Why Your Body Fights After Weight Loss with Rudy Leibel

James 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.

James 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.

James Hill:
Ready for the “And” factor?

Holly Wyatt:
Let's dive in.

James Hill:
Here we go.

Holly Wyatt:
Today, we're talking about one of the most frustrating experiences people have with weight loss. You do everything right, you work hard, you lose the weight, and then your body fights you to gain it back.

James Hill:
Yeah, not in a small way. Hunger goes up, energy goes down. Oftentimes, weight regain can happen faster than the weight loss itself.

Holly Wyatt:
And for years, people were told that meant they had failed.

Holly Wyatt:
But what if the truth is your body was doing exactly what it was designed to do?

James Hill:
So, yeah, Holly, that's what we're unpacking today. Why weight loss is so hard to sustain, what's happening biologically, and what that means for the future of obesity treatment. Now, to help us understand this, we brought in one of the most influential scientists in the history of obesity research. We have a superstar with us today.

James Hill:
Dr. Rudy Leibel is the Christopher J. Murphy Memorial Professor of Diabetes Research at Columbia University, where he serves as head of the Division of Molecular Genetics, co-director of the Naomi Berrie Diabetes Center, and co-director of the New York Obesity Research Center. And he served as the director of that center for many years. Rudy's a pediatrician and endocrinologist by training and spent more than five decades, Holly, five decades. That's more than me. Five decades studying the biology of body weight. Rudy was part of the team that identified and cloned the leptin gene, demonstrating that fat tissue is not just storage, but an active endocrine organ that communicates directly with the brain to regulate body weight. That discovery fundamentally changed how we understand obesity, from a behavioral issue to a biologically regulated system, and he laid the groundwork for what we're seeing today with the GLP-1 medications and beyond. Literally, Rudy's research led to what's happening today with the new version of weight loss medications. Rudy, we're honored to have you here on our show.

Rudy Leibel:
Well, I'm delighted to be here. Thank you for that very kind introduction.

Holly Wyatt:
All right, let's jump right in with what I think the big question is for our listeners. They lose the weight, and then why does it feel so hard to keep it off? Why does it feel like a losing battle? What's going on?

Rudy Leibel:
I think one way to think about this is to consider how we as a species evolved over many millions of years. And if you think about where we were a million, 500,000 years ago, we were in environments in which it was very hard to get food. You had to hunt and spend a lot of energy doing that. There was no agriculture at the time. and you were in a situation in which the availability of food was intermittently severely restricted. At least that seems like a reasonable perspective or a hypothesis.

Rudy Leibel:
And if you think about that, then what we are designed to do as a species, the ones who survive our forebearers, is to be able to survive circumstances in which we weren't getting enough to eat. And what that means is that we were very efficient at conserving calories when we were in circumstances of reduced availability of food. Our bodies made adjustments to that situation that led us to conserve energy and to be hungry so that we would seek food very aggressively. And if you now fast forward to today, what we're living in is an environment which is entirely different. It's very easy to get food. We don't have to spend much energy to get it. But if we undergo intentional weight loss, we still trigger the same biology that was there a million years ago, so to speak, which is conserving the expenditure of energy and a very strong drive to seek additional calories. So I think what we're seeing, at least from that very sort of high altitude perspective, is not surprising.

Rudy Leibel:
And what I've spent a lot of time doing, and Jim emphasized this in the introduction, is trying to understand the physiology of that situation. And what I can say sort of as a quick summary is that's exactly what happens to almost or virtually everyone when they lose even rather small amounts of weight. The body kicks in to conservation mode, sort of echoing evolutionary acquired biology that's hundreds of thousands of years old to conserve energy expenditure. In other words, energy expenditure actually declines in a weight reduced individual relative to your new body size and your drive to eat is increased. And sometimes we refer to this as the perfect storm for weight regain. Your lower energy expenditure, higher drive to eat, it's virtually inevitable unless you apply consistent attention to both trying to reduce your drive to eat and increase your energy expenditure, you're going to eventually tend to go back to where you started. And it's very interesting. That process doesn't tend to overshoot. People who've successfully lost weight don't regain weight above where they started. They simply go back to where they were.

James Hill:
Yeah, Rudy, as you know, I've been working with Rena Wing on the National Weight Control Registry for many, many years. And we had hoped that we would find that over time, these biological pressures lessen, but they don't seem to. The people that are successful seem to find a way with lifestyle to sort of compensate for this drive to regain, which seems to be always there.

Rudy Leibel:
It's absolutely true. I mean, at least in my experience and in the registry that you mentioned, if you ask people who have managed to successfully sustain weight loss of 10, 15 percent, they will virtually all tell you that they're doing it by ongoing continuous attention to their food intake and energy expenditure. It just doesn't seem to let up. And again, to hark back to my sort of evolutionary perspective, you wouldn't expect it to let up. In other words, those of our species in whom it did let up are probably in the fossil record somewhere because they didn't survive these very adverse circumstances. So it's not as if your body would say, “Well, you've done it for 15 or 20 weeks. Now it's fine. We'll let up on you.” It doesn't work that way. It's similar in that regard to blood pressure or cholesterol. If you get it down with a drug, either of them, and you stop the drug, it goes back to where it started.

James Hill:
Yeah. And this doesn't mean you can't be successful. We find people that are successful, but they succeed by doing the lifestyle things that compensate for this drive to regain.

Rudy Leibel:
That's correct. I mean, that's certainly been my experience.

Holly Wyatt:
So you talked about two things and their appetite goes up or you have a drive to eat more food and then also decrease in energy expenditure. And I love that you specified it's both what we would expect from losing weight and then a little bit more. And we call that kind of that metabolic adaptation or that's the term I tend to use in this. And I've always wanted to ask you this. You've done the studies. I've read your papers so many times on this. Why not, when we look at the papers and you can see a small decrease, that adaptive energy expenditure decrease, it doesn't predict who regains the weight. It's not really predictive of success or gaining back the weight. So how do you interpret that? I believe it's there, but how do you, is it an important part of that regain?

Rudy Leibel:
There are some studies that are at least partially suggest that you can predict the amount of weight regain from the decline in energy expenditure. Some of the data from the so-called Biggest Loser TV show suggests that, in fact, you could predict, you know, by virtue of the decline in energy expenditure, how likely they were to regain and what amount they were going to regain.

Rudy Leibel:
One of the answers to your question, though, is that it's not so much that individuals reduce energy expenditure in proportion to the amount of weight they've lost. Again, thinking from an evolutionary point of view, you wouldn't want this thing to be proportional to weight loss. You would want it to kick in almost full force. Immediately, it detected a threat to your survival. Again, it fits with your observation. That is, we've often thought of this as a threshold effect rather than a stretching effect so that once you pass that lower threshold of your normal range of body weight, this mechanism kicks in full force. And whether you then lose another 5% or 10% or 15%, the strength of the resistance stays the same. It's not trying to titrate the amount of resistance. Again, from a survival mode, you don't want to wait if you're in an adverse environment until you're 15% below your normal or usual body weight. You want the preservation to kick in fast. And that's what it appears to do. Like I said, we call this a threshold rather than a set point.

James Hill:
Rudy, I have known you probably for over 40 years, and you have always been looking at the biology here, where not everyone studying obesity at that time were doing that. And we knew not a lot about the biology then. Briefly, walk us through how we got from there, through leptin, ultimately to these GLP-1 medications.

Rudy Leibel:
When I started this work, which was around 1978, the conventional view of this was that many individuals with obesity would benefit from having psychoanalytic or psychiatric or psychological support because the entity was viewed almost as a choice rather than something that was biologically mediated. And I very early on, by virtue of my incipient training with Dr. Jules Hirsch, then at the Rockefeller University, was convinced, as he was, that this was a biological entity that we simply didn't understand well enough. And so, like many other earlier biological or medical entities, was blamed on the patient rather than our lack of biology. So we committed ourselves to trying to understand the biology better. And that desire led ultimately, actually, relatively quickly, to the effort to actually identify a genetic mutation, in this case from a mouse, that clearly indicated that this had to be a biological entity as opposed to some behavioral quirk on the part of the mouse or ultimately on a human.

Rudy Leibel:
And this is what led us over a period of a decade to work on the cloning of what turned out to be the leptin, the gene leptin. It was from a mouse called the obese mouse, which was known to be a genetic form of very severe obesity in mice totally not understood with regard to mechanism. And that's what made it a very attractive sort of primary goal was to show that there actually is a biological basis, at least in one species, for the etiology of the obesity. Now, it turns out that that discovery led to the identification of many other genes. I would say there are probably 80 single genes now known in humans to produce severe or relatively severe obesity, and all of that insight actually follows from that initial discovery, which proved that there was a biological basis for obesity.

James Hill:
So, how do you handle the comment people make that obesity rates have increased so quickly that it can't be genes changing. The environment has to play a role. How do you look at this interaction between genes and environment?

Rudy Leibel:
Yeah. So again, I like to go back to my evolutionary biology. If you consider what our forebearers encountered, they were in an environment of low access to food and high energy expenditure to get it. So over hundreds of thousands of years, you would predict, and I think it would be correct, that our gene pool is enriched for genes that favor conservation of energy and high food intake under circumstances when body weight is reduced or when food is available. Now switch to the present day with that gene pool that we acquired hundreds of thousands of years ago. And you're in an environment where you can get unlimited amount of food with a cell phone and you don't have to get up to get it. So it's what's happened. You're absolutely right. There's always a powerful interaction of genetic predisposition with environment. And what we've done is inherited a gene pool designed for the absolute opposite environment that we're now living in.

Rudy Leibel:
So it's no surprise that we're increasing body weight and the gene pool is not changing that rapidly. So again, your statement is absolutely correct. It's the environment that is driving, must be driving, this very great increase in rates of obesity. We’re designed for another era, so to speak.

Holly Wyatt:
Yeah.

James Hill:
We just need a good famine, Rudy.

Rudy Leibel:
And when it happens, unfortunately, that's exactly what happens.

Holly Wyatt:
I'll win in a famine, but I hope we don't have to go through that. So with that in mind, that both are important, what do we do? I mean, this is kind of depressing. We've developed these genes over time that are doing what they're supposed to do. And now we're an environment where that is going against us, so to speak. So how do we push back? Do you believe we should be looking at the genes and the physiology involved in the genes and trying to manipulate there? So to change that physiology somehow? Or do we work with the environment and try to push back in some ways against what's naturally occurring in our environment?

Rudy Leibel:
So I mentioned that we now, as an enterprise in biomedical research, have identified 20 genes or rather 80 genes that will, as single events, produce rather severe obesity. But the vast majority of individuals who have excess body weight in them, it's not caused by one of these 80 genes. It's caused by the concatenation, the interaction of an additional thousand genes that have been identified or thousand regions in the human genome that each play a tiny role, but in the aggregate can produce a predisposition to more or less body fat. Again, to harken back to the original, one of the original questions, I find this, at least in terms of talking to individuals with obesity, very reassuring to be able to tell them this is not a psychological problem any more than high blood pressure. High cholesterol is a psychological problem. This is a biological problem that in a sense we inherited from our predecessors. And the approach to this is, in the vast majority of instances not to try to change the individual genes, although increasingly we're gaining the ability in very specific instances of single-gene severe obesity, ultimately to perhaps do that at some point, but again to try to help individuals, both by addressing the environment and by the onrush of pharmacology that is now has succeeded in producing agents that are very effective at weight reduction.

Rudy Leibel:
The caveat there, of course, is exactly what we were talking about before. Those drugs, these so-called GLP-1s that are now very popular, are extremely effective at producing weight loss. But when you stop them, the physiology is still there, and you go back inexorably to where you came from. So again, this is a long-term problem in well analogized to the situation with blood pressure and blood lipids. we now have excellent drugs to control those, but they require long-term application.

James Hill:
Okay, Rudy, I've been dying to get your take on the GLP-1 meds. And here are some of the questions I want you to address. They are very good at reducing food intake, whether that's through appetite or something. But what you result in is a lower energy expenditure. So on the GLP-1, these people are maintaining their weight at a low energy flux, whereas, you know, some people say that it's better to do a high energy flux. So I want you to comment on that. And the other thing is, are these medications correcting something that's wrong with their biology? Are they changing normal biology to better address our environment?

Rudy Leibel:
So I'm going to take the second part of the question first. And in terms of the role of GLP-1 and its receptor and some of the other molecules that are now part of the pharmacopeia, so to speak, with regard to the use of these injectables, these genes or molecules actually play very little role in normal body weight homeostasis. So to answer your question, they are not replacement therapy. To take another example that's extremely different from that, the rare humans who are totally deficient in the hormone leptin are severely obese. And if we give them leptin, their body weight comes down, their food intake goes down, their energy expenditure goes up. The vast majority of humans who are obese are not GLP-1 deficient. So these drugs are pharmacologic answers that are not directly related to the biology. The analogy I sometimes use is people who have fever are not aspirin deficient, but you can give aspirin and reduce their fever. I think the GLP-1s are in that category. Extremely effective, but they're not addressing the underlying physiology.

James Hill:
I love it, Holly. I love it. That's my view totally. So these people are maintaining their weight, low energy flux, which sets them up to regain weight very quickly if they stop the drugs. Are you concerned about that over the long term? We only have about four year data for weight on these things. What's your view of these as a forever kind of medication?

Rudy Leibel:
I think we just don't know. I don't see anything inherently dangerous about them in that regard, but we simply don't know. And I want to bring up another aspect of the pharmacology here that I think to me is fascinating. We now know that if you take the same individual at their usual body weight, and once they've lost 10, 15, or 20% of their body weight, they're not the same person physiologically. They have this lower energy expenditure, elevated drive to eat. We know that. We understand the physiology pretty well. It's primarily conveyed through the brain. Now, the question is, should we be trying to develop therapies or approaches to maintenance of reduced body weight that are different from the ones that we use to drive the weight down?

James Hill:
Love it, Holly. Love it.

Rudy Leibel:
These are two different physiological situations. And what works well in one may not be the optimal solution to the other. And I would predict that the treatment of reduced body weight physiology, which is what we're talking about here, is the next frontier in the treatment of obesity. Because if you can't maintain the lost weight, you are not going to ultimately have the full benefit of the enormous effort and cost of losing the weight. And I'm predicting that the agents, the pharmacology and other interventions that will be effective in maintenance of reduced body weight may be quite different from those that are effective in causing weight loss. And again, the pharmaceutical industry, the biotech industry is not in the business yet of studying the response of animals primarily to these agents when the animals have been purposefully reduced in body weight. I think that's a very fascinating frontier, which will ultimately benefit obese individuals enormously and answer some of the concerns that are implied in your question, Jim, about the maintenance of a low energy expenditure state and this constant drive to eat. There may be other solutions to that. I'm pretty sure there are, actually.

James Hill:
Well, we couldn't agree with you more, and that's where we're focused right now, that weight loss is different from weight loss maintenance. That's one of the first things I learned with the National Weight Control Registry. And I think the key is going to be the medications work incredibly well for weight loss. And as you know, there are new ones coming on board. And I think in two or three years, there will be a medication that gets everybody at or near their goal weight. The key then is keeping it off. And so I believe the future research is focusing on maintenance. Holly and I have tried to do this for years. The problem, Rudy, is with lifestyle, very few people got to their goal. So they would say, “Yeah, I'll think about maintenance when I lose another five or 10 or 20 pounds.” The medications have change the game. Holly and I are largely lifestyle people so we welcome the drugs, use the drugs to get the weight off. I think maintenance is going to be a combination of every tool we have, medication, lifestyle, maybe even surgery. And that to me is where the future is right now, figuring out how people keep the weight off. Because right now, something like 60% of people that go on the meds don't stay on them and most regain the weight.

Rudy Leibel:
We have currently underway, it's now in a week or two, maybe it already, maybe in April 1st, it will enter its sixth year, an NIH-funded study under the acronym POWERS, which is designed to study exactly the physiology that your statement refers to, which is we're taking individuals at usual body weight, reducing them, and studying them both before and after weight loss, and then during the ensuing 12 months, because many, not all of those will regain weight. And we're trying to look in detail at both the behavioral as well as the metabolic physiology of these individuals against exactly the kind of premise that your questions suggest, which is that the ability to maintain reduced body weight will probably require polyvalent attention to the phenotype. But again, it's very different than the phenotype or the physiology of an individual at usual body weight. So we're hoping that this NIH-funded study will shed some light on where the ideal pressure points are for trying to help people to sustain lost body weight.

Holly Wyatt:
So this is a perfect kind of segue into where do you think the science is going next? What do you think the biggest breakthrough may be coming?

Rudy Leibel:
So again, let me back up just for a minute and make it clear. And again, you guys will recall this but the listeners may not, there was a period when the pharmaceutical companies were very reluctant to spend the time and effort and resources to study obesity, partially because they thought, again, with the public, so to speak, or insensitive to the public's view that this is a quote, behavioral psychological problem and not really worthy of the attention of the pharmaceutical industry, that barrier has now obviously been broken.

Rudy Leibel:
The second reluctance that they have had over time is to try to interfere with the function of the central nervous system in this regard. Although there's a huge experience of the pharmacology of psychiatric disease, they've been reluctant to address obesity as a central nervous system CNS problem, which it clearly is. All the physiology points there, the GLP-1s have broken that barrier. So they are clearly acting in the central nervous system. The pharmaceutical industry now, I think, has more confidence in approaching the central nervous system in this regard. And I think what we're going to see is an outburst of pharmacology related primarily, not all, but primarily to the central nervous system in addressing the issue we've been talking about, which is maintenance of reduced body weight.

Rudy Leibel:
I think Jim is absolutely right. There will be, within a relatively short period of time, agents that can get an individual to their desired target reduced body weight, but the addressing of the long-term maintenance of that weight is the next frontier. And I think it will be addressed primarily, not totally, through behavioral as well as pharmaceutical approaches to the central nervous system. And now the pharmaceutical industry is more comfortable with that model. I think we're going to see a lot more inventive approaches to this question.

James Hill:
Holly, I hope our listeners realize that he's validating everything we've been saying on this podcast.

Rudy Leibel:
Well, then I feel more comfortable.

Holly Wyatt:
It makes me feel good, too, because it's like sometimes I wonder if we're out here by myself. We're out here alone thinking about this. So in the future, some of these medications may start to deal with energy expenditure. Some of the newer ones, the triple agonists and some of the ones that are being studied. Any thoughts on that? The current medications mostly deal with appetite on the energy intake side. But what if we start adding in energy expenditure, increasing that?

Rudy Leibel:
Yeah, this is a very interesting piece of biology. So let me say, again, as a piece of history, one of the fantasies in the obesity pharmacology field has been something to drive energy expenditure in an obese individual that will cause them to quote, burn off their excess body fat. But what we know, and the pharmacology, again, bears this out, is that if you drive up the energy expenditure of an individual at their usual body weight, you will get consequences of this that have to do with blood pressure and CNS effects that are essentially intolerable or not optimal.

Rudy Leibel:
When you think about a weight reduced person, and we've mentioned this at least a half a dozen times now, they're not the same person physiologically that they were at usual body weight and their energy expenditure per unit of their new reduced body mass is in fact lower than you would predict on basis of that body mass. That seems to me to be an excellent pharmacologic target because there what you would be doing is driving the energy expenditure back up to normal rather than supra-physiological. So I think it's an excellent target in a weight reduced individual in a way that it is not a useful target or a safe target in an individual at usual body weight. And that's one of the places, I think, that the pharmacology will strike in the next near future in terms of raising the energy expenditure and taking some of the pressure off the food intake side of the proverbial equation. I think it's an excellent point.

James Hill:
Love it. Holly, I think we should do some listener questions.

Holly Wyatt:
All right, Jim, you start off.

James Hill:
Okay. I've been on semaglutide for about six months and I've lost 35 pounds, but now my doctor is telling me I might need to stay on it long-term or the weight will come back. Am I really going to have to be on this forever?

Rudy Leibel:
I think we've sort of addressed that question in some of the comments that we've made before, but the answer is you're almost certainly going to have to be on something in order to maintain your reduced body weight. And that something could be a compound and likely will be of behavioral and perhaps pharmacological approaches to helping you maintain the reduced body weight. It may not be persistent use of semaglutide. And if it is, it may be at a lower dose. And there are a number of other sort of interventions that may be helpful in this regard. But if you stop the agent and don't introduce some kind of combination of lifestyle and other perhaps pharmacologic approaches, the likelihood of weight regain is extremely high.

Holly Wyatt:
I have a follow-up question. I meant to ask you this. Kind of what we're seeing now or what we could be in store for as we're trying to figure out weight loss maintenance a little bit better is people losing weight, regaining it, losing it again, regaining it. We've always had that yo-yo that we call it, but it might even be bigger than before, meaning they're losing more weight and regaining more if they go off the drug, losing it again. Do you see any problem with that?

Rudy Leibel:
So this, again, addresses a kind of interesting area of debate within the field, whether or not there are adverse consequences of yo-yoing, as you correctly refer to it, at least in the literature, it often gets called that. I think, in short, the risk is low. I don't think that there are adverse consequences of doing this. We've not seen this kind of capacity, though, before where one could go from minus 25% back to plus 10 or whatever. So extreme yo-yo may be different than the rather modest yo-yoing we've contended with in the past. But I would say modest yo-yoing is not a physiological. In other words, we've never seen evidence that an individual at one point in a yo or a yo up or yo down is different metabolically than they were the first time that they did it. And I think the other point of this is even if you're yo-yoing, you will be spending more time ideally at a reduced body weight. So the clinical benefit may still be there.

Holly Wyatt:
What about the possibility of ratcheting down your lean body mass over time, especially with the GLP-1?

Rudy Leibel:
I think with the modest yo-yoing we've seen in the past, people tend to regain the lean mass when they go back up and lose it when they go back down. At the extremes, I think we simply can't be sure, but I have no reason to predict anything significantly different from that. I think it's unlikely you would be able to yo-yo yourself into a true deficiency of lean mass. But the magnitude of the yo-yos that are going to be created now may make what I just said not entirely accurate.

James Hill:
So I agree with you mostly on that. Two things. One is, you know, in look ahead, Rudy, we found that the older people who lost weight and regained it, there was a tendency to regain more fat and less lean mass. That's not muscle, lean mass. So I do worry about maybe the big yo-yos in the older group. And the other thing is, I think you're right, sort of metabolically, biologically, I don't think there's a lot of negative. I just wonder psychologically, though, if people go through bouts of success and failure. And I have no data on this, but I think if there's a negative effect, it's not going to be biological. It might or might not be psychological.

Rudy Leibel:
Yeah, I agree with what you said, both about the proviso with regard to older individuals who do this and whom there will or may be a long-term consequence with regard to their, lean body mass, which is obviously important for all sorts of reasons in the elderly in terms of other consequences to bone and so forth. So I think that's an important proviso. And I agree with you. Psychologically, this is a very difficult situation. Again, you've probably seen as many people as I have who've had this situation, and psychologically, it's very upsetting. I'm hoping that what we're talking about today will end at least a substantial amount of the yo-yoing if we can come up with some way of successfully maintaining reduced body weight.

James Hill:
We got to stop the yo-yo. That's a phrase Holly and I use a lot is stop the yo-yo.

Rudy Leibel:
Exactly. And I think the consequences are psychological in most people, but potentially biological in some.

Holly Wyatt:
Agree. All right. Here's one more listener question. Obesity runs in my family, my parents, my siblings, and now I'm starting to see it in my kids. At what point does this become something you can't really change? At what point should we just say it is? It's genetic. I can't do anything about it. And is there anything I could do to help my kids have a different outcome?

Rudy Leibel:
I think that about somewhere in the neighborhood of 50 or 60 percent of an individual's body fat stores are, in fact, determined by genetics. Not by a single gene, but by the congregation of maybe 50, 60 genes out of the thousand that I mentioned before or potentially thousand that I mentioned before. And what the caller is asking about is, what do I do if I'm in a family that's a little bit enriched for some of these genes that tend to favor excess body fat? And the answer is, this is something that you will have to contend with by virtue of your genetic heritage, so to speak, probably indefinitely throughout life. So the critical question is partly, can this be successfully managed? And I think the entire discussion we've had is increasingly the answer is yes, by a combination of drugs and behavioral and other interventions.

Rudy Leibel:
And now the question relates to the children in this family, when is it optimal or best to intervene? And that's a very tough question for which we don't yet have a fully informed answer. What I generally say in circumstances like this is keep an eye on it from the period of time when you begin to see evidence of excess storage of fat, encourage physical activity, try it modestly to control excess food intake, but don't make a strong issue out of this. The time probably to apply maximum sort of intervention, at least before adulthood, is during puberty.

Rudy Leibel:
That's when a lot of this seems to lock in physiologically. So again, this is a tricky, tricky question and does require, I think, consultation with physicians and others who are expert in this area. But the answer globally is this is a family problem and it's going to stay that way by virtue probably of the genetics we're talking about. But there are successful interventions. And the question in children is when is it optimal to intervene? And too early is almost certainly a bad idea because it can affect other aspects of the growth of the child, most notably the brain.

Rudy Leibel:
So you don't want to be too aggressive about this early on. Keep an eye on it. Get professional advice and apply maximum, if that's the right term, sort of impulse at the time that puberty is occurring.

James Hill:
Okay, Holly, it's time for your favorite segment, the rapid fire questions.

Holly Wyatt:
So, Rudy, these are just quick questions. The first thing that you think about? And we're going to go through several of them. So first one, the new GLP-1s, breakthrough miracle drug or overhyped?

Rudy Leibel:
Breakthrough. I would give it more of a breakthrough than overhyped. They are overhyped, perhaps, but breakthrough, the stronger answer, the more correct answer is breakthrough.

Holly Wyatt:
Got it. All right. Calories in, calories out. Useful or misleading?

Rudy Leibel:
Calories in, calories out is the fundamental physical principle of the control of body weight and is absolutely the principle that people should adhere to in thinking about this. Count the calories in, count the calories out. It doesn't really matter how they get there.

Holly Wyatt:
Useful then. Strong useful.

James Hill:
I love it. I love it.

Rudy Leibel:
Very useful.

Holly Wyatt:
Okay, here's another one. The gut, the brain, or the fat cell? Which is the key to unlock obesity?

Rudy Leibel:
So this is the triumvirate, I would say, in which none is preeminent other than the brain is the place where all this information is treated and acted on. So I would say all three are critical. The brain is the ultimate modifier of the behavior.

Holly Wyatt:
I love it. He's good at this.

James Hill:
He is good at this.

Holly Wyatt:
Some people won't. He answers and he's rapid about this. All right. Here's another one. One myth about obesity, you want to disappear.

Rudy Leibel:
That it's a psychological problem. This, I think, is absolutely critical to people understanding it's not your fault in the fundamental biological sense. And there are answers to this. We understand the physiology well enough to know that what I'm saying is true. And there are now interventions that can help act on this biology.

Holly Wyatt:
Will there ever be a single solution for obesity? People want there to be one thing they need to do. Will we get there? Will there be a single solution?

Rudy Leibel:
I think almost certainly no, that this is such a complex physiology, as we were talking about before. This is baked into our physiology. We got here by virtue of the ability to get obese, if you want to think about it that way. And it's not going to go away with a single intervention.

Holly Wyatt:
Well, what's impressed me when you said thousands of genes and combinations. And thousands, I mean, that's the number people need to think about. And so why would there be one solution?

Rudy Leibel:
Exactly.

Holly Wyatt:
All right. Last one. When you see GLP-1 ads on TV, what goes through your mind?

Rudy Leibel:
That I think this is too much of what may be a good thing. In other words, people should be aware that these agents are out there, but I don't think that this needs to get hammered home incessantly.

James Hill:
I love it, Holly. He's good at this. All right, last segment, vulnerability. I want you to go first because I want to ask mine second.

Holly Wyatt:
All right, so I'm going to ask, what has frustrated you the most over your career?

Rudy Leibel:
The fact that early on, there was not acceptance, either at the level of the National Institutes of Health or the research community in general, that this was an issue worthy of scientific enterprise. Again, these ideas die hard. And I think in terms of my experience as an investigator, as Jim pointed out, I've been at it for 50 years, this was a hard thing to get the community to change its view. It's now quite different, but that was extremely frustrating.

James Hill:
All right. Here's my question, Rudy. You've been at this for 50 years. What are you going to do with the next 10 years of your life?

Rudy Leibel:
I'm very interested in, first of all, trying to find better solutions to the physiology of the weight-reduced state. That's where I'm going to spend a lot of time trying to answer some of the points that we've raised in this discussion. And secondly, to try to make better models of the parts of the brain that regulate energy intake by using what are referred to broadly as stem cell based approaches. We now have the ability, I can take your blood cells or skin cells and make the brain cells that are absolutely correspond to your own brain cells in a dish, basically. And I'm now interested in studying those in individuals who have different types of obesity, different predispositions, both to understand mechanism and to use as vehicles to study new interventions.

James Hill:
Holly, did you notice he didn't mention retirement at all in that answer?

Holly Wyatt:
I did. And Jim, I can't help but think that there was a little bit of vulnerability or personal aspect for you asking that question, wasn't there?

James Hill:
Maybe, maybe. Okay, Rudy, this is where I generally sum up, but I'm actually going to do something a little different. It's rare that these days, I get to talk to someone whose papers influenced me as a graduate student and who has been a leader, not just a good scientist, but a leader in the field for 50 years. What I want you to do is talk to our listeners who may be trying to lose weight. They may be thinking about losing weight. They may be trying to keep weight off. What's your objective view of the future for these people? Will it get easier? Will it get harder? What do they have to look forward to, in your opinion?

Rudy Leibel:
I think what the community of obese individuals has to look forward to is, number one, remembering that their predisposition to obesity is actually what got us here as a species. So they should take some...

James Hill:
Love it. Love it.

Rudy Leibel:
They should have confidence in their excess body fat in the sense that it does represent something which has gotten us through all sorts of exigencies in the past. I think their future is very promising in terms of being able to control the medical consequences of their excess body weight. We didn't discuss this very much, but one of the things we now know, and Jim, you've been seminal in some of the studies showing this, that modest amounts of body weight reduction can improve things like blood pressure, altered blood lipids, certainly make diabetes easier to manage or to go away. And that remains true. We're going to have very effective ways of getting this weight loss, but there also are very effective drugs now that will treat those so-called adverse consequences of obesity without having to lose weight. So these individuals are actually living in an environment medically where their problems can be addressed both by efficacious weight loss. And if they're not inclined to do that, those medical consequences, if they're present, can be treated in other ways. So I think it's good days for individuals who have obesity as a problem.

James Hill:
Wow. What a great message to end on. Rudy, thanks so much for sharing your time. What a great episode. Thank you. And we'll see everybody next time on Weight Loss And.

Holly Wyatt:
Bye, everybody.

James Hill:
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:
If you want to stay connected and continue exploring the “Ands” of weight loss, be sure to follow our podcast on your favorite platform.

James Hill:
We'd also love to hear from you. Share your thoughts, questions, or topic suggestions by reaching out at weightlossand.com. Your feedback helps us tailor future episodes to your needs.

Holly Wyatt:
And remember, the journey doesn't end here. Keep applying the knowledge and strategies you've learned and embrace the power of the “And” in your own weight loss journey.