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. Welcome to another episode of Weight Loss And, today we're going to tackle the topic of what is metabolic success in weight loss. To do that, I'm very excited to welcome our guest today, Dr. Sam Klein. Sam is one of the world's foremost experts on obesity in general, but he's done a ton of research on metabolic consequences of obesity and weight loss.

Let me tell you briefly a little about him. In academia, titles are often given in place of salary increases, and Sam has accumulated an impressive number of them. He's the William Danforth Professor of Medicine and Nutritional Science at Washington University in St. Louis. He serves as the director of the Center for Human Nutrition and as the chief of the Division of Nutrition Science, and Obesity Medicine.

Now we've talked before about the NIH-funded Nutrition Obesity Research Centers. There are 11 of these nationwide. We have one here in Birmingham, Alabama, but Sam also has one in Washington. He's the director of the NORC there. And Sam, you and I have known each other for a long time. I can't even remember not knowing you. And you are one of the people that I would turn to who knows the most about the metabolic benefits of weight loss. So let's dive in.

January is a time for New Year's resolutions and weight loss is always at or near the top of that list. So we know that becoming overweight has a lot of negative consequences. And some of these can be helped by weight loss. So what are the top metabolic issues that overweight or obese people suffer from and how can weight loss help?

Sam Klein: It's a very important question, Jim. And weight loss is a critical underlying cornerstone of therapy for people who are obese with obesity-related metabolic abnormalities. These abnormalities are very common in people who are obese, and they consist of having increased plasma triglyceride concentrations, low HDL cholesterol concentration, and resistance to the action of insulin in terms of regulating glucose metabolism and other metabolic functions. Also having increased fat in your liver, which is now metabolically dysfunction-associated steatotic liver disease, or fatty liver disease, and pre-diabetes as well as type 2 diabetes. All of these are important risk factors for coronary artery disease, stroke, and heart failure. And so by treating people who are obese, by having them lose weight, really reduces these risk factors and ultimately can improve survival if you lose enough weight over a period of time. And I should mention one more thing. We often focus on metabolic abnormalities, but we should remember that these metabolic abnormalities, which are risk factors for heart disease, there are also important effects on quality of life. And that's being able to function, being able to move.

Jim Hill: Well, Sam has evolved.

Holly Wyatt: I was going to say, you knew.

Jim Hill: Holly was going to ding you on that one, Sam. She was waiting to spring a trap.

Sam Klein: Well, because you asked me about metabolic abnormalities. So I have to put them. I moved from Neanderthal to caveman.

Holly Wyatt: Because we talk about this a lot. So I love it that you got all those titles, and then you were able to man all those big words like metabolic, they all sounded perfect. But in a nutshell, what is it? What do they not want? What's that metabolic issue? What's the end result of having all those things, Sam? Why should people care?

Sam Klein: So these are things that affect multiple organ systems at the same time. Your pancreas, your liver, your blood vessels, your heart. So metabolic abnormalities are dysfunctions in multiple organ systems, including the kidneys, which can give rise to various diseases, adversely affecting both the quality and length of one's life. Consequently, not only does it shorten the lifespan, but it also diminishes overall well-being. And so not only are you alive for less duration of time, but also your quality of life suffers because of the medical complications that you have from obesity. This is a major public health problem in the United States and now in many other countries worldwide.

Jim Hill: Given the considerable impact of obesity on multiple bodily systems, is it accurate to say that weight loss can lead to improvement in several of these systems? So rather than managing one thing at a time, diabetes, cholesterol, lipids, et cetera, weight loss can do much of that.

Sam Klein: Weight loss does it all. And so weight loss improves multi-organ system function. It improves your metabolic health, as we discussed, which is a waste-basket kind of term. But it depends on whether you have metabolic abnormalities to begin with. Some people are obese, who are metabolically healthy, who are obese, but have normal blood lipids, normal blood glucose, normal blood pressure, et cetera, et cetera. When they lose weight, they're not going to benefit from the metabolic effects of weight loss because they're already healthy. So you have to be unhealthy to benefit from weight loss. That involves the majority of people who are obese. But there is a subset of people who are healthy obese that won't benefit metabolically from weight loss but they very well might benefit from joint pain and physical function, and who knows what other diseases that are associated with obesity might benefit that have not been studied as well.

Jim Hill: And they might look better and feel better. And that's okay, too.

Sam Klein: That's all right, too. They all can't look as good as Jane Hill, but that's a goal we all strive for. And I like your toupee, Jim. It looks perfect.

Holly Wyatt: What about prevention, though? So maybe someone doesn't have any of those metabolic diseases that you talked about at the beginning. What's the likelihood? Could they develop them in the future? Or if you don't have them, you don't have them. You don't need to worry about it.

Sam Klein: Absolutely, it's an excellent question as the classification of metabolically healthy obesity is dependent on the specific definition used. However, it's a complex issue as there are over 30 different definitions in the literature, making it a highly nuanced topic. So no one has a good definition. However, about half of those people may transition to metabolically unhealthy obesity over time. And so those people, anyone who has excess body fat and is obese should look to reducing body fat and body weight, which will reduce the risk of developing these diseases in the future. But the aggressiveness of therapy, if you're going to put your resources into something and you only have a finite amount of money, maybe should be directed more to the people who are at the highest risk than those at the lowest risk, but does not mean at all that people who have metabolically healthy obesity should not be losing weight to prevent a transition over time.

Jim Hill: If there's someone out there listening, Sam, who happens to be taking three or four medications, including diabetes and lipid medications, they might be curious about the impact weight loss could have on their health. What kind of improvements can they expect to see from weight loss and how much weight loss would be necessary to observe those improvements?

Sam Klein: Yes. So it's also a very good question. If people with obesity-related conditions experience significant weight loss, they will likely need to decrease or even discontinue their medications. This is because weight loss can improve the underlying pathophysiology of the disease responsible for these abnormalities. The amount of weight you lose depends a lot on your goals and outcomes. So even a little bit of weight loss, four or five percent body weight loss will cause improvement in multiple organ system functions. So you'll say some improvements in reducing your plasma insulin concentrations, and insulin sensitivity, meaning insulin's ability to function. You may also reduce your blood triglycerides, increase HDL cholesterol, and decrease blood sugar. If you have type 2 diabetes, you can enter remission through significant weight loss, depending on the severity of your diabetes. But that requires a greater amount of weight loss. It looks like somewhere between 15 to 25 percent weight loss can put people with obesity and diabetes into remission of their diabetes, meaning they have normal blood sugar concentrations without the need for medications.

Holly Wyatt: So if someone is sitting out there, can you predict who's going to get the biggest bang for their buck if they do this?

Sam Klein: Generally, there is a remarkable variation in the response to weight loss therapy, with some individuals experiencing greater weight loss than others. Some even gain weight during weight loss therapy. There's incredible heterogeneity there. And there's also incredible heterogeneity in the beneficial effects of the same amount of weight loss. But it seems like the worse you are, to begin with, the better the effect you'll get of weight loss. So if you have high blood sugar or pre-diabetes, losing weight will yield a more significant and advantageous outcome compared to having normal blood sugar levels and a glucose tolerance test that shows no signs of pre-diabetes.

Holly Wyatt: Well, I think that's some good stuff, right? Because, okay, if you're in a sense, the worse you are, the better the outcome for you. So that I think is motivational, like, okay, you're not too far gone. The further along you are, perhaps the better.

Sam Klein: You can be too far gone. So if you're way off the end, then weight loss may not have such a beneficial effect. If you have had severe diabetes for many, many years and the real dysfunction of your pancreas to make insulin, that may not come back. But if you have run-of-mill - diabetes for eight years, or nine years, your pancreas function will improve with weight loss.

You'll make more insulin for the same amount of glucose challenge than you did before you lose weight. We don't even know about the beneficial effects of reducing the risk of cancer so well. The benefits effects on sleep apnea, we're not talking about those other things besides the direct metabolic effects. And don't forget dementia, cognitive function may also be related to insulin resistance and obesity. And so it's potential that losing weight and improving your metabolic health will reduce your risk of getting Alzheimer's disease in the future as well. All these are areas that need more study.

Jim Hill: Sam, addressing excess weight is crucial for overall health as it impacts numerous bodily systems. And what you've shown in your work is more is better. I believe that 5% weight loss can help metabolically, but you know as well as I do, 5% is a tough sell for most people. They look at 5% as not very successful. But now we've done a previous podcast on the new weight loss medications. Nowadays, there is a genuine opportunity for individuals to attain significant weight loss that can remarkably enhance their overall well-being.

Sam Klein: So I think the goal of weight loss therapy is to improve your health, not to lose weight or to get to a certain weight. It should be what do you need to improve your health? And so there are different levels of health improvement and it would vary from person to person. That requires a doctor-patient discussion of what are their goals, how much weight they want to lose, and for what reasons. That's very important to understand to make sure that people are realistic. These new medications, which are quite hard to obtain, have been delivering outstanding results in terms of significant weight loss for individuals but some people don't lose much weight on these medications. We don't understand why. And some people lose an extraordinary amount of weight. Then the question is how much is enough? When it comes to metabolic health, as mentioned previously, achieving a weight loss of 15 to 25 percent may represent the optimal point where the beneficial effects on metabolic health reach their peak. And that might mean that you're still not a lean person after the end of that 25 percent weight loss, but you'll be much healthier than you were beforehand.

Holly Wyatt: I agree. I think metabolic is a great goal and health and all of that. And I'm all for that. But I don't believe that has to be your only goal. And I don't know that that's what you're saying either. Some people are motivated because they want to look different in a pair of clothes. They want to be able to hike the Grand Canyon. They want to be able to do things with their grandkids. And that to me is just as important. And so it's an and situation. The metabolic health and what else you want to do with your life and how you want your body state, which is kind of the new term. I've gotten rid of weight, Sam. Too much baggage. Your body state is why I think is motivating and allows people to say, OK, you get to choose. Doctors don't choose for you. You get to choose what's important. to you.

Sam Klein: I agree. I believe it is crucial to engage in a conversation between the doctor and the patient in order to establish their respective goals. These goals should encompass more than just enhancing health. They should also aim to improve physical functionality, foster better family interactions, enable the pursuit of personal desires, and alleviate discomfort such as knee pain. It is imperative to consider all these aspects. And that requires a discussion, and negotiation with the physician, but also putting some realism into what's possible with the available tools. And some of these tools are powerful, but they're not available. They're not, they're too expensive, they can't be afforded, or the patient doesn't want that tool. For example, bariatric surgery. Very few people get bariatric surgery who are eligible for bariatric surgery for various reasons. So you can't force someone to take a treatment they don't want to do. So this is a real patient-doctor discussion that requires this approach.

Holly Wyatt: So does the way you lose weight impact your metabolic health? So is there one way? We have lots of tools, but just thinking about diet and exercise medications, does the way that you choose to lose it impact metabolic health? There are differences.

Sam Klein: It is not entirely evident whether the method you use to lose weight, be it through surgery or lifestyle therapy, yields similar results in terms of weight loss. However, some medications may have weight loss-independent effects on improving your health. So if you lose weight with SGLT2 inhibitors, you seem to have an increased benefit on cardiovascular disease and cardiovascular outcomes.

It's not clear if that's the same for the GLP1 receptor agonist, but that needs to be studied. By losing weight by GLP1 receptor agonist, will give you a better beneficial effect than cardiovascular outcomes than losing weight by diet alone. And losing weight by diet alone is not the same as losing weight by diet and exercise (physical activity). We recently published a paper showing that if you lose 10% of your body weight by diet alone, compared with losing 10% of your body weight by diet and regular exercise (supervised exercise training), you double your insulin sensitivity in people who do it with exercise training. So you have a marked improvement in metabolic function.

If you lose weight with diet plus exercise, then lose weight with diet alone. And then it comes to this question of, what is exercise and how much should be done. And one of my bugaboos is this recommendation of 150 minutes a week, you know, that people should do. And you have a person who weighs 300 pounds, they can barely get out of a chair and you're going to tell them, you know, go into 150 minutes a week of walking, brisk walking, that has to be individualized. So life's intervention including diet as well as physical activity, has to be individualized, the patient's ability to conduct those interventions.

Jim Hill: Sam, I'm glad you mentioned exercises. We've been very interested in that. Through our collaboration with the National Weight Control Registry, we have consistently discovered that exercise is not only a significant factor in weight loss, but it is also crucial for maintaining weight loss in the long run. And while I agree with you that you need to go slowly, if you haven't been off the couch in 20 years, you're not going to go out and start exercising, walk to the end of the driveway and back. But I do think that if we're going to be successful over the long term, we've got to dramatically increase the amount of physical activity that people are doing.

Sam Klein: I think that's right. In fact, and so all of these interventions that we have now, except for last long, so drug therapy, bariatric surgery, and scopic therapies, none of them require exercise. And so you could say there's no need for lifestyle therapy anymore when you have these other interventions, but they don't do exercise. So you might argue that exercise should be the focus of lifestyle intervention if you're losing weight with a GLP1 agonist or other interventions.

Jim Hill: Good point. Sam, are there people who should not lose weight? We receive numerous inquiries regarding older adults. There have been media reports indicating that if you fall under this age range (which we can further discuss, it most likely includes both you and me), but if you're an older adult, you may lose more lean body mass. Are there people who shouldn't lose weight?

Sam Klein: Probably not. In fact, in older adults, we have done studies on others as well. In older adults, you're not so much treating people to reduce their metabolic risk because they're already 70 years old. They've shown they can withstand the adverse effects of obesity on their longevity. But what you do want to do is improve their quality of life and physical function. That's a major goal for them in addition to improving medical health at the same time. Even as an older adult, losing weight can still improve your physical function, despite having less muscle mass. And so the relationship (even though you lose muscle mass) between your muscle mass and your body weight is higher. That ratio is higher, your physical function is better, and muscle mass is not a direct determinant of physical function. It’s the quality of the muscle as well. I've never seen any study where people who have lost weight have decreased their physical function, and their ability to function. And so this hype about preserving lean body mass and having a really large attention to preserving muscle mass and lean body mass when you lose weight is really probably not clinically relevant.

Jim Hill: This is a crucial message, especially for people in my age group who are looking to lose weight. It's highly likely to be beneficial for you. So don't pay attention to the hype that you shouldn't lose weight. Do it in the right way. Again, I think exercise, again, movement is important.

Holly Wyatt: You must prioritize the quality of your weight loss journey. Strive to achieve the best possible outcome, which involves shedding body fat while preserving as much muscle and lean tissue as you can. But I agree, it's not a reason not to lose weight. But I do think then that kind of comes into using the exercise. And I also think using diet to help with that. That quality of the weight loss to get that best quality. And you mean your study shows that added the activity to the diet, you got some additional benefits with that insulin sensitivity, right? So it does kind of matter. And that quality, there could be other things that you could lose the same amount of weight, but it could have a very different outcome overall on you, depending on how you lost the weight.

Sam Klein: Right. Physical activity and exercise are crucial as they enhance physical function in older adults who are trying to lose weight. Physical activity and exercise alone give you the same benefit in physical function as 10% weight loss without any weight loss. If you add 10% weight loss plus regular exercise, you increase it even further.

And these are older adults 75 and over who have done it. But if you try to maintain weight loss with diet manipulation, you may shoot yourself in the foot. We've shown that increasing protein intake, which reduces lean body mass or muscle loss, enhances insulin resistance with weight loss.

And so you have to balance these things. And remember the difference in muscle mass between preserving muscle mass more with exercise or with a high protein diet: you're talking about 0.6 kilograms or one kilogram of lean body mass, which is trivial in terms of its statistically significant, but probably clinically insignificant. The physical function part though, the exercise part, not only does it preserves slightly your muscle mass, but it's improves your ability to use your muscles and your muscle strength. And that's what's critical about physical function.

Jim Hill: Amazing. And we're going to do a deeper dive into physical activity and exercise in future episodes. Sam, traditionally, a lot of people succeed in losing weight, but many of them regain it. What happens metabolically if you lose weight and then regain it?

Sam Klein: So this is a very controversial area. And what I say now would be dismissed by many experts in the field. But if you lose weight, you benefit from that weight loss for that period. And then if you regain weight, you're back to where you started from. You're not worse. You don't regain more fat than you lost before. You regain about the same, but depending on which study you believe and which study you read. But the beneficial effect of having lost weight for that period is a beneficial effect. Losing weight throughout one, two, or even six months can greatly benefit your metabolism and overall health in ways that would not have occurred if you had not lost weight. So losing weight and regaining it, I think is better than never having lost weight at all. As Shakespeare says, is it better to have lost and regained or never to have lost at all?

Jim Hill: Wow. Great point.

Sam Klein: So I think it is better to have lost to regain as a DPP study showed where people lost weight over four years and then they began to regain, but they still had a lower risk of type 2 diabetes 10 years out than those who were in the placebo group who never lost at all.

Jim Hill: Sam, you're really in the throes of a great scientific career. What excites you the most about your research right now?

Sam Klein: Retirement.

Jim Hill: No, you've still got a couple of good years. Come on.

Sam Klein: So, well, I'm hoping that there'll be better therapies for hair restoration. So the things that interest me and my group right now is really why excess adiposity causes multi-organ system metabolic dysfunction. We don't understand why fat, a lot of fat is bad and we don't know why losing the fat is good. We know that if you lose fat by sucking it out with liposuction is not beneficial. But if you lose fat by eating fewer calories and you burn up, that's very beneficial. And so why does adipose tissue cause so many problems in most people? Why are some people protected from the adverse effects of excess body fat? And then why does losing body fat cause so many benefits to all the organ systems combined?

Jim Hill: Well, you can't retire until you answer those questions.

Holly Wyatt: You've got years and years and years. So, Sam, it's time for the vulnerability question. We have to ask something that gets at you. I got one too. So, do you want to go first?

Jim Hill: We both. I'll go first.

Holly Wyatt: All right.

Jim Hill: So, Sam, I've known you for many years. You and I go way back and you've always been a slim guy. Is this genetics or do you have to work at it?

Sam Klein: I work at it. It's, and partially genetics. Growing up, you know, my mother couldn't stand the fact of how thin I was. And so we had 15-course meals every day and you eat 5,000 calories and she'd wonder why you weren't hungry after dinner. So, part of it is genetic, but also I work at it. I watch what I eat. I exercise regularly and you have to be constantly vigilant. Still, it's easier for me to do that, I think, than many people who are obese because they have other factors - psychological, neurological, chemical, and environmental factors that drive them to be a higher body weight.

Jim Hill: And I can attest to that. I've seen Sam leave many important meetings to go to the gym. So, he's serious about the exercise.

Sam Klein: Only the boring meetings.

Jim Hill: Hope NIH is not listening to him.

Holly Wyatt: So, Sam, have you ever had to lose weight? Have you ever had to be in a negative energy balance for an extended period in your life?

Sam Klein: Yes. I did. This has happened in college. I was part of the cross-country team and I used to eat a lot of calories every day because of the intense running and thin physique required. Huge amounts of calories, but I was flunking organic chemistry. So, I dropped off the team to focus on, and luckily in organic chemistry, if you did better in the final than you did in all your tests, you would get the grade of your final. So, that was a good deal. So, I stopped running and I gained a huge amount of weight in a short period by eating the same calories I did every day, but not exercising at all, which was serious exercise, you know, long-distance running. And so, that was the one time when I gained a lot of weight in a quick period, very sedentary and studying every day. And I got an A- in organic chemistry.

Jim Hill: Congratulations. So, we always end the sessions with what Holly calls pie on the plate, not pie in the sky, but pie on the plate. So, we've talked a lot about the metabolic benefits of weight loss. If you had a couple of messages to our listeners who have excess body weight, and may have a New Year's resolution to lose weight, what would you tell them?

Sam Klein: So, I think for most people, it's trying to lose weight with lifestyle intervention first, but that's very hard to do without some expert support and expert help. So, I would seek out a professional or professional group, a weight management center, or a weight management program to do that. If you have tried expensive drug therapy and bariatric surgery without success, you can move on to the next step. But a little bit of weight loss is very good. Losing four or five percent of body weight will improve your health dramatically, potentially. And you need to appreciate that that's not easy to do and that's a successful goal and achievement. Losing more is probably even better depending on your medical background and medical problems. But it's much harder to do with lifestyle therapy alone and might need additional help with medications, endoscopic, or surgical therapy.

Jim Hill: Fantastic. Fantastic. Sam, thanks. And again, thanks for all you've done in your career. You have made a difference. You've been an amazing colleague. Sam is lots of fun at dinners and parties. But he has been one of the leading obesity researchers for decades. So, Sam, thank you for all you've done, and thanks for being on our podcast.

Sam Klein: You're very kind.

Jim Hill: This is another episode of Weight Loss And, we'll talk to you next time. 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.

Jim Hill: We'd also love to hear from you. Share your thoughts, questions, or topic suggestions by reaching out at [weightlossand.com](http://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.