How body fat affects your metabolic health and risk of metabolic disease | Dr Robert Eckel

OBS City is one of the most talked about healthy shoes of our time and also one of the most misunderstood. We often treat it as a number on a scale, a matter of willpower or a diagnosis that begins and ends with body weight. But the deeper science tells a far more nuanced story, one that depends on where fat is stored, how it behaves, and whether it disrupts the metabolic systems that keep us healthy over time. Today's guest is Dr. Robert Eckle, one of the world's leading experts on obesity, insulin resistance and cardiometabolic disease. Dr. Eckle is a former president of the American Heart Association, a past chair of the AHA nutrition committee, and a scientist whose work helped shape how we think about obesity as a driver of heart disease decades before it entered mainstream. In this episode, we step back from the noise and ask more fundamental questions. Is obesity a disease or a risk factor? Why can some people carry more body fat with little metabolic consequence, while others develop metabolic resistance and cardiometabolic disease at much lower body weights? And is so called metabolically healthy obesity, real or just a temporary state. We also unpack the obesity paradox and look ahead to the GLP1 era, what it may change, what it won't, and what we still don't know. This is a conversation about mechanisms over labels, metabolic health over weight, and why the future of obesity care may look very different from how we approach it today. Please enjoy. Over your extensive career, Dr. Eckle, what belief about obesity or metabolism have you changed your mind or evolved your thinking on the most? Well, obesity is really a complex topic. And the whole etiology of obesity is really debated in terms of what the importance of genes in terms of genetic predispositioned excess body fat is. How to define obesity, in fact, I'm involved in the Lancet Commission, which was released, released a year ago that's redefined obesity. And then ultimately, the role of the individual subject and the environment that he or she lives in, in terms of the impact that they have on the origin of excess body fat. We're living in a world now where it's not only, you know, urban populations, but growing urban populations and underdeveloped areas of where obesity is a major problem. And I've seen some recent data in China that I'm really part of reviewing and ready to publish that ultimately in China, the increasing prevalence of obesity has been dramatic over the last decade. So we're looking at a real global problem. And in terms of the metabolic aspects, which relates to your question, I think that's really a very complicated question and not simply answered in a one-liner. I certainly believe that the condition called clinical obesity, which is when obesity causes illnesses or diseases related to it, is probably not the majority of people that have excess body fat, but certainly when it becomes a clinically apparent obesity that needs attention therapeutically. And that particular setting, I think that most of the complications of excess body fat, which include metabolic disturbances such as type 2 diabetes, the metabolic syndrome, ultimately hypertension, inflammation, cardiovascular disease, liver disease, kidney disease, and even perhaps neurocognitive impairment, relate to a concept called insulin resistance. Now insulin resistance does not cause obesity, but insulin resistance, I believe strongly the evidence suggests, is a consequence of excess body fat. And that relates not to necessarily only total body fat, but body fat distribution. In other words, a more central distribution of body fat relates to more insulin resistance, and if in fact you put excess body fat in your legs and your arms. Now that redistribution of body fat is male-only basically, but it's also women after the menopause, and we see an increase in many of the so-called comorbidities or illnesses we call clinical obesity in women after the menopause. So that's a long answer to your very clear question, which is not simply answered with a one-liner. No, I think that's great, and I think that sets us up for a lot of things which we'll dive deeper on today. And what I really heard from you is an appreciation that perhaps when it comes to the metabolic consequences of excessive body fat, that not all obesity is the same. And obesity can look different depending on the person as to, you know, as you just spoke to where the fat is distributed and the effect that that's having on metabolism. Yes, Simon, perhaps we can revisit this concept of pre-clinical versus clinical obesity, which is what the Lancet Commission addressed. Ultimately, obesity should be defined as an excess in body fat. That's the definition. Now we can debate a little bit as to where to call, you know, call the thresholds for excess body fat. But BMI is a starter. Body mass index has been out there for decades, in fact, for centuries as an assessment of body fat. But BMI has come into question much more recently because we have more ways of assessing whether patients with obesity may develop illnesses for the internexist body fat. So as I mentioned earlier, central distribution is more likely to be associated with clinical illnesses. But the important thing is we go beyond BMI now. We need waist-type ratios or we need waist circumferences or we need DexA, a imaging technology to look at body composition. So when we define excess body fat, then the challenge to the clinician or the healthcare provider is to decide whether that excess body fat is currently harmful, as it resulted in illnesses that relate to excess body fat. And if it doesn't, we're calling this preclinical obesity. In other words, you have excess body fat. But right now we cannot define any consequences of your excess body fat that make you ill or sick. Now this has been debated because the commission that we were asked to address, and by the way, some 50 plus experts from around the field, so called, I was called once I joined up. But all that aside, we define preclinical obesity is something that were excess body fats defined by these additional criteria. But the challenge of the definitions is, well, what do you do if somebody has too much body fat, but has preclinical obesity? Don't you treat them? Well, the challenge to us in the commission was not to define therapeutic approaches. It was simply to find the diagnostics of obesity and how to list the patient is either having preclinical obesity or having clinical obesity with illnesses related to it. But we could all comment on therapeutic interventions. Should everyone with preclinical obesity not be treated? No, but I think we would recommend certainly we don't need to gain any more body fat. And over time, we would recommend for most people that they lose some body fat. But the challenge before us was not to address therapeutic implications for preclinical obesity versus clinical obesity. So what you're saying is that BMI is not enough. We have to go past that to understand is excessive fat causing metabolic consequences now. And even if it's not and that someone is sort of classified as a preclinical obesity, then I guess the question that I have is, is that saying that this person can tolerate more out of policy for the remainder of their life? Or is this looking at a single data point and in the next five or 10 years that person is going to begin to suffer the consequences of having that excessive that policy. Is it a matter of time? Well, I'm going to answer your question in two ways. First, we came up with what we call a risk gradient. In other words, if people have preclinical obesity and they have no risk gradient that relate to a lot of factors that might predict illnesses to follow. And we could say a borderline blood pressure elevation, for instance, we could say a borderline glucose elevation or something that we can't call a disease yet. But their risk appears to be higher, maybe with a family history where excess body fat has resulted in heart failure or ultimately stroke or some other consequence. In that patient, we would really recommend a more aggressive therapeutic intervention. So again, remember the Lancet Commission did not define what these therapeutic interventions would be. But this risk gradient might suggest Simon, if you had excess body fat and had no risk radiance, no signals at all of family history or environmental influence or quality of life abnormalities, we would tend to say just don't just keep your body where it's at, I think you ought to eat normally and exercise as much as you can and do the all the right things with lifestyle. And you should lose weight perhaps, but at this point in time, again, I'm going beyond the commission. So that's the answer to that. And I think the second component of your question would be, if in fact you do have a clinical obesity, then therapeutic interventions are necessary, which are directed to reducing body fat, and of course other therapeutic modifications of those illnesses that exist that may be beneficial and reducing long-term outcomes that are unfavorable, related to those conditions. I've been using Woop for over six years, and I can confidently say it keeps me on track when it comes to my sleep and exercise routines. The next generation of Woop isn't just tracking your workouts, it's monitoring your sleep quality, your recovery state, and even giving you insights into your biological age. No screen, no distractions, just continuous data on what your body actually needs. And here's what matters. Daily Woop, where is linked to increased physical activity, to better sleep, and improved heart rate variability? I have no doubt that my Woop is helping me train smarter, recover faster, and make decisions that support my long-term health. Head to join.woop.com/simon. That's join.woop.com/simon to get one month off your first subscription. Let me understand if I'm getting this straight, because another terminology that often comes up hand in hand when we're talking about obesity and metabolic consequences is metabolic syndrome. Are people with preclinical obesity, folks that have obesity but don't have metabolic syndrome? Is it as simple as that as the definition? Well, that would be a metabolic view of the world. I mean, many of these illnesses related to obesity may not be directly related to insulin resistance to the metabolic syndrome, which I define almost equally. I think the metabolic syndrome is almost entirely insulin resistance. And we can go through the various components of the metabolic syndrome as defined very simply as three out of five criteria. But in fact, the metabolic syndrome goes far beyond these five criteria. And again, many of the comorbidities or complications or illnesses related to obesity are not simply the metabolic syndrome that be on. But to get to the question more directly, the metabolic syndrome would categorize a patient with a clinical illness from the metabolic consequences of excess body fat. Now, in the absence of the metabolic syndrome, that just is one component. Maybe your quality of life is modified by your excess body weight, which, and by the way, arthritis could be a clinical illness related to excess body fat that may not be so directly related to insulin resistance. I mean, arthritis is a complicated deal. But we know that arthritis, meaning joint disease in the knees and ultimately in the hips often, and sometimes in the upper extremities, has an inflammatory component. And that inflammatory component is also part of the extended metabolic syndrome. But for me to make a strong statement that say all arthritis, the related to obesity is directly caused by insulin resistance. I would ignore the physical factors that relate too much pressure on big joints for people that are carrying too much body fat. So maybe that was a little laborious in terms of response to your question. No, I think this is very helpful. And perhaps we bring it back and make it super practical for the listener here to kind of underscore why this is an important conversation. So why, why the fuss and the research on looking at different types of obesity and who has obesity and is suffering metabolic or other consequences from that excessive fat versus not. If someone was to just sort of ask a very simple question here, why not encourage every single person that has a BMI over a certain amount to lose weight either through lifestyle plus or minus pharmaceuticals? Well, important question. And I think it relates to data that we're evaluating in four cohorts from around the world in China, in Spain, in the UK, and also in the US, the all of us study in the United States. We have data from all those four cohorts from around the world. And in a sense, we can answer your question directly with data that has not been submitted yet, but is close to being submitted for publication on. I can't give you the numbers. But we have the data for the transition over 10 years for three of those cohorts from preclinical to clinical obesity. And over time, there is a transition from a subset of people that have preclinical obesity to obesity. So we have that kind of information. And again, I can't share that data now because it's not published and peer reviewed. But we know that there is this transition. Now, ultimately, I think that transition would demand us to look back at what factors may have been present in people who transition from preclinical obesity and clinical obesity. And there are more aggressive approach to weight reduction with the entirely appropriate in those people that have preclinical obesity. Now, your point is, is been one of the criticisms of the Lancet Commission. Why not have everybody who has excess body fat lose weight? Well, what we found is a lot of people with excess body fat do not have clinical obesity. I mean, many of them are over diagnosed or underdogs those based on the BMI of the criterion. So I think Simon, we have to dismiss BMI is the only way to assess accurately how much body fat is present. Now, by the way, if somebody has a BMI of 40 and above, the Lancet Commission says we don't need these other measures. And, and you know, my Tyson had a BMI of 32 when he was in prime shape in the boxing arena and the BMI of 32 is but present body fat was like under 5%. So I mean, the BMI is sometimes inaccurate in assessing excess body fat. For the most part, I think above 30 is too much body fat. That's been used historically, but we find that people above 30 can have normal body fat content and normal body composition. So again, I don't know whether the audience, I think they'll know a little bit about when your doctor orders a sed rate, that sed rate, if it's elevated, may indicate some inflammation that's going on in your body. But it's not specific. And we're saying the BMI is like a sed rate for obesity. It's a good tool to say something's going on here. And here specifically body composition, excess body fat is likely. But we think we need more than that to determine the accuracy of the BMI in detecting excess body fat. And at the individual level, the reason this is important is if I'm listening and I'm someone who has been told I have obesity, the question is what is that doing to my risk of developing type 2 diabetes or having a heart attack, stroke, etc. That's what we're talking about here. Your what I'm hearing is if someone has preclinical obesity, it's not that they don't have excessive out-of-pulsity. They do have obesity from a out-of-pulsity, I guess traditional BMI diagnostic perspective. But what I'm hearing is that that person despite the excessive out-of-pulsity doesn't have increased risk of these cardiometabolic conditions compared to someone of normal BMI. Is that accurate? Well, again, you're using BMI, I think, in some way, an out-of-order here in terms of the importance of getting additional assessments. Again, remember, we have data to suggest we're over diagnosing and under-dying, diagnosing obesity based on BMI alone. I can't give you those numbers right now because they're not peer-reviewed and published. But this again is in four cohorts from around the world. This is not a small sample. So that's kind of that kind of data is going to be helpful. Now it's up to the clinician, sheer heat, to make good decisions about management. And who am I to say that someone that has excess out-of-pulsity? I'm going to bond with that patient. By the way, the clinician who approaches the patient with obesity has to leave all their biases behind. There's so much bias clinically in the evaluation of people that have excess body fat. That needs to be left on the shelf. And there's paper after paper. And I'm included in one or two of those that relate to how biases exist and impact evaluation and care. We need to leave those behind. But for me to see a patient that has excess body fat. And by the way, Simon, the term overweight is dismissed in the Lancet Commission. This whole BMI between 25 and 30 is a gray zone by which many people rely on overweight as cause of excess body weight. Well, that's not necessarily true, meaning body fat. So we want to do away with the term overweight. But I think the clinician, she or he needs to be judgmental in terms of the decision to be aggressively approaching that excess body fat in terms of this risk gradient that I mentioned earlier. And that's not saying we need to ignore most people that have excess body fat and have preclinical obesity. We know now from our data there is a transition over the next decade from preclinical to clinical. And I can't again cite the numbers for you yet. But all that aside, we know that people are at risk. But I think to be critical of us when we were not asked to address who should be treated and who shouldn't, this risk range that we've created really says some people should be treated as if they have clinical obesity because they have high risk for developing clinical obesity. Is preclinical obesity different to metabolically healthy obesity, which some people may have heard? Yeah, you wouldn't believe, you know, it took two years for this commission to be completed in terms of the amount of data that was analyzed and what the report would say. We did away with metabolically healthy obesity, although the literature does reflect that concept, I kind of like it myself because I'm a metabolic kind of guy. So when we call somebody metabolically healthy, I'm thinking of glucose, I'm thinking of blood pressure, I'm thinking of triglycerides and HDL cholesterol and all these other cardiovascular disease risk factors. But I think again, as I alluded to early, there can be impacts of SS body fat that may not be directly metabolically driven. I can claim that they might be indirectly related insulin resistance and metabolic syndrome, kind of phenotypes. But ultimately, I think we need to make decisions really related to other things like quality of life and also things that relate to the arthritis and maybe polycystic ovarian syndrome, although that's really very much a urine insulin resistance related paradigm. You mentioned that there are biases often at play, which perhaps stand in the way of clinicians giving people with preclinical obesity or clinical obesity the best treatment. What are some of those main biases that you see? Well, it's all your fault. Why does you get your act together? Maybe we have other environmental influxes in terms of energy, dense foods are cheap, but I can't afford, you know, better foods, more fruits and vegetables and whole grains and all that aside. I think it begins with a good medical history. Let me review that just briefly with you. When I see a patient with excess body fat now confirmed by more than the amount here are my questions. What was your birth weight? Most people know their birth weight. Some people don't. Next, ask them, do you remember as a child, whether you were told by family members or your friends, whether you were obese or not? So I asked during early childhood development for women, I asked, what was the age of your first menstrual period? The age of your first menstrual period relates to body fat and that's data of Ruth Fresh in the 1940s that showed the girls who had more body fat menstruated earlier. So the idea of menarchy, that first menstrual period, reflects to me for females at least something that related to earlier onset of excess body fat. Most people remember their weighted high school graduation. That's another question. And then for women particularly during their adult reproductive years, I want to ask about pregnancies, how much weight did you gain? And did you lose all the weight after delivery? And by far, a very common cause of excess body weight in women is the failure to lose the excess body weight they gained during pregnancy postpartum. So that's another very important question. Then I ultimately, the biases may relate to just concepts that are delivered to the patient such as you're exercising up or you're looking to what you're eating. And by the way, I think observations of eating behavior in terms of cravings and other things, we often don't see in public places. I think a lot of the excess food intake occurs in the evening or even at night. And that's another series of questions. Do you crave for food? And in my practice over many years, I ask a question, do you eat because you're hungry? And many people don't eat because they're hungry. So those may be more kind of, if you will, emotional eaters or anxiety related eaters that need a different kind of approach. Many areas of psychiatric disease, depression and anxiety relate to obesity. And those need to be addressed clinically very carefully. So I think there are a series of biases that work into this history. That's an objective history. That's gaining information that ultimately give the clinician some better understanding of what the factors are, both individually and in their environment. Do you eat together as a family or do you eat on your own? All these kinds of issues, I think, are importantly defined by an accurate medical history. On the questions related to kind of how long someone has perhaps had excessive out of the city, was it something that they kind of had early in life, was it something that came out to pregnancy? What's the significance of that? So as a clinician, you know, I understand you're asking that for obviously an important reason. Is understanding when the excessive out of the city sort of came on relevant and important to the treatment? Yes. And I think one thing I really didn't mention is part of the history, which is an important answer to your question is, have you tried to lose weight and how many times have you lost more than 5% or 10% of your body weight and were you able to maintain your weight loss and often they can't and why? So this gets more directly to your question. You know, the brain really probably has a fat stat. That means there's a place in the brain that knows your body composition. And you know, there's tremendous evidence of over-feeding studies, over finite periods of time, months to six months, where people lose all their weight after they've been over fed. And so we know we don't force feed people to excess body weight, but over years and perhaps five to ten year intervals, if excess body weight continues to occur and ultimately then plateaus, I think in the environment that we live in, which is one of basically energy dense foods that are cheaper and more available and also not much physical activity, we settle into a body weight that reflects starvation benefit. In other words, if there's a lot of data assignment that relates to like World War I data, which is not very replete, but it's there, but World War II data during the Dutch famine and also the IRA starvation to Northern Ireland. You know, these guys that went behind bars and didn't eat at all for days and weeks and months, the fatter they were or more obese, they were when they went behind bars the longer they live. So excess adipose tissue has a survival advantage in environments in which there's not much food. Now, that doesn't mean developing obesity is a good thing in the world we live in. It's not. It has risk for disease and ultimately mortality related to it. By the way, the data that we're sharing ultimately with the literature has mortality data as it relates to these new definitions. But back to the question, so after a certain time of weight stability, I think that's why it's so hard for people to lose weight because the brain is happy where you're at and losing weight hard enough. And we know from people who diet repeatedly, they can lose some weight, but over time they regain it. We'll talk about things they can do to maybe prevent that weight regain, but we'll stop there for a second. But ultimately, over time, they regain the weight because the brain seems to be unhappy with losing fat mass after you've in fact regulated your body to a higher fat mass. So I think the strategies that relate to how the central nervous system or the brain relates to fatness really deals with this whole starvation mindset in terms of food availability. Right now in most areas of the world, we don't need to worry about where our next meal's coming from. So ultimately, that's the biology and the physiology of weight maintenance. So people with preclinical obesity have that same physiological phenomenon as people that have clinical obesity. So back to this final comment, I'll give it back to you, is that the National Weight Control Registry looked at people who had lost like 30% of their body weight and maintained their weight for many, many years. And that study, really, this is a subjective observational study. This is not a randomized control trial. The people that ultimately lost a lot of weight and kept it off for like a decade or longer were people that did two things. They continued to watch their chloric intake. I mean, they weren't as extreme as they were during active weight loss. But the thing they did was really substantially increase their physical activity. They became very, very active. So when I ask a patient to do they want to lose weight, how much do they want to lose, and what do we think is necessary medically to be beneficial. I only concentrate on food intake for the active weight loss period. But after the weight loss, then I really want to emphasize physical activity. And Simon just final comment, I said that once before. But I think when you mix too much physical activity with too little food intake, you have too much behavioral change all at once in the clinic. So I think working on the food intake is a predominant way through lifestyle to get people to lose weight and then get them more active in the attempt to help maintain that weight. I think you're point on the fact that having excessive adiposity offered a kind of survival benefit, evolutionary advantage in environments that were very different to today. Actually, when I hear that, it's like a reassuring message in some ways because it kind of speaks to if someone's really struggling with this, that their biology is not broken. there's more of just a mismatch between that person. their genes and the environment that they live in. Yeah, that's very true. And I think the whole genetic and environmental influences are debated left and right. There's no questions genetics play a role. But other than rare recessive mutations where you get a gene hit from both parents, both mom and dad, which occur in childhood, the genes that relate to excess body fat are like multiple, like hundreds and hundreds of genes that have a modest effect. But genetic mutations that affect like the leptin pathway, which is a protein made by adipose tissue, or affect certain brain nuclei that have hormones that are sensed and mechanisms that relate to body fat presence and maintenance. Those kinds of mutations occur in childhood and then kids are very obese. So those kids can be diagnosed at age one or two. So those are rare recessive mutations. But the genes that relate to excess body fat are numerous and they have minimal effects. But when they add all together, there's no question of the genetic influence. And secondly, if you look at twins, the overfeeding studies done in twins by Claude Bouchard, should the twins tended to gain the same amount of weight when overfed a thousand calories for months? And the twins lost the same amount of weight. And ultimately, if you look at family studies, which are just looking at, at, uh, lineages of weights and families, the genetics are there. No question. The problem with familial data is you have the environmental influence that impact the family too. And that's hard to sometimes to dissect the importance of one versus the other. But we know that both genetics and environment are involved and to ignore one or the other is a mistake. I love it called like really, really called my ideal bed feels like an igloo when I first get in before slowly warming up overnight. And eight sleep lets me dial that in perfectly. The pod five is a smart, very intelligent mattress cover that automatically adjust temperature and elevation throughout the night to help you reach and maximize deep restorative sleep. To be honest, at the beginning, I was a little skeptical of the whole temperature modulation thing. But once I started to stack deep sleep night after night, I noticed the difference almost immediately, better recovery, clearer thinking and much more energy throughout the day. This isn't just about sleeping longer. It's about fine tuning the quality of your sleep so that your brain can do its overnight housekeeping and consolidate what you learned the day before and you wake up genuinely feeling restored and ready to take on the day. Use my code, the proof at eight sleep dot com forward slash the proof for up to $350 off the pod five ultra. And the best part is that you get 30 days to try it at home and return it if you don't like it, but I'm confident you'll love it. Trust me, your body will thank you for this investment in better sleep. Is it genetics that explains to your earlier point why some people have a higher, greater propensity to store fat centrally at a given body weight versus other people who store more of their fat subcutaneously? What explains that because that seems to be particularly relevant to at least the metabolic consequences that can come with having excessive weight? Yeah, that's true. There are genetic plethora of genes and relate to some relate to body fat distribution. But we can't identify a single gene that says you're going to get more of these centrally. We know hormones play an important influence here. So ultimately, you know, the best demonstrations in women postmenopausal where the estrogen levels fall and they have more androgen dependency or male hormone dependency. Men don't distribute their excess body fat in the pelvis very often. Occasionally, I'll see a man who comes to the clinic with pelvic adiposity excess, but that's an unusual phenotype. It makes me ask additional questions as to why the body fat distribution is there. Because the central adiposity is clearly why waist circumference is one of the criteria. We are assessing, you know, the presence of excess body weight to begin with and may make us more clued in to the fact that people with that distribution may be at greater risk for all the cardiometallic complications of obesity. Now we know that insulin resistance with central body fat is a major player here. And I don't know how much detail you want to go into here, but I think we can outline multiple, multiple illnesses related to obesity that we call clinical obesity that are related to insulin resistance. Yeah, I think I think we need to go a little deeper here. So, firstly, when you're talking about central fat, you know, visceral or a topic fat, maybe we just get a bit clearer on what that is, where that is, and then we can talk about how that relates to insulin resistance. Well, the central fat distribution is an attempt to assess intra-dominal fat. That's the fat below the peritoneal cavity. In other words, there's a lining that we have over the gut. And the fat that's in that area of the body drains fatty acids, which are a byproduct of excess fat into the liver. And when those fatty acids hit the liver, there's a lot of metabolic consequences that ensue, both in the liver and systemically, that's a result of the increased delivery of free fatty acids to the liver. And we can go in that more detail. Now, the wasar conference can be sometimes a little bit misleading because the data in African Americans and to maybe a lesser extent in a native of Africans who live in the African continent is that when we measure wasar conference, particularly in patients with excess adiposity, some of that abdominal wasar conference is due to excess subcutaneous fat. Now subcutaneous fat is the fat between the skin and the lining of the tissues. And in our arms, if we pick up our arms, there's a little fat there. That's subcutaneous fat. The fat in our legs is subcutaneous fat. And in the abdomen, we do have a little fat between our skin and the peritoneal lining. And again, the peritoneal lining is this lining of all the tissues within our abdomen. But keep in mind, the drainage of adipose tissue from our arms and our legs and even the abdomen from the subcutaneous tissue does not go directly to the liver. It goes to the heart. And so those fatty acids are diffused systematically and throughout the body circulation. Whereas when the fatty acids from the intradomal area go to the liver, that's where a series of metabolic consequences occur in terms of the term insulin resistance, which kind of begins, I think, an adipose tissue, but then has a cascade of downstream events that involves the liver and then the systemic circulation of other organs. Can someone modify or redistribute fat? So if they are someone who has more body fat stored inside that abdominal cavity and they're getting increased fat levels within the liver, is there anything that they can do to redistribute that fat? So it goes out to subcutaneous fat cells. Okay. I'm going to go on a rabbit trail for a second first and then I'll answer your question. The rabbit trail, and I'm not promoting me or my size, but there was an interesting study we did in mostly women that wanted liposuction surgery. Now the protocol related to you can have your fat removed, your adipose tissue removed below the umbilikas, your belly button, in your lower abdomen or in your hips or thighs. And you know, they ultimately we took fat biopsy from both organs and we weighed people we did imaging using magnetic resonance, imaging, etc. And the results of the surgery were great. We took out seven pounds, I'm not the surgeon, I'm the medical guy, but the surgeon took out seven pounds of body fat for women who basically were normal weight. They just didn't like the cosmetics or where their body fat was distributed. You know, they had below the umbilikas a little pouch down there or they had hips that they wanted to have trim. The interesting part of the study is this was a three year outcome study to look at body composition and body fat change. And ultimately what we found within one year, seven pounds of fat had been regained, but the women were still happy with the results cosmetically. So the question is where did the fat go and it went intradomally. Can you believe that? I mean, so that's the rabbit trail for a second. Now back to the more important question. And I think I can answer this fairly directly when surgeons have gone in and removed peritoneal fat or visceral fat or intradominal fat and large amounts, it had no metabolic consequences ultimately on the patient. So the idea of this visceral depot is so important, removing a certain percentage of it did not seem to have a metabolic impact. So what does that mean? What means either the fat cells that are still there are now increasingly metabolically active to release additional fatty acids that cause the same kinds of metabolic outcomes or in fact are regenerating new fat cells to replace those that have been surgically removed. So we know that that just doesn't work. So the idea of does fat come back elsewhere or I think our liposuction surgery, that's why I mentioned that, it did come back elsewhere. It came back intradomally. But we couldn't publish the paper in a major high impact journal because we didn't have any metabolic consequences. remember, these women were normal weight or slightly overweight women. I'm using the term overweight because at that time we define them as slightly overweight or normal weight. They just didn't like where their body fat was distributed. How long was your follow-up on that? Because I mean, when you say that, when you say there was liposuction followed by weight regain, but the weight wasn't in those same areas. So the assumption is that it was central. Immediately what I'm thinking is that, okay, you've taken those cells, the fat cells out of the subcutaneous fat storage and providing the body conscious produced more fat cells. If there's just like a set amount of fat cells, then you've limited the capacity now of that area to store fat so it spills over to the abdominal cavity. But could that mean that women, that are getting liposuction to these areas, thighs, lower abdomen, hips, etc., could be setting themselves up for increased risk of metabolic disease in 5, 10, 15, 20 years over a longer period than what you were studying? Well, that's a good question. I think the fact that we didn't see immediate metabolic concerns one year later. By the way, it was a one year observational study. The grant was funded for three years. We did genetics on the adaptation from various regions. That's another part of the story, which I thought share with you. But ultimately, I think it relates to another thing we just discussed. The brain knows how much body fat's there. And to remove it surgically and have it recover means the brain's not happy when you take out fat surgically or when you lose weight or any other means, heard from the reducing fat. The only thing that I think we can say therapeutically that relates to a sustained reduction of body fat is ultimately bariatric or metabolic surgery. Now, surgery has a better long term outcome because there there's major anatomic changes, which explain partly some of the impact of energy intake in its metabolism, but also through mechanisms that are not entirely understood. So metabolic surgery. By the way, I'm sure Simon, you're aware of data when people stop the GOP1 receptor agonist that cause a lot of weight loss within one to three years. All the fat is back. I mean, so we know that obesity, some people like to call it a disease, but one thing the commission did, we're not calling this a disease. We're calling it preclinical obesity or clinical obesity when there are diseases associated with excess body fat. But if we call a BC to disease, it has recidivism. That means it needs lifelong treatment. I'm okay with that biological and physiological concept of it needing to be chronically treated. But the call of a disease, a preclinical obesity doesn't result in any outcomes long term, which of course we don't have data yet to really say. We know that we can't call it a disease. I want to dive a little deeper into insulin resistance. So you explained a little bit there around what happens when you have excessive fatty acids in the liver, for example. But maybe we can just further explain the relationship between obesity and insulin resistance and why you care so much about insulin resistance. Well, insulin resistance is a systemic phenomenon that relates to the inability of insulin to do what it normally does. Now, a bit aside for a second, to measure insulin levels is one way that people have approached this concept, but that's not the gold standard and is not a very good way to assess insulin resistance. The first manifestation I think of insulin resistance, first of all, let's pause here just a second. What organs does insulin have a metabolic effect on? Antipose tissue, both visceral and subcutaneous antipose tissue are fat. The liver and ultimately minimal effects on the kidney directly, and we'll come back to that. And muscle, including skeletal muscle and cardiac muscle. So those are the organs in which insulin action occurs. The brain is highly debated in terms of what insulin does in the brain, and it probably has some effect on the brain, but it doesn't mediate the metabolic effects in the brain like it does in these other organs. Now, the next question is what's the most sensitive parameter of insulin action? That means the lowest concentration of insulin, what does insulin do in terms of all its metabolic effects better than anything else on a very low level? And that's anti-lipoluses. Now, what's lipoluses? Lipolusus is the breakdown of triglyceride in adipose tissue to free fatty acids. Okay? So, you know, when we fast our interlivals fall, and ultimately now the fatty acids are being released from adipose tissue, because when we fast, we need to do one thing. We need to preserve glucose delivered to the brain. Now, one of the most important things I taught fellows and students, and many people in the academic track when I was out there full time, was this define metabolism in one sentence? And to define metabolism in one sentence, it's very simply this, and I'm going to be simplistic, but it really is true. Metabolism is making sure the brain has enough glucose. It's that simple. So, back to the issue of insulin sensitivity. Even fasting for 12 hours. Now, insulin resistance develops a little bit, and when that happens fatty acids leave the fat tissue. They go to the liver, and they make ketone bodies. Now, ketone bodies are a metabolic fuel for the brain to spare glucose utilization. And by the way, when people starve themselves to death, the less they, the less thing they do is have hypoglycemia. They, they, to have the brain not have enough glucose, is really a cause of death only under extreme conditions. And that's because metabolism through ketone bodies through fatty acid production of ketones, that's a black, back up substrate for the brain, not glucose. When the protein starts breaking down into protein fragments called amino acids, those amino acids go to the liver to help the liver make glucose to get, deliver excess glucose to the brain. And lactate, which is ultimately made when we're not eating lactate is a byproduct of metabolism that can be used by the brain to spare glucose utilization. These amino acids themselves sometimes are backup substrates for the brain to spare glucose. So the whole body is geared towards making sure the brain has enough glucose, because the neurons, the cells in the brain that work and think and do everything we do are glucose dependent. It's the only organ in the body that is absolutely glucose dependent. And the body responds in a way that's going to preserve glucose levels until the very end. Now back to insulin sensitivity. Antipose tissue is the most insulin sensitive organ. So I think insulin resistance starts in anapostitium. So when people develop excess body fat, particularly visceral or intradomital depot, these fatty acids are released now in excess to the liver. Now what happens to the liver? What's insulin doing the liver? Let's leave the liver and go to muscle first. Insulin in muscle, cardiac heart or skeletal muscle increases glucose transport. So the idea of insulin moving glucose in the cells is something very, very well known for I think decades if not centuries now. So when people have insulin resistance, the ultimate you know third organ of involvement, the muscle hyperglycemia occurs for several reasons. One, the insulin doesn't mediate the glucose transport into muscle and heart. And secondly, what the liver does with insulin is now modified. Insulin normally in the liver does not increase glucose transport into the liver cells. But what insulin does in the liver, it suppresses two mechanisms by which the liver releases glucose. So the two mechanisms by which the liver releases glucose is breaking down glycogen. Glycogen is glucose stored in the liver and that happens very quickly when insulin resistance occurs within maybe even a day or two. The glycogen stores are gone. But the other thing insulin does in the liver is block gluconeogenesis. Now that's a big term, but gluconeogenesis is the ability to the liver to make glucose out of other substrates. And that includes amino acids that come from the muscle and also lactate and glycerol that come from the antipose tissue. So this fattiest delivery to the liver now ultimately makes the liver available to make more glucose and causes insulin resistance, which relates to the inability of insulin to suppress that pathway. Now this is maybe graduate graduate course in metabolism. Oh, thanks. So, but I'm trying to explain this the best I can. So insulin blocks lipoluses and antipose tissue. It blocks glucose production by the liver and blocks protein breakdown from muscle to keep the glucose homeostasis perfectly normal. And finally, it increases glucose transport into cardiac muscle and skeletal muscle. So insulin is an incredibly important molecule. And when insulin resistance develops, we got all these metabolic pathways that go a ride including better bikes and and Rome, type 2 diabetes, and beyond. So. (laughs) - And you believe that ground zero, if I heard correctly, is insulin resistance in subcutaneous fat stores? - All out of post tissue. And because of that developing insulin resistance there, you don't get the same anti-liposis, sort of blocking fat breakdown effect that insulin normally would have at a given concentration. And therefore, more fat is broken down. You have an increase in free fatty acids, which downstream at the side of the liver, that increases insulin resistance in the liver, which then affects insulin no longer working as well at the liver, so it can't decrease gluconeogenesis. And now the liver's pouring out more glucose into bloodstream. - Beautiful Simon, you've done a tremendous job explaining what I maybe didn't explain as well as you did. The other thing about the metabolism that exists is when the fatty acids go to the liver in excess. And keep in mind, this is why visceral fatter intravenous fat is so important, 'cause it drains all the fatty acids directly to the liver. Or subcutaneous fat ultimately drains it into the systemic circulation. So the fact that too much wasser conference, which is typically related to too much intravenous fat, the liver is being bathed with more fatty acids. So the final thing metabolically that your statement needs to include is people with insulin resistance, the metabolic syndrome includes hyper-tragulsaridemia. That means triglyceride levels are elevated. When these excess fats go to the liver, not only do they block insulin action in pathways, downstream that relate to the suppression of gluconeogenesis, these fatty acids now can be available to make triglycerides in the liver. So fatty liver can occur, you know, hepatic steatosis or fatty liver, mesh and other consequences of fatty liver. And also hyper-tragulsaridemia, where the liver takes those fatty acids and makes triglycerides, normally stores them, but now secretes excess of amounts of triglycerides from the liver to make plasma triglycerides be elevated. - So what's the relationship there between secretion of more triglycerides and another topic we've spent a lot of time talking about on this show is like apoby containing lipoprodeins and atherosclerosis. And Thomas Deis bringing others have come on down. So for who I think link dust up, have spoken a lot about how the liver produces VLDLs and then IDLs and LDLs and the VLDLs are more triglyceride rich. So as you get insulin resistant in the liver and as you have less of this kind of anti-lipolysis effect happening because you're insulin resistant in fat stores, does apoby tend to go up hand in hand? - Yes and I think you're relating to a topic, just interestingly enough I'm going to veil this week and there's an annual meeting of the Colorado Diabetes and Endocrine Institute that ultimately I'll be speaking about an update on lipidoltering therapy. And I'm posing this as an overreaction or not an overreaction as to whether we need more LDL drugs, more triglyceride drugs, more HDL drugs, more LPA drugs, back to your question. I think the triglycerides that come out of the liver may be the larger form of triglyceride rich particles which maybe apoby content is maintained whereas other studies have shown maybe apoby is somewhat elevated. But to get to the question, I think triglycerides themselves don't cause heart disease. I think there's this discussion that you've had with previous speakers that apoby containing particles which get metabolized downstream to smaller particles is where the risk factor for triglycerides relates to heart disease. But I don't believe for a minute that triglycerides themselves cause heart disease. But it relates to a B and your question is a very good one. So here's my take home message. If your patient has triglycerides that are elevated, let's say 250 milligrams for a desider if we're assuming that 150 is normal and that could be debated. So let's say triglycerides are 250 but their LDL cholesterol is under 100. Let's say it's okay and they have preclinical obesity. Maybe don't have the metabolic syndrome yet would be defined clinical obesity. But let's say the triglycerides are 250. Their HDL cholesterol is normal, which is often not true cause triglycerides and HDL are inversely related. And their apoby is normal. I would not treat that patient's triglycerides. But if apoby is elevated, then I'm gonna be more concerned and be more aggressive in modifying their lipids. But keep in mind, the metabolic syndrome is insulin resistance to the T, at least almost all aspects of the metabolic syndrome can be described in part if not nearly completely by insulin resistance mechanisms. And that includes hyper triglyceridemia. The APOB question, I think, the question would come up this insulin action in the liver, control APOB production and secretion. And I would say no, it controls the triglyceride content of the particles that are leaving. But APOB is, it may be an innocent bystander just as a structural protein in many circumstances. But when APOB is elevated, there may be other genetic factors at play in to why APOB might be elevated in those patients. - I see. So it's not necessarily that if the liver is producing more triglycerides that it means more APOB containing lipoprotein count, it could just mean that you have more triglycerides within each lipoprotein. And given that, it's the number of APOB containing lipoproteins that drives risk, I understand exactly what you're saying there. - In my paradigm, Simon was always in people with hyper triglyceridemia, a major apobee, if the LDL was low. Now, if the LDL's elevated, I'm not gonna major apobee because we know most apobee is at LDL. But if the LDL is under, let's say, a hundred or under 70 or in the very low range on treatment and the triglycerides are elevated, apobee helps me know whether I need to be more aggressive in treating those patients. Yes. - So coming back to the individual here, and again, thinking about preclinical obesity versus clinical obesity, and you sort of just alluded to the fact that metabolic syndrome is almost insulin resistance. At least from a cardio metabolic point of view, when we think about clinical obesity and what the goal is, is the goal to lose weight in order to have an effect on insulin resistance? - Well, I think when you lose weight, almost always insulin sensitivity is improved. It may not be normalized. And I think we ought to pause just a second and say, type diabetes, by the way, is also defect in insulin secretion. It's just not insulin resistance. But I work with the idea that the insulin resistance in the periphery, meaning the systemic circulation, makes the beta cell that makes insulin strange to make more insulin. And when the genetics are there to develop type to diabetes, that beta cell just doesn't keep up. So anyway, we'll leave that aside. But I think when one loses weight, almost always insulin sensitivity is improved. Now, how much weight lost do you need? I would say a minimum of five, but typically 10% or greater. I mean, I'm using those terms fairly loosely, 'cause people could challenge those numbers. But when my clinic was fully operational and I recommended weight loss for somebody, I never recommended 5% weight loss. Let's get 10% above before we can. So above 10% of weight loss, almost always insulin sensitivity is improved. In every aspect. - And I guess to go a little bit further on my question there, from a clinician's point of view, when you're trading clinical obesity, and we're thinking about the cardiometabolic risk profile of this person, what are you retesting, measuring, that tell you that that person has lost enough weight to now put them at a lower risk of cardiometabolic disease? Is it just various tests that give you an idea of that person's insulin sensitivity? - Well, let's think about how one measures insulin sensitivity, the gold standard is what we call the Euglycemic Clamp technique. And I've done many of them over the years. So many people have done a lot more than I have. But the insulin sensitivity assessment is where a patient is put in a metabolic unit. And ultimately they have an intravenous line placed. And then they have a gradient of insulin delivered where many aspects of insulin needed metabolism is measured. So the idea of the Euglycemic Clamp is the glucose level is maintained by the amount of glucose that's infused into the patient. And the insulin stepped up to a very low level of to a moderate level and up to a higher level. So the interesting thing about this at a low level of insulin infusion, we suppressed lipolysis. Remember, that's the most insulin sensitive parameter of insulin action. At the second level of insulin, we suppressed hepatic glucose production. So we shut the liver down. And at the highest level, we increase insulin mediated glucose, uptake and transport into muscle, cardiac and skeletal muscle. We have biopsies of tissues that we can prove that that's what's going on when we step up insulin. Now by this Euglycemic Clamp technique, we can measure all of those rates, rates of anti-lypolicis, rates of hepatic glucose production and rates of glucose assimilation by the tissues. That Euglycemic Clamp is not a practical tool for the clinician and the clinic, okay? So we're, and by the way, tests that are out there to measure insulin sensitivity need to be validated by Euglycemic Clamp Technology. And although Quest has an assay, which I think is somewhat useful, people use equations and assays that ultimately are inadequately validated by the gold standard to really say that they should be used clinically. And all of them involve the insulin level. Now, remember what I said about type 2 diabetes. Type 2 diabetes have insulin resistance. So before they start not making enough insulin, their insulin levels can be high. That is the diabetes develops those insulin levels dropped because the beta cell can't keep up with the insulin resistant. So using an insulin level measured in the clinic to assess insulin sensitivity is flawed. I mean, in many people who have glucose intolerance are typed in diabetes. So what I'm saying is here's the way we assess it. We get on the scale. So if we got 10% or greater weight loss, I'm going to be pretty content that that's a pretty good assessment of insulin sensitivity improvement. Secondly, we can measure ultimately fasting glucose. I mean, the patient doesn't have diabetes. Even they have preclinical diabetes. Maybe the borderline fasting glucose, we can see that improve. We can do a glucose tolerance test if we've done it previously to show the improvement in glucose tolerance. We can measure triglycerides at HDO cholesterol to see that TG's of fall, HDO cholesterol's come up. We can measure blood pressure. We know that insulin action involves the stimulation of nitric oxide, which is made by the endothelial cell and very related to insulin sensitivity and blood pressure regulation. We can measure C-reactive protein, which is an inflammatory marker which may be reduced. We can measure adiponectin. Adiponectin is a hormone made by adipose tissue that reflects insulin sensitivity in the systemic circulation. Adiponectin levels tend to be lower in people than are in some resistance. We can measure adiponectin levels. I think some of these tests are more costly and we don't need to be measured clinically. We're looking at an outcome that is easily measured by fairly cheap tests that are part of a basic metabolic panel or in fact a comprehensive metabolic panel. These are routine tests in the clinic. Back to the mechanism a little bit here, coming back to sort of ground zero of insulin resistance beginning in adipose tissue. What is it that kind of causes that insulin resistance to begin in those fat tissue sites? Is it just crossing a certain threshold of total body fatness or are there other kind of known risk factors and what I'm getting out here is what can someone potentially do to protect themselves against developing insulin resistance in the first place in the fat stores? I'm not sure there's any way they can crawl their own fat cells and response to insulin. The idea here is that insulin has metabolic effects that are mediated by certain downstream signals. The inhibition of liposis relates to the ability of insulin to suppress enzymes that are involved in breaking down those triglycerides in the fatty acids. Ultimately insulin also stimulates an enzyme in adipose tissue called lipoprotein lipase, which is a physiological parameter of maintaining fat cell size. Those are all biomarkers of insulin sensitivity in adipose tissue. The idea of the large fat cell is probably more likely to be insulin resistant than if you have hyperplasia or more fat cells that develop. The biology of adipose tissue relates to some threshold of adipose site size that then will generate new fat cells. You mentioned a question maybe a half hour ago about the idea that fat cells can be replaced ultimately when they're removed surgically. That's true, but that's new fat cells that are made. We're not given at birth a certain number of fat cells that are going to be developed. We tend to maintain at a certain body weight that number of fat cells. For ultimately fat cells as we continue the gain weight can be generated anew. The idea only a certain number of fat cells were dictated to have. How insulin controls what the fat cell sizes versus the hyperplasia of adipose tissue or more fat cells is an interesting parameter, but insulin does stimulate transcription factors or factors that control gene signatures that make fat cells to be developed. Part of insulin sensitivity is actually maintaining the adipose tissue environment at a steady state wherever it's at. And maybe within its own resistance that whole physiology of maintenance of fat cells allow the existing fat cells to get heavier and as they get bigger than insulin resistance develops. One early parameter may be the increase in fat cell size. Looking at this again through an evolutionary perspective, what's the evolutionary explanation for insulin resistance? I think it relates to food intake under situations of food deprivation. I think in general the insulin resistance is a very, very important systemic adaptation to food deprivation or starvation. I think that's work. And people criticize that a little bit because the data rolls a circumspect and historical and observational, but we're not going to star people to death to prove how and when insulin resistance develops. It was clearly with even 72 hour fast people are very unsolvable after 72 hours of fasting. Maybe all the parameters are equally impacted at that point. In that when food is not coming into the system, you want more fat to be broken down and you want to live it to be producing more glucose. And you remember why? So that your brain's continuing to take it and energy substrate. Yeah, we preserve glucose available if the brain. Remember the brain, the neurons, the thinking cells of the brain and go beyond thinking they control motor symptoms, sensory symptoms, everything else. The neurons of the brain are glucose dependent. There's no question. And everything we do metabolically in the absence of food really are backup substrates to prevent the glucose utilization by the brain as being ultimately reduced. So they preserve glucose. And by the way, I can refer to classic fasting studies done decades ago in the 50s by Steve Fions and his group of the Irvice and Michigan where they fasted men and women for 72 hours. And what they showed is glucose levels can fall as low as 40 in women and 45 in men and actually even in some women, 35 in their normal. So that's enough glucose that they were functioning physiologically and ultimately thinking normally. But ultimately it just shows that glucose falls, but then it doesn't fall any lower than that. I think that becomes very relevant because of a glucose of 45 in a fasted patient may not be symptomatic. But in other circumstances, an insulin treated patient with diabetes, it would be something we need to treat for sure. On this idea of insulin resistance, I'm interested. Is there a difference in terms of metabolic consequences between the insulin resistance that we're talking about here that can often come along with excess body fat versus what's often described as or what I've heard it described as physiological insulin resistance when someone adopts like a low carb or a keto diet, for example. I think the physiological response to a ketogenic diet is a expected response by having no carbohydrate. And what happens when you don't eat any carbohydrate or very low carbohydrates is ultimately you have very low insulin concentrations. Fatty acids are leaving out a position like crazy. In fact, we've done a study that relates to fatty acids stay up the entire day as ketone bodies are being made. That's because fatty acids need to be delivered to make ketone bodies. And so we don't think that's a very physiologically normal setting, but this is a really insulin resistance paradigm, the very low carb diet. And in general, what people have found, and you may know of these status, who else I do, in general, the low carb diets work pretty well for a while in terms of more weight loss. And it may be partly the insulin resistance. And I think it's partly the fact that the ketosis reduces appetite. So when people become ketonic, they tend to be less hungry. And so they tend to stay on their diet a bit longer. But we know data one in three years that the low carb diet, you know, the induction phase can't last for that long. And people ultimately gain lose about the same amount of weight one in three years after they were initiated on a low carb diet, even when it was modified somewhat favorably in the interim. So it works initially. And I think the insulin resistance in that paradigm would be expected and ultimately very much like the starvation kind of situation that we would see in someone who is food deprived for unexpected reasons. Now the insulin resistance develops with excess body weight is the same metabolic kind of insulin resistance. This is as extreme or severe as it would be in the absence of food intake or with a low carb diet. I don't know that I can really make those comparisons. I really, I mean, I'd have to look at data under both circumstances, all the substrate levels, et cetera, and see if there's a difference between those two types of insulin resistance. The thing about the low carb diet with an outcomes or approach historically is that people are losing weight and ultimately many things improve. Like, you know, the triglystides don't go up. They in fact fall. The HDL cholesterol is also fall by the way, all the lipids fall when you're not eating and losing weight. Well, so I think that's a difference between the two. because with the insulin resistance of excess body weight or visceral out of posity, one has high triglycerides and low HDL. But of course, again, that's that's so mechanistically different because of the nature of the insulin resistance in the type of individual developing it. So in the person who has insulin resistance, not from a ketogenic diet, but from excessive out of posity, coming back to the mechanisms here, what specifically is it that is driving the increased risk of the metabolic conditions? Is it the elevations in insulin or is it something else because you mentioned there that that many people with insulin resistance don't actually have the elevation in insulin? Well, I think the metabolic effects I think are driven naturally by the free fatty acid available in all tissues. The antipositure releases excess FFA free fatty acids. The liver has Downstream signaling that's impacted. Insulin doesn't work as well on suppressing glucose production and release and muscle. Clearly, the fatty acids block into many glucose transports. So we can blame the metabolic consequences on that. I think ultimately, the insulin resistance paradigm that relates to other aspects may not be all insulin resistance directly. In other, it's people have tried to point out that the mitogenic effects of insulin, that means on gene expression and certain metabolic pathways like in the ovary and in the brain may be stimulated by insulin. And we know part of the obesity phenotype can be an increase in stress hormones, like cortisol. And we know that ultimately insulin can increase the production of out dosterone, another adrenal steroid that increases blood pressure. So the insulin effect through that pathway may be a direct stimulation that's independent of the direct metabolic effects that relate to things like glucose and lipids. So we can think maybe of an insulin stimulatory part of insulin resistance. And I think this is particularly true in the polycystic ovarian syndrome where women who develop polycystic ovarian disease are very insulin resistant. They have all the manifestations metabolically of hyperdricositidemia and higher insulin levels. And ultimately, now have perhaps a direct stimulation of insulin on making male hormones in their ovary. So that's an example of an insulin stimulation of hormones that are part of maybe some of the clinical obesity phenotypes that we describe in people with excess out of posity. Is it possible that earlier you were talking about pretty clinical obesity versus clinical obesity? Is it possible that one of the differences between someone with obesity that has underlying metabolic risk or insulin resistance in someone with obesity who does not? Did you look at whether there was a significant difference in the cardiovascular respiratory fitness of these individuals? And if perhaps individuals who are doing more exercised but are obese are protected against insulin resistance and the downstream consequences of that? Well, this activity clearly is a beneficial therapeutic recommendation for all people. I think people who are well and not even obese based on current criteria. Physical activity has and fitness. I mean, fitness is tough to define in the clinic, by the way. I mean, fitness really requires more systematic measurements under controlled environments. But I mean, people talk about this six minute walk test and things like that. But I think in general, fitness is needing to be defined more systematically by people who deal with that definition. But all that aside, I think physical activity in general, both aerobic and now resistance training, both are beneficial metabolically. Now, whether they cause weight reduction is questionable. You need to be really a pretty extreme athlete to really have changes in body composition to the extent that you lose weight from your physical activity. But in general, physiologically, fitness is really a good thing. If I was obese, I think a question that I'd have right now, based on our conversation so far. And let's say that I'm someone that has tested my blood glucose and HB1C and blood pressure and all these things and they seem to be normal. A question that I would have to you is, do I just keep monitoring those things? And if they start to move in the wrong direction, then I have increased kind of motivation to go on a diet protocol or consider pharmaceuticals. Or how do I know right now if I'm someone that should intervene? And let's say, for example, I'm someone that is not, I don't worry about my weight, psychologically, and I feel good otherwise in my joints and everything. What's your family history look like? I mean, you could be theoretical or you could be personal. I think most people would say that there is some chronic disease in their family. So let's say for it, let's say, let's take one that's pretty common. Let's say I've cardiovascular disease in my family. At what age? These are good questions. Let's say I've had a, and this is hypothetical, because this is different to my own family history. But let's say I've had parents who have developed cardiovascular disease in their 60s. All right. So now you, you're, you're, I won't see your glucose in normal, your lipids are normal. You maintain your weight with, let's say, a BMI that's in the high 20s, and we've proven by weacer conference or by weasight ratios of greater than 0.55 or weas tip ratios. I mean, they're all ratios for these various parameters that we would define excess body weight. And there's a family history of heart disease. Then I'd want to know where any of them smokers, are you a smoker? Were any of them hypertensive? Do we know their lipids? Do any of them have diabetes? So we're looking at other aspects. What about their own, their weight with cardiovascular disease in the 60s? I mean, I'm going to try to get into some potentially genetic and historic environmental factors that might be important for me to say you need to lose them weight. I'm going to try to remember I described this risk gradient of low risk versus higher risk. And ultimately how that might relate to a therapeutic decision to have you lose weight. And I think again, this returns me to this criticism we've had. Again, our job was not to define the therapeutic approach to these people. We're just trying to define them better. But people with the higher risk, we're going to say we need intervention. Those people will need to lose some weight. And we would recommend weight loss. So based on those factors, by the way, your quality of life I'm assuming it was perfectly normal, you feel well, your your job is going well. If you're using a desk job or you're getting enough physical activity and you're a non-smoker, all those things are favorable. I may say we just need to see you annually and measure these factors and make sure everything's continued to look normal. If I see a tendency or trend to a slightly higher blood pressure. And by the way, the blood pressure in the clinic we know is just a tip of an iceberg. People that have pre-hypertension, that's a term that's not used anymore. And people have this borderline blood pressure below 130, I think need to have home blood pressure measurements. So we're going to take steps to assure that we're maintaining you in as much of a physiological condition as we possibly can. Do you get pushed back from other clinicians who who maybe say, yeah, well, this person's test results, maybe they maybe they classified as normal by our classification standards, but are they optimal? So is there is there a difference between, let's say for example, LDL cholesterol, what the normal reference range is versus what's optimal. I think that's that's a debate that people are certainly having out there. I think that's where, you know, I always say that guidelines are meant to inform, but they're not meant to mandate. So we all use guidelines, we depend on them because it's a series of thought leaders should get together and this is what the evidence says and we follow them. But ultimately at times the optimal issue comes up and depends on individual factors that relate to both lifestyle, environmental influences, etc. that can mandate a decision to be more aggressive than previously. I mean, you know, an issue comes up right now that I know a fair amount about in terms of the SGLT2 inhibitors, which are drugs that are used to treat diabetes initially. These were approved as diabetes drugs, but of course now benefits on other outcomes, including the progression of renal disease and also heart failure, hospitalizations, etc. They're not approved for type 1 diabetes, but that's because the number of randomized controlled trials and diabetes is near zero for all cardiovascular disease risks. So in fact, I have prescribed a SGLT2 inhibitor to patient with type 1 diabetes based on the evidence we see in type 2 and even people with that diabetes who have prognuria or have evidence of renal disease. So I want to do that to protect their kidneys to maintain current kidney function, but the impact on heart failure is just more common type 1 is also higher if you follow them longitudinally. Now, so is that appropriate? Well, no, it's a non-label prescription, but it's based on an understanding that we may be doing benefit while we don't have randomized controlled trials. So in fact, I'm involved now with a person you know by name, who I won't mention, but we're beginning to work with the NIH and been called by the NIH to establish a course. party of the East outcome trial type 1 diabetes, which is real. At their 1.6 million people with type 1 diabetes in the United States, but everything's been done on type 2 and obesity. And by the way, the type 1 population has gained a lot of weight. And why have they gained a lot of weight, no different than the normal population? They used to be thought of as lean because they were glucose, very glucose intolerant. By the way, they're insulin resistant. So many of the issues we're talking about here were the obesity and we think a type 2 diabetes is being much more commonly a population as a business now occurring in type 1. So I think I used that as a case in point of making an individual decision based on non-FDA approved indications. And ultimately, I guess the critics might say that everyone who has excess out of post-ordinary Bialogial P1 receptor agonist, but that would break the bank globally. And many people don't have access to these drugs. So I think we need to have some way to streamline our approach, both from a cost effective and also a long-term maintenance strategy. Because if you go on a GOP1 receptor agonist, when you stop it, we know the data that people regain the weight. So anyway. Do you have a sense of what percentage of people, let's say with obesity, let's say over a BMI of 30, do I think is the cut off or least in some places? Okay, we're going to use the old BMI standards, right? I'm looking at that. A sense of the percentage of people that have a BMI over 30 who would not benefit from weight loss at least today. Well, how much weight loss? 5 to 10 percent, like you like the kind of typical amount that's required. Well, I'm going to use 10 percent because I feel much more strongly that many more things are modified at 10 percent than at 5 percent. So the question again is what percentage of people would not respond? What percentage of people who have a BMI over 30 would be considered in that preclinical obesity and perhaps it's not indicated that those people need to lose weight and especially don't need to target this 10 percent of weight loss target? I don't know, but I think we have the data. We've not looked at that carefully with this four cohort study, but I think this gradient risk that we're defining and is in the commission, Lancet paper. I think that's a good question we would need to go back carefully and look at four different global populations with kind of different environmental influences from around the world. I think that's a really good question. I can't answer it. I don't know. Well, I'll have to have you come back on when that's that dot has been analyzed. Well, that's a question that in this initial report that I described is not possible just because of the amount of hours and time to go back into it. Keep in mind, these data come from existing cohorts where adequate data has been gathered to define obesity by the clinical obesity phenotypes versus. And by the way, the 18 organ systems we've defined the clinical obesity phenotype has also been challenged and that it's not arbitrary. We have evidence to support all of these 18 organ systems in terms of manifestations, including the kidney, the liver, the heart, the brain, lifestyle, et cetera, the joints, et cetera. We have all these systems that have been identified with substantial evidence, but we can improve on that. Ultimately, the question you ask is a way to improve on it. How well are these 18 organ systems in the criteria we've organized and described how proven are they in terms of looking at outcomes that follow? But we do know that somebody who does not have these at this point to find his pre-clinical obesity, we know there's a transition over 10 years for three of those cohorts, the clinical obesity. And again, those numbers I can't reveal right now, but we don't know in the people who don't convert. How will the risk factors, in fact, we could retrospectively go back and see whether we can identify them based on some of the existing data that we have in those patients before they did convert. So I think that's something we'd have to do. In your presentation that you sent me over email, you had a few slides on what you described as the obesity paradox. And you unpacked for us what this obesity paradox is and whether there are any circumstances where being obese, overweight, having excessive body fat, however we want to put it, is actually advantageous to living along the life. Well, I think the approach to the obesity paradox is a controversial area in science and medicine. I think in general to recommend people maintain higher BMI for this paradox effects to be developed I think would be not good medicine. However, I think, you know, again, observational data, these are not randomized controlled trials where people are left to be overweight to look at outcomes. In general, when people admitted to the hospital, sometimes for congestive heart failure, that's particularly where this database is a little bit more robust, is that having a BMI in the overweight category or modestly a B, sometimes it's been associated with better outcomes and people who reach the hospital or hospitalized in intensive care units are maybe even short of that with heart failure. So that's one area where the excess body fat observationally has been beneficial. And I think that returns to the challenge that we had in the Lancet Commission and that defining excess body fat alone by BMI may not be really representative. These people who have been observed to have better outcomes who are hospitalized for heart failure did not have further estimates of their body composition by Dexo or by race shows or in fact, race or conference. So I think in general the obesity paradox is something that needs to be understood a little bit better. But I don't think everyone with excess body fat, by the way, have diseases associated. Now heart failure was one of the diseases we called as a now come of clinical obesity. I mean, that included people within that category. Now why the outcome would be better if you had more excess body fat. I don't have a good answer to that. I don't think we out of dwell on the obesity paradox, but there are dangers that just that does exist. Something else that I found interesting was I think you wrote a paper back in 1998, which is going back going back a little while now. And so I'm not going to expect you to remember this specifics. But you wrote this with Ronald Kraus. And the reason it stuck out to me was it seemed like in 1998 this idea that obesity was contributing to cardio metabolic disease was not going to say a new idea, but maybe it wasn't as accepted as it is today. Yeah, that was a call to the action. When called action to the American Heart Association when Ron was chairman of the obesity or actually the lifestyle committee now at that point called the nutrition committee. And I became a member of that and was I was asked to join the nutrition committee of the HA because much of my science has been an obesity. I mean, both in human obesity, looking at things like insulin action, insulin sensitivity and cardio metabolic medicine in its beginning and also in the basic science laboratory. I mean, I ran a basic science lab for 40 years. So I mean, many of the models we developed in the laboratory related to body weight regulation and obesity. So they asked me to join. I said, well, look, I'm not trained in nutrition. I mean, that's not a formal education. I have, but we do a lot of nutritional modifications with high carbon, high fat diets. And that's really something I've been very interested in comparing the metabolic impacts of those two diets. So as I was called on board these maps, these USA maps, you know, that ultimately started to be made available in terms of the fact that the America is getting heavier. And of course, those maps over the last 25 to 30 years now have changed dramatically. With now the majority of states having at least a 30% prevalence, if not higher. It's a major epidemic of our time. The call to action, Ron and I stated as the American Heart Association now is interested in how obesity may relate to cardiovascular disease. And at that time, obesity wasn't called a risk factor and wasn't called it clearly an independent risk factor. And it just brought attention to the fact that there are many metabolic abnormalities occurring obesity that put people at risk for cardiovascular disease. And including glucose intolerance and type 2 diabetes, the metabolic syndrome was just beginning to be defined at that point. The World Health Organization in 1998, the same year Ron and I published that called action for the HA, came out with the first definition which was so complicated and so difficult to apply clinically that ultimately that I got very involved in the global approach with the HA to defining the metabolic syndrome more carefully. And of course, as I mentioned earlier, the five criteria that utilized to have three out of five present is very much an under simplification of what insulin resistance is all about. insulin resistance not only relates to blood pressure and glucose tolerance and lipids, but it relates to ultimately blood pressure. I mentioned that but the insulin resistance paradigm of blood pressure is really something that is underestimated by the metabolic syndrome criteria. But it relates to influx. inflammation in relates to thrombosis and we think it relates to neuro cognition too. So and done, you know, the metabolic syndrome didn't have anything to say about the kidney or the liver other than the metabolic consequences of insulin resistance. So it's a long answer to your question, but the Ron Kraus and and the echo contribution, I think was the beginning of the H.A. getting interested in this. And now they have this concept called C.K.M. And by the way, I know that pretty well. The C.K.M. thing from the H.A. was not part of that group, but I reviewed it and I know about it. I've spoken about it, but C.K. M. is really just the the metabolic syndrome revisited a little bit more detail with a new term connected to it to make it sound kind of current. I don't think there's anything really current about it. I'm not being critical. It's just kind of revealing increasingly the importance of excess body weight in all the consequences relate to heart disease. If you had to put a number on it, what percentage of cardiometabolic disease would you say is driven by excessive body fat? You know, if you think about when we updated to look at the percentage of people with existing what we call clinical obesity illnesses that do not have obesity, we've looked at that pretty carefully. So that means that some of diseases like heart failure and like coroner heart disease and fatty liver disease would be an unusual one. But typed in, I'd be just going to occur occasionally in a normal weight person without excess body weight. But if we look at the kind of the prevalence of that in people without obesity, I mean, the significant minority of the population have these same diseases that are not obese. So I would say 50% to 2/3 of people with cardiovascular heart disease have obesity as a major contributing factor. So with that in mind, I also read your, you had an AHA presidential advisory looking at the last 100 years of cardiovascular science. I think you were part of that paper. And there was a graph in there that just insured, found really interesting because it shows cardiovascular mortality. So from heart attacks and strokes over the last 100 years. And you can say that there's been a big reduction for both of these, particularly for heart attacks, huge, huge reduction. And the thing that is fascinating about that is that those reductions have occurred in the background of increasing type 2 diabetes and an increase in obesity. And so given what we're talking about today and where we sit in 2026 with different interventions available to us with more precise definitions of obesity and clinical management of obesity, what do you predict is going to occur? Let's say over the next one to two decades in terms of the incidence of obesity and type 2 diabetes in America and how that further affects those cardiovascular mortality rates. I think some of the explanation, in fact, most of it in terms of the reduction in cornea events over the last several decades relates to more rapid assessment better technology to assess disease, the whole process of preserving coronary blood flow. We're talking about now with stenting and/or bypass. We have a lot of technology now that makes people more easily and more quickly diagnosed, particularly through a stroke where we have thrombolytic agents that can preserve life and brain function in that particular setting. So I think the technology and the clinical care aspects of acute coronary syndromes and their treatment relate to a lot to that data. Now your question relates to kind of projecting going forward. I think in the US, we have a little bit of data that's showing up now that the obesity prevalence may be plateauing. By certain criteria, we may have up to 75% of people that have X's body fat. And if you put overweight and obesity together using BMI alone, it is around 70 to 75%. So the question comes up then, what about preclinical obesity? You know, you mentioned something very important with this increasing prevalence of X's body fat defined either by historic ways to be a myelone or now with the clinical obesity phenotype and preclinical phenotype. You know, maybe I think the idea of assessing body X's fat more readily, assessing presence of clinical obesity and more strategic approaches to prevention of the occurrence of clinical obesity and people with preclinical obesity, really will be an important strategy to kind of continue to despite the presence of X's body weight, be favorable in terms of outcomes related to cardiomyelite disease. So, and by the way, the cardiomyelite disease, you know, waterfall of you will in terms of the liver, the kidney, the heart, and beyond. I mean, we have so many organ systems that are impacted. I think we have to look at each kind of one of these outcomes more carefully. I think if I put my priority and the most important thing that relates obesity to disease, we can control to some extent without weight reduction. I'm saying hypertension, glucose intolerance, hyperlipidemia, particularly focus on LDL or APB contending lipoproteins, controlling those risk factors even in the patient with clinical obesity without weight loss may be very possible. But keep in mind, and we published an editorial with my colleagues in France and Germany fairly recently that people now who's being mice are reduced by GOP-1 receptor agus, or people who in fact are at lower body weights and treated with GOP-1 receptor agus, or as JLC2 inhibitors appear to benefit equally as well. And that gets beyond how these drugs work. We think that's mostly weight loss, but I think that data is becoming increasingly suspect, Simon. I think weight loss alone is only explaining probably a minority the benefit. And that really raises additional inquiries into what these additional mechanisms are. And Dan Drucker from Toronto is the father of kind of GOP-1 receptor therapy and science. Ultimately, I mean, there's no receptors in many tissues where GOP-1 receptor action is being attributed to its benefit. And so I think, you know, it's kind of like one hypothesis deserves three more. And again, like I said to you before, I think the more you learn the more you realize you don't know. And that's what helped me going for four years at science and medicine because it's just incredibly challenging and inquisitive to address new things that come up based on what we thought we knew. As we sit here today, I think there's 30+ Americans that that are currently have a prescription for a GOP-1 receptor agonist. And that number probably will go up. And I know there are a lot of people out there, especially those not from the scientific community who have concerns. They're worried about a new pharmaceutical entering the market and kind of being prescribed to so many people so quickly and what the long term effects of that drug could be. What could you share with someone who maybe is of that position and is wondering whether there are any valid concerns about long term use of GOP-1 receptor agonist specifically? Well, at this point, there are potentially of benefits to go beyond what people are expecting in terms of weight loss, reduction of cardiovascular disease, events, prove kidney function, improve liver function, etc. And that includes addictive behavior, there's some hint of benefit in terms of addictive behavior. And that may relate in part to obesity in terms of the reduction in food intake and appetite that occurs. But in terms of a really adverse long-term outcomes, I think that at this point, we don't have anything really to be scared of. But keep in mind, how many patients are on these drugs out 10 years and longer? I don't know that we have that kind of data. I've seen some recent reports where impacts on sexual desire and sexual activity may be a negative and I'm not sure that's not related to the amount of weight loss or expectations or whatever. I'm not sure I've looked at that data carefully, but that's not a long term major impact, but it's like an impact that may be important to some people. I mean, many people perhaps. But I don't see anything that really relates to this. I think the whole issue of cancer incidents, if anything, the data suggests potentially a benefit there, but there's not enough data to say cancer treatment with these agents is beneficial or prevention. But there's a bit of a little hint that colorectal cancer may be in part reduced by people who are on GOP-1 receptor agonists. But to be more direct, I don't as a profit, which I'm not, have anything to say that there's anything to be feared to long-term therapy in GOP-1 receptor agonist. Only fear to me is the pocketbook, but ultimately maybe changes are being made. But by the way, are you a sport fan? I am, yeah. Are you a Lakers fan? I do. I do love the Lakers, yes. Okay, I was at the Lakers Nuggets Game Plus night here in Denver. Oh wow. And you know, they scan with the cameras, the fans constantly. You know, it's amazing how many GOP-1 receptor agonists patients I saw those scanning all the people attending the Nuggets Lakers game. And that's not particular to the Lakers being there. I mean, we talked about 30%. I mean, you know, if you will, if you say preclinical obesity should be treated with weight reducing pharmaceuticals, 70% of the, I guess, urbanized world should be treated with these drugs. I mean, it's an incredible problem we have. I mean, based on what you said earlier, I think you said 50% to 2/3 of the body metabolic disease. Yeah. It would seem, at least from a cardiometabolic disease point of view, that if the majority of people with obesity were taking GOP1 receptor agonists, that death from heart attacks and strokes would be cut significantly. Orchidia disease or end-stage liver disease. I mean, those organs are in a major way affected by this too. And also diabetical edification, which relates mostly to cardiovascular diseases, which we included in all the organ suspension above. Yes, but keep in mind, we have to die of something, don't we? I mean, the question is, is that healthy aging? And I would think we were likely quality of life, healthy aging, with reduced body weight. That kind of data was going to be forthcoming and going to be gathered long after I'm out of here for sure. So we'll have to kind of see whether that's a cost-effective utilization too. Just as long as people, to your point earlier, you emphasized the importance of exercise, but also skeletal muscle in metabolic health, and ensuring that you're protecting that organ during significant weight loss as best as possible. Well, that's another point that maybe I should have mentioned in response to your question a few minutes ago, and that's the loss of lean body mass. I mean, when you lose weight, you just don't lose that weight. You lose maybe up to 25% or 30% of your lean body mass, which is organ weight and muscle. And that's been challenged a little bit in terms of prove the functional effects of that muscle loss during active weight reduction or after GOP1 receptor agus therapy. And by the way, it happens after metabolic surgery also. And I think those are questions that are attempting to be addressed now. So this is a topic for many meetings and has been one of the co-chairs for the Cardinal Ike Health Congress in Boston. That's something we addressed to some extent in last year's meeting. But the muscle loss does concern us. This muscle weakness ensue. That's debatable. And I think we need to understand a little bit more whether that's just an expected physiological change. It's related to weight reduction or something that needs a rehabilitation program to be developed to prevent muscle weakness and loss of function in the setting of GOP1 receptor agus therapy. So back to your question, Simon, I think if that area is addressed as a problem, the loss of lean tissue, then that needs to be addressed. And there are pharmaceutical companies that are developing antibodies now that modify muscle, strengthen function favorably in the setting of GOP1 receptor agus weight reduction. So that's a promising note going forward. But I don't know yet whether we can say for certain that this lean tissue mass is a problem to the patient or his or her outcome. I heard you say a little bit earlier, prevention of occurrence, which gets me to thinking about root causes here. So as an endocrinologist, as a scientist, I believe past president of ADA, AHA and a whole long list of other places where you've been a president, how do you think about preventing the occurrence of excessive out of paucity in the first place? And is that a systemic kind of question related to the food environment? Well, I think it is. And I think controlling government in terms of what food choices are, I think is a place I don't want to venture. And I think the public policy of prevention of excess body weight gain is an important problem. I mean, I often cite tobacco data. And in the United States in the mid 1950s, 50% of adults smoked. In 2024, the less data I've seen, it was 12% of Americans. So it's taken 70 years, ultimately, to reduce tobacco use from 50% of American adults to 12 percent. That's still one out of eight people still smoking is really not good data. But when it was 50%, and it's taken 70 years to go to 12%, take a long time to modify a behavior we don't have to have to begin with. Now preventing obesity is a much more challenging problem from a public health perspective. I think there are a few things that seem to be beneficial. The perhaps eating breakfast has been suggested be beneficial. Family dining in the evening rather than people of getting their own meals at their own schedule. The whole issue of the government's approach to food stamps and the whole SNAP program, et cetera, is another thing we can discuss. And clearly energy dense foods should not be rewarded and they're cheaper. And if you're a sports fan like I am, I work out every morning to sports center. And I mean, there's lots of advertising going on for energy dense foods and they're cheap. So when people are socioeconomically strained in terms of their income and their ability to get fruits and vegetables and whole grains and a healthier dietary quality, then I think we need to have maybe some type of government intervention. I hate to think what that's going to be, but taxing like sugar, sweet and beverages has been really very effective in New York City, I know. Whether that kind of change is important. And is it sugar or is it fat? Energy dense includes both of those, but it's overall calories. We've got to find a way that during growth and development that parents need to take a greater responsibility as pediatricians do to the growth of kids during their early years, particularly young kids during their high school years in terms of high school graduation rates. And for women during pregnancy, you don't need to gain that much weight and put you need to lose it afterwards. I think there are times in life where the healthcare profession could take more responsibility. But you know, in families where there's a bit of strain both because of diversity and socioeconomic conditions, ultimately there's a single parent home. I mean, and mom's working and trying to make ends meet and she got a couple of kids at home and often there's a grandmother or something that's helping out, but those are difficult circumstances. How am I in my current circumstances to comment very intelligently on how to solve those kinds of problems? But I think this is a biggest health policy problem that exists within America. And I think in the world basically, and that's because of the impact of your previous question on excess body weight on so many organ systems that affect quality of life and major events to follow, many of which relate, I'll cause mortality. Well, Dr. Aikle, thank you so much for joining us. This has been a real treat for me. Clearly, you know, I could talk to you all day about this and I'm sure we'll have to get you back on because honestly, I've learned a lot from you. You have such a depth of knowledge and a really clear way of explaining it. So thank you so much for joining us. You're welcome Simon. And I might make one comment when people ask me what I do and I say, well, what do I do? I'm an endocrinologist, but I say, I kind of cross-dress as a preventive cardiologist with my clinic's been in the heart center. I had an appointment cardiology, but here's what I say from a sports metaphor. You know, if you're behind tend to nothing in the bottom of the eighth and your right field or gets injured, I can go out there and maybe play one inning and right field or maybe it's third base or don't put me behind the plate or don't put me on the mound, but I think the utility players, the best description of who I am and what I do. And again, I'm really humbled by the fact that I've had a wonderful career and I thank so many other people for it, but it's not about me. It's about why I have a patient for and why I represent scientifically and medically. And I want to help so many people and I feel so inadequate of helping many, but it's been a pleasure to have the opportunity I've had and I've been very, very fortunate. I like to so many. So I'll end with those comments. Well, thank you. You're certainly very modest and I do have one more question that I want to ask you to lead people with. If we were to finish this conversation with something very practical and it may be something that we've discussed, so feel free to kind of bring back, reintroduce something that we spoke of out. If you had to give people one simple principle to judge whether their body fat is becoming a health problem or one instruction, something that they could go and organize after listening to this episode, what would that be? Or despite all the guidelines that are evidence based scientifically and all of the advice we're getting from multiple channels these days in terms of social, medium, beyond healthcare professionals even, I think ultimately there is a personal responsibility for each and every one of us. And I would encourage people on a daily basis or at least a weekly basis to get on the scale. And I think ultimately we need information going forward that prevents obesity to begin with or at least maintains current level of adiposity without increasing it further to ultimately transition into the clinical obesity phenotype. So we need personal responsibility with all the information that's being guided by guidelines and healthcare professionals to keep herself healthy throughout your entire life period. And that's related to food intake, it's related to physical activity, but it's related to all the things your doctor has measured to assuring they're kept in an optimal range for health and survival. you again in the next episode.