Dr. Samuel Klein, Division Chief and William H. Danforth Professor of Medicine and Nutritional Science at Washington University Medicine, joins The Future of Medicine for a conversation about obesity, metabolism, insulin resistance, and the revolution sparked by GLP-1 medications like Ozempic.
In this episode, Dr. Klein explains why obesity is far more biologically complex than many people realize — and why some individuals with obesity remain metabolically healthy while others develop diabetes, heart disease, and fatty liver disease.
The conversation explores how fat functions not only as stored energy, but also as an active endocrine organ that communicates with the rest of the body through hormones and inflammatory signaling molecules. Dr. Klein discusses visceral fat, insulin resistance, inflammation, and why procedures like liposuction do not produce the same metabolic benefits as weight loss through diet, surgery, or GLP-1 medications.
Dr. Klein also reflects on the unexpected rise of GLP-1 therapies, including how medications originally developed for diabetes transformed obesity treatment and may hold broader implications for cardiovascular disease, addiction, and other chronic conditions.
Together, Dr. Klein and Euan Ashley discuss the future of metabolic medicine, precision approaches to obesity care, and why understanding metabolism may reshape the future of healthcare itself.
Intro
“Obesity increases your risk of hospitalized infections. GLP-1 therapy seems to reduce that risk.”
Dr. Samuel Klein is an expert in metabolic health and the division chief of nutritional science and obesity medicine at Washington University in St. Louis.
“This is a revolution. As you say, this is like when insulin was discovered.”
We know that obesity adversely impacts organ systems throughout the body. But why is that the case? We talk about the mechanisms at play, the gaps in our knowledge, and what the future might hold for obesity medicine and metabolic health.
“Fat is not just a fuel reserve that keeps you alive during periods of food deprivation, but it's also an endocrine organ that produces things and regulates metabolic function."
At a time when approximately 40% of adults in the United States are obese, Dr. Klein's work is both timely and urgent.
“The only way to lose fat in a healthy way is to eat less than you burn up.”
Welcome to Stanford Department of Medicine's inside look at the future of medicine.
Tha Conversation
Dr. Euan Ashley: Well, Sam, welcome to Stanford.
Dr. Samuel Klein: Thanks for having me.
Dr. Ashley: And welcome to the future of medicine, our podcast here. You just gave a remarkable grand rounds here in honor of one of our faculty, no longer with us, Gerald Reaven, but really the father of metabolic disease. And I know that we're going to talk a little bit about that, but you gave just a tremendous talk. Before we get to some of your work, which I think our listeners will really be interested in, tell us a little about yourself. Where did you grow up? How did you first get interested in science and medicine and what paths did you take? We love to talk a little about the paths taken and the paths not taken.
Dr. Klein: I'm born in Philadelphia, first generation American. My parents are immigrants. And they came to Philadelphia from Europe after the war.
Dr. Ashley: Where from?
Dr. Klein: Poland and Czechoslovakia. The old Czechoslovakia, not Czech Republic. And grew up there and became interested in how the Obesity & Metabolism body worked and nutrition and metabolism. From a pretty young age, in college I started, and there were at that time a lot of people writing nutrition books that weren't based on evidence, which is still the case. That hasn't stopped. Nutrition is a target for that. And decided to go to medical school to learn how the body works even better. That interest continued through medical school and from there I went on to do a residency in internal medicine. I chose Boston because that was a nutrition hub at the time. And went to graduate school after my residency at MIT for nutritional biochemistry and metabolism. And then from there did a GI fellowship because that's where food enters the body.
Dr. Ashley: Makes sense.
Dr. Klein: And from there I had great mentors and great people who trained me and was interested in fat metabolism because no one was working on it at the time. And if you're interested in fat, you eventually become interested in obesity and that's how I ended up here.
Dr. Ashley: That's a great story. Nutrition is so central — it's on the front pages of our newspapers. There's lots of books. There's advice everywhere. It seems to change all the time. But we're also in the middle of a metabolic revolution, triggered mostly by the GLP-1s, which has really made your work provide the foundation and the context for that. But I think despite that, it's now some time since your work and originally work from Jerry Reaven and others demonstrated some of these findings, and some of them have still not made it into the general understanding that's out there. So that's what I'd love to pick apart a little. In particular, you showed some really fascinating data from studies across many years where you show that obesity itself doesn't necessarily mandate that you'll have metabolic compromise. Tell us a little about how that idea came to you and how you decided to pursue that.
Dr. Klein: Jerry Reaven was one of the first to identify that — to show that some people with obesity have normal insulin sensitivity. Insulin is a hormone made by the pancreas, and it's a critical hormone that really regulates metabolic health. And by metabolic health I mean your blood sugar, your blood lipids, your liver health, cardiac health. He found that some people who were obese had really normal insulin sensitivity and were healthy, and others weren't. And the question is why are some people resistant to the adverse effects of excess body fat and other people are predisposed? Most people, when you become heavier and gain fat, for some reason we're trying to figure out, everything goes bad. Obesity has adverse effects on every single organ system in the body. And when you lose weight, they all get better.
Dr. Ashley: So that's I think what we're used to hearing. What was surprising was that there's also a group of people who are obese but metabolically healthy. So given all the things we've heard, how does that work?
Dr. Klein: It means that the mechanisms of why excess body fat causes disease are not working in those people — they have blocked that. And so that's the question: what's the signal from fat tissue, from adipose tissue, that tells other organs to be healthy or unhealthy? We know that excess adipose tissue is bad, but there's a signal from adipose tissue, from fat, to other organs. That's really the trick to try to figure out.
Dr. Ashley: Let's go down that path first because that is I think what we all think of and expect. You had some nice slides on the idea that fat causes inflammation. It's a very vague term, although we mean it in a very specific way in medical circles. But it's also a word that's now broken out of its medical boundary and people talk about inflammatory diets --
Dr. Klein: Inflammatory personalities
Dr. Ashley: — the whole thing. It's interesting for our listeners to just pick apart a little the mechanisms through which excess body fat can cause unhealthiness first, and then maybe we could revisit this group that seems resistant to it.
Dr. Klein: It used to be thought — and still is — that body fat is a fuel reserve. It's a way you store fuel. It's mostly triglyceride, which is fat and very little water. You can carry around this gas tank with you wherever you go in a compact form. In fact, the amount of fat you have determines how long you live if you don't have any food. There's a person in the Guinness Book of World Records who underwent a therapeutic fast — no calories at all — for 382 days, losing more than half of his body weight, 125 kg, without any adverse effects, just drinking acaloric fluids.
Dr. Ashley: Wow.
Dr. Klein: But if you have a thin Irish Republican Army hunger striker, they'll be dead in about two months if they don't eat food and only drink fluids. So fat determines how long you live. That's why women live longer than men if there's no food, because they have more body fat than men. But now we also learn that fat is not just a fuel reserve that keeps you alive during periods of food deprivation, but it's also an endocrine organ that produces things that go around to other parts of the body and regulates metabolic function.
Dr. Ashley: It's like a gland that sends things into the circulation that then have an effect — and these are measurable molecules. What sort of molecules are we talking about?
Dr. Klein: One is a molecule called adiponectin, which is healthy, made by adipose tissue and body fat. Another is leptin, which regulates food intake. So if you have a lot of fat, leptin may go up and may decrease your desire to eat, but that can be dysregulated in people who are obese. And now we're trying to understand what are some of the other things released from body fat that might signal other organs to be unhealthy. Those are things like free fatty acids, which is the breakdown product of triglyceride, the fat in the adipose tissue, but also maybe a breakdown product of the collagen, the structural framework of adipose tissue. It lives in a structure that houses all those fat cells — otherwise it would just flop down. So the breakdown of that structure releases some proteins into the blood that can go to other organs and cause harm. One is called endotrophin.
Dr. Ashley: And these are pro-inflammatory molecules in general?
Dr. Klein: It's not pro-inflammatory, but it can cause resistance to the action of insulin. And insulin's main function is to drive glucose into your cells, into muscle cells, and keep your blood sugar low. If you're resistant to insulin, your blood sugar goes up because glucose is not being driven into your muscle cells, and also your liver is making too much glucose.
Dr. Ashley: So most of the people out there who are either pre-diabetic — that's a very large group — or frankly diabetic with type 2 diabetes, have insulin resistance.
Dr. Klein: And insulin resistance will cause pre-diabetes and then diabetes. But you also have to have a defect in your pancreas to make insulin. If you don't make an adequate amount of insulin, you can overcome the resistance to insulin by making a lot of insulin. So people who are obese may have normal glucose because they're making more insulin to counteract the resistance, but at some point the cells that make the insulin aren't making enough and your resistance is too high. And then you become abnormal metabolically and that leads to all kinds of problems.
Dr. Ashley: There are both simpler ways — through a lipid panel — and more complicated ways through some very intensive physiology studies you've done for measuring insulin resistance. Tell us about those.
Dr. Klein: You can measure insulin resistance by infusing insulin at a physiological level and measuring how much glucose you have to infuse into someone to maintain a normal blood sugar. If you're very sensitive to insulin, you require a lot of glucose to be infused because your muscle tissues are responding to insulin and taking it up very aggressively. If you're very resistant to insulin, you require very little glucose to be infused because you're resistant to insulin and blood sugar goes up. That's a measure of insulin sensitivity.
Dr. Ashley: For that, someone has to come to your lab, lay on a couch, and be there for a few hours while you're infusing these different things. There's a surrogate for that through a lipid panel — the triglyceride to HDL cholesterol ratio.
Dr. Klein: Jerry Reaven developed this. That ratio can help determine who's insulin resistant or not, because insulin is also involved in regulating blood lipids. Having a high triglyceride and low HDL cholesterol is very common in people who are insulin resistant. The resistance to insulin makes you increase the fat in your liver because it stimulates the production of fat there, and that drives the triglyceride that goes into your bloodstream.
Dr. Ashley: This work you showed, where essentially fat is sitting there like an additional organ sending maybe some good things but mostly bad things into the circulation, causing insulin resistance — I think that's the right model for people to have in their minds. What was fascinating though were your studies on liposuction. There were some early studies from the liposuction community that suggested metabolic health might improve after that, but that's not what you find.
Dr. Klein: It's really fascinating, because we know if you reduce body fat by eating fewer calories — through dieting, bariatric surgery, GLP-1 medications — your insulin sensitivity and metabolic health improves. But if you remove the body fat by sucking it out with liposuction or cutting it out, you don't improve your metabolic health. When you reduce your fat by liposuction, you remove billions of fat cells from the body, but the fat cells that remain stay large. They stay in adipose tissue that's unhealthy. And you don't do anything to the fat that's inside other organs like the liver and muscle tissue, which causes insulin resistance in those organs. So the only way to lose fat in a healthy way is to eat less than you burn up.
Dr. Ashley: You also talked about the difference between fat that's on the outside of the body and visceral fat — fat in and around our organs — including a surgical study where surgeons would go in and remove fat from inside the abdominal cavity. What did we learn from those studies?
Dr. Klein: Most of your fat is underneath your skin — subcutaneous fat — about 80% in people who are obese. About 15% or so is inside the abdomen. In lean people, 95% is under the skin and about 5% is inside the abdomen. The fat inside the abdomen is correlated with metabolic disease, diabetes, heart disease, high triglycerides, insulin resistance, but that doesn't mean it's a cause. It's associated — just like if you have pancreatic cancer, you might be jaundiced, but being yellow isn't the cause of your illness. Naji Abu-Hamdeh at Vanderbilt actually removed a chunk of visceral fat surgically — about a third of visceral fat, the omentum, which is like an apron that hangs down from the large intestine. It takes about 10 minutes to do the procedure, and it had no beneficial effect on improving insulin sensitivity in people with type 2 diabetes or their blood glucose. So sucking fat out from subcutaneous tissue and removing fat by cutting it out of the abdomen doesn't seem to be beneficial. You have to eat less than you burn up in order to get the beneficial effects of fat loss.
Dr. Ashley: Well, that makes sense. This leads us inevitably to talk about — it must be everyone's dinner table conversation now, but probably your everyday conversation — the new world of GLP-1 medications. A whole host of follow-ons, everyone has heard of them, and probably knows people who have tried them. Weight management as a category of drugs is now here, and a decade ago that wasn't clear even though the science is decades old. How has that changed your world and what have you learned from that revolution?
Dr. Klein: This is a revolution. This is like when insulin was discovered, when antibiotics were discovered. This is huge because it really regulates food intake and it's just the beginning. In 10 years, there'll be a whole slew of newer, more potent drugs with fewer side effects. But it shows that you can help people lose weight by taking a medication, when other medications in the past were not very effective and you had to rely on bariatric surgery to get significant weight loss. Now you can get that weight loss with these medications, and it's caused dramatic improvements in people's health. And there might be some weight loss-independent benefits of GLP-1s on the heart. There are weight loss-independent effects where you get beneficial effects of these medications before you lose that much weight — reducing the risk of heart attacks.
Dr. Ashley: In the studies where they match the weight loss, the patients who also took the drugs actually did better from a cardiac standpoint, which I'm not sure was expected.
Dr. Klein: The curves diverged — the cardiac effects in high-risk people who took placebo started to spread apart at 6 months. Six months of therapy, you started to get beneficial effects on the heart before much weight loss.
Dr. Ashley: And we've seen some data, still unclear, relating to neurological disorders and addiction disorders as well. We had Anna Lembke recently here on the podcast. We find lots of reasons to talk about GLP-1s. Probably nobody whose world is more changed by the advent of these medications. I certainly didn't see this coming even though the science was decades old. Did you see it coming?
Dr. Klein: No, this was really unexpected. It was pretty fast. GLP-1s were first identified in 1987, and then 20 years later, boom — amazing effects. It was being used to treat diabetes.
Dr. Ashley: The early ones were short-acting diabetes medications.
Dr. Klein: They increased the dose to get better diabetes therapy and it turned out it caused a lot of weight loss. That hit a light bulb and I thought, there might be some other value here. These drugs stimulate the secretion of insulin, so that's why they were developed for diabetes therapy.
Dr. Ashley: Weight loss was really a secondary phenomenon. When I initially heard of it, the thought was, it causes nausea, that's why it causes weight loss. But as we've done the studies, we realize that it really does cause dramatic weight loss for many people, and also appears to have these other benefits — food noise, addiction, potentially neuromuscular disease, cardiovascular disease — and not everything can be connected directly to obesity.
Dr. Klein: Even infection. Obesity increases your risk of hospitalized infections, and GLP-1 therapy seems to reduce that risk.
Dr. Ashley: Remarkable. I'd love to draw a line then — more fat in general bad, less fat in general good. But you've done this fascinating work with a group who are obese and yet metabolically healthy, and you've started to show some data to try and explain why that might be. Tell us about that work.
Dr. Klein: That's really the key question because obesity is a heterogeneous disease — a real spectrum, like all diseases. At the two ends are people that are obese and healthy, and people that are obese and unhealthy, meaning pre-diabetes, type 2 diabetes, high blood pressure, high liver fat content. Those are most of the people who get those abnormalities. So why does a small percentage of people with obesity not have those diseases? It turns out they have different adipose tissue biology. Their adipose tissue seems to be different from people with unhealthy obesity, and that difference in biology is what we're trying to understand better. They secrete things differently — less of some things than people who have unhealthy obesity — and they secrete some things that are actually healthy and beneficial by comparison.
Dr. Ashley: Do you think it's the secreted molecules from the fat that are key to its unhealthiness, rather than just the fact that it exists?
Dr. Klein: It has to be, because how does the fat communicate to other organs? Having bad fat is meaningless unless somehow it tells other organs it's bad or good. It's got to be a communication system — a hormonal type of system that communicates with other organs. That's the key: trying to understand what those mechanisms are, because if you understand them better, you can develop therapies to break the link between excess body fat and metabolic disease.
Dr. Ashley: There are some people who have plenty of fat, but it's not signaling in a bad way and they're metabolically healthier.
Dr. Klein: They tend to be women — it's very hard to find men who are metabolically healthy obese. They tend to be women with a lower body fat distribution — large hips, large buttocks, large legs — and not such a large waist circumference.
Dr. Ashley: I'd love to go back to the inflammation question, since it's so much in the public domain. You've also measured some pro-inflammatory elements. What are your findings there?
Dr. Klein: Our findings actually go against the dogma of many people. Inflammation — meaning increased immune cells as well as increased expression of genes that are pro-inflammatory — is increased in people with unhealthy obesity. But what's the communication to other organs? We found that the proteins that come out of these adipose tissues from unhealthy people, that are supposed to be pro-inflammatory and causing metabolic harm in other organs, are not different in concentration compared to healthy obesity — except for some. One of the major ones is plasminogen activator inhibitor-1, PAI-1. PAI-1 is very important in the cardiology field because of thrombosis and blood clots. And now we're appreciating it's also a very important metabolic hormone that regulates insulin sensitivity. If you have a genetic deficiency in producing PAI-1, you have a lower risk of getting diabetes and heart disease than people with normal PAI-1 production.
Dr. Ashley: One of the questioners at the end of your talk asked what I was also interested to ask: many people listening will be wondering, which one am I? Am I one of the metabolically healthy ones? Does that mean I don't need to exercise, or don't need a GLP-1? Can someone going to their doctor get a sense of that by measuring something, and what should they do? How can your work inform precision medicine?
Dr. Klein: The first thing is just what you look like. If you have a large waist, a beer belly, you're more prone to have unhealthy obesity. If you have large hips and legs and not much of a belly and you're a woman, you're much more likely to have healthy obesity. Then a doctor's regular blood test — triglyceride levels, HDL cholesterol, blood glucose, and blood pressure — will all identify people that are metabolically unhealthy. Jerry Reaven described this early on as Syndrome X, which is now called the metabolic syndrome. That can be identified on a routine clinical exam. But we know the cut points are artificial — everything is a spectrum — and even high-normal is unhealthy. A high-normal blood pressure is unhealthy compared to a lower blood pressure, and a high-normal glucose like 90 is not as healthy as a glucose of 75.
Dr. Ashley: What about HbA1c? That's the long-term glycated hemoglobin, the ultimate test for where your glucose level has been over several weeks.
Dr. Klein: That's another important measurement that might become part of the routine clinical exam. A high HbA1c also helps determine healthy versus unhealthy obesity. The normal cut point of 5.6 or lower is not really "so normal" unless you're down around 5.0 or 5.1. The high-normal in that range is also not so healthy.
Dr. Ashley: In medicine, we always have our 95th percentile population norms, and depending on the lab, they may be derived from thousands of patients — but often from quite a small number for certain assays — and from a population that's never particularly well described and is probably not that diverse. There's been some work recently suggesting that your own personal normal, measured over several years, might be a better guide. Speaking as someone without a completely normal HbA1c, I wonder if my measurements from my 20s, 30s, and 40s, if they were all the same as today, would be truly meaningful versus where I am on a population scale. How do you think about that?
Dr. Klein: You have to think about obesity-related metabolic diseases as a constellation of diseases that track together. If you have one abnormality but everything else is good, you're not at the same risk as someone who has that same abnormality plus these other abnormalities. If you're a runner, fit and healthy, and you have a slightly high HbA1c, but your triglycerides are low and your HDL is high — that's not the same as someone with a high HbA1c who also has those other risk factors. What we often do is focus on individual organs instead of the multi-organ system, which really determines your health.
Dr. Ashley: One of our new programs here in the Department of Medicine at Stanford is thinking about metabolism because it touches on so many of our historically divided subspecialties — but in reality, it touches on all of them. We've been interested to bring together researchers and clinicians all focused on metabolic disease — whether they're primarily a fat cell person, a macrophage person, or a vascular biologist — who can practice and do research together. I'm hoping you approve of that model.
Dr. Klein: I'm so supportive of that. As chairman, doing this, you're a visionary. People are organ systems, not individual organs. Treatments are also often the same for all the different organs. Putting them together, tracking that, putting the best individualized treatment forward for each person, and adding exercise — which is often overlooked — is critical to addressing this. And having a clinical population with whom you can also do research is a real benefit to advancing the future. Every medical school should do that — except the ones near you, to avoid the competition.
Dr. Ashley: Well, Sam, I think you're describing the future of medicine. Thank you so much for spending time with us today and for doing Grand Rounds.
Dr. Klein: My pleasure.