. As a patient, you can only get it if the physician prescribes it.

Holly Wyatt:

Right.

David Allison:

But I'm going to go further. I'm going to talk about non-medical use. Let's take another hypothetical. Let's take a woman who is a recreational, what do they call it, the coxswain, the person who calls out in a rowing competition. It is to the advantage of the team for that person to be as light as possible, so the team is not carrying that weight. And that person themselves is not rowing, so they don't need a lot of strength. And let's say that that person is of normal body weight, but would like to weigh a little less. The person is not making their living through this. They are not even an Olympic competitor, but for them, it's the thing that makes their life thrilling. It's everything for them.

And they say, I want to take this drug, it's a performance-enhancing drug, let's assume it's not illegal by the standards of the people running the competition, because it'll make me a better contributor to the team. And I understand the risks, and I'm willing to pay for the drug myself. I would say, as long as you understand the risks, let's make you sign a release form, let's make sure you've read what we do and don't know, personal decision. Who am I to say that my interest in not getting diabetes or in reducing it if I already have diabetes is somehow more valuable than her wanting to be better on the rowing team?

Jim Hill:

I love this perspective, Holly.

Holly Wyatt:

I align with this, but I'm not the standard doctor. We've had many MDs on here who basically think, I'm like, why do you think as an MD, you get to decide where the value is in this? And I understand we have data that we look at risk-benefit, and I understand that aspect of things. But still, it feels like, why do MDs or committees that get together to decide, get to decide something like that? I don't quite get that, but that is the common thing. That's what most people believe.

David Allison:

Well, it's a common struggle within our society. We're a complex society with mixtures of views. So we mandate that people wear their seatbelts, for example, when they drive, which I think is a really, it's really smart to wear your seatbelt when you drive, assuming you don't want to be killed or have a major injury. And I wear my seatbelt when I drive. But as a libertarian, I say, who am I hurting besides me? If I don't, shouldn't I have that right to not wear my seatbelt if I want? That's two different views. And yet in that part of our culture, we say it's okay to mandate that. Now we have other things like marijuana use. That's where people seem to more rally to the other side. And they say, we want to allow freedom. You say, but you're bringing smoke into your lungs. Like smoke in your lungs intentionally, not a good idea.

Holly Wyatt:

Complex. Definitely. Complex.

Jim Hill:

Holly, we didn't get through 10, but this has been fantastic, the ones we got through. Do we have time for a really quick listener question and then a vulnerability question?

Holly Wyatt:

Yeah, I want to do one listener question, and I know the one because I want David's answer on this one.

Jim Hill:

Short on this one because we don't want to go too long.

Holly Wyatt:

Yeah, but I don't know if he can be short on this one, but I think he can. So this whole concept, and we were just at the Obesity Society meetings, and actually the opening session rubbed me the wrong way because of this. So the question is, from this listener is, “I know that obesity is not my fault. I know that it's driven by genetics and environment and there's factors that we're born with that we can't change. I know it's a disease, but is it my responsibility to make changes or is it really not possible to change my weight?” In other words, where does this, you know, I think the drugs have come out and said, oh, look at this, you know, it's genetics, it's physiology, and we're not responsible anymore for changing our diet. And even at TOS, it was almost like you shouldn't even bring up diet with your patients because you're crossing this line. And I was like going crazy in the audience because that was just so not what I believe. So what do you think about this kind of the genetic physiology to disease versus responsibility to change behaviors?

David Allison:

Responsibility, blame, and fault are not scientific concepts. They are social judgments. People often say, well, you know, can I conclude that it's someone's fault or blame them? I say, you start blaming people whenever you want. That's up to you, depending on your judgment. There is no scientific study any of us have ever done or could do that would say, this person is worthy of blame for this or not. I often hear from my colleagues, it's not fault, it's not blame because we've now shown genetics. This is ridiculous. Yes, of course genes influence obesity. That's not in question. That is a scientific matter and we know that genes influence obesity, as does the environment, etc. However, none of that goes to fault or blame, right? Genes and the environment influence everything. There's the very famous movie M with Peter Lorre, M for murderer, when he's captured at the end and he's a serial child killer.

And he makes this plea to the people who have captured him. He says, “Don't you understand? I know I'm a monster. I didn't choose to be a monster. Somehow I became a monster. I don't want to be a monster any more than you want me to, but I am. It's not my fault.” Right? So everything is causes, but as a society, we've decided that if you kill other people and you do it knowingly and you understand it's wrong, we're going to say you're entitled to blame and retribution. And that's a social judgment that acting as though there's free will is useful. But that doesn't mean there is free will. And the same thing goes for everyone else. Now, when we get into medical treatment, my feeling is, you know, as a human being, I don't want to blame anybody. I don't want to get a fault. You know, I don't care. You're not hurting me. You're struggling with your weight.

You're the one who's suffering. I don't want to add to that by blaming or saying fault. But if you say as a scientist, then I say, I don't even want to talk about it. It's irrelevant. What's relevant is how big things are, what causes things, what treats things. And so then I would just say, you can blame people all you want and say it's their responsibility and blah, blah, blah. And what we've been saying for decades, it's your responsibility to do this, change these behaviors, and it's not very effective. What works is GLP-1 agonists, bariatric surgery, SGLT2 inhibitors, and a few other things, and hopefully many more on the horizon. I think we just need to come at it as though we are the aliens, put our passions, our moral beliefs, our cultural preconceptions aside, and say, “There's this species called humans. They have a variable called fatness. Fatness seems to be affected by this and not that. Long-term reductions in fatness seem to be able to be achieved through the use of these interventions.” That's it. Just treat it like we treat anything else. Put the morality and the preconceptions aside.

Holly Wyatt:

Got it.

Jim Hill:

Oh, my gosh, Holly. I think we're going to have to wrap it up here. This has been really fun talking about these issues. There's still so much we don't know. And David, I think you have been the champion in our field of calling into question what we think we know, maybe based on less evidence than we need to make a conclusion. So again, thank you so much for being our guest today. Lots to think about. We didn't get through all of ours, so maybe we'll have you back at a later date to do some of the others.

Holly Wyatt:

Part two.

Jim Hill:

Part two. Love it.

David Allison:

I'm truly honored to have been here. Great topic. Two great friends and scholars to dialogue with at a great university. It's my privilege. Glad to come back.

Jim Hill:

Thank you. Thanks. Bye, everybody. And that's a wrap for today's episode of Weight Loss And. We hope you enjoy diving into the world of weight loss with us.

Holly Wyatt:

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Jim Hill:

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Holly Wyatt:

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