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Ben Bickman (23:55)

Now let's revisit an idea that would normally be surprising and illuminating, but now it's going to make a little more sense. If hypertrophy of the fat cells is harmful, what happens when Fat expands through hyperplasia instead. Well, here is the paradox. A person who gains fat primarily through hyperplasia can be measurably fatter than someone gaining fat through hypertrophy, and yet be more metabolically healthy. This has been demonstrated in elegant animal models, and we see instances of this, of course, throughout all of human biology. In one particularly striking example within the animal models, where we can just do a lot more, of course, to the animals and we can to humans, there were mice that are engineered to expand their adipose tissue through hyperplasia. And no surprise, these mice had both greater total fat mass than control animals when they were forced to get fat with a fat inducing diet. And yet they were just as insulin sensitive as the control or lean animals. Their individual adipocytes were small, and of course there were a lot more of them. And so they were bigger or rather smaller, but more in number. And because of this, the fat tissue, while being of course greater in mass, had very normal vascularity, had a very normal inflammation profile, and were perfectly insulin sensitive. The conceptual framework that has emerged from this kind of research is called the adipose expandability hypothesis. The idea is that adipose tissue has a finite capacity to safely expand. I'm going to revisit this idea in just a moment at the whole body level. But when that expansion occurs through hyperplasia, new small fat cells, the tissue maintains its function and can continue to safely store any energy as fat tissue. But when the capacity for hyperplastic expansion is limited, maybe the person doesn't have the right genetics to stimulate the growth of new fat cells. Then the fat cells must grow through hypertrophy instead, and we have crossed this threshold, the expandability. The tissue, of course, now becomes dysfunctional with the mechanisms that I've noted, where they become insulin resistant to prevent further fat storage, which leads to ectopic fat deposition, and at the same time becomes very pro inflammatory to try to correct the hypoxia. Critically, the subcutaneous adipose tissue, that is the fat just beneath the skin, which is the vast majority of how humans store fat, that usually accounts for about 80 to 90% of total body fat. This is the preferred site because of its potential for hyperplasia. Subcutaneous fat will naturally expand first through hyperplasia. When that capacity is exhausted or they don't quite have the genetic ability to continue to make new fat cells, then hypertrophy takes over in that subcutaneous depot and then we have more of these consequences. Now, visceral fat, which surrounds the abdominal organs, that is the fat Tucked deep within our stomach space within our abdominal cavity that is much more metabolically active and pro inflammatory by nature. And because there is such a limited space within the center part of our body, there's a lot going on there. There's kidneys, there's liver, there's intestines. We don't want our fat tissue to be able to grow limitlessly. It's no surprise as a result of this that visceral adipose tissue will selectively grow through hypertrophy. That is why visceral adipose is such a problem. It's not because of its inherent location, but rather the location determines how the fat tissue will grow. And in this case, it determines, it dictates that the fat tissue grows through hypertrophy. So that is why visceral adipose is more problematic. That's why it contributes more to inflammation and more to insulin resistance. And unfortunately, that fat feeds directly to the liver, meaning that the liver is the first organ to receive not only all of those excess free fatty acids, but also all of the pro inflammatory cytokines that come from it. In my mind, this helps complete the picture. Individuals with a limited capacity for healthy subcutaneous hyperplastic expansion will begin ectopic fat deposition, like storing it in the liver at much lower absolute fat levels or lower fat mass. And this is precisely where we can now talk about ethnicity. So ethnicity enters the enters the story. Now, with these principles in mind, now, before I talk separately about ethnicity, the overall concept that I've been hinting at is sometimes known as the personal fat threshold. I first heard of this term from the work of Dr. Roy Taylor at Newcastle University. And it's his research on type 2 diabetes remission which really sheds some light into the metabolic science on this topic. The personal fat threshold is the idea that every individual has their own maximum capacity for safe subcutaneous fat storage. And once that capacity is exceeded, fat begins spilling over into ectopic sites like the liver, but also the pancreas and others, where it drives dysfunction there. Now, what makes the concept so powerful is the word personal. The threshold is not the same for everyone. It is determined by your genetics, which of course is influenced by your ethnicity, but even also your developmental history, you within your mother's womb and your infancy. But also all of this then touches on the inherent expandability of your adipose tissue in that subcutaneous space. One person may exceed their personal fat threshold at a BMI of 22, while another may exceed it only at a BMI of 35. Both outcomes are Very biologically viable. They're real. And neither is really captured just by stepping on a scale or even just simply looking at the BMI chart. This reframes the entire clinical question. The relevant issue is not whether someone is obese by global population standards. The relevant issue is whether this individual has exceeded their own storage capacity, whether their subcutaneous depot has crossed the line from healthy hyperplastic or small expansion into hypertrophic dysfunction, and then the inflammation and overflow that follows. And this is precisely why the ethnic differences we've been discussing are so important. South Asians and East Asians and Southeast Asians on average have a lower personal fat threshold than Europeans and Africans, not because they are weaker or less healthy, but because their subcutaneous adipose tissue has a more limited capacity for safe expansion. The threshold is lower, the overflow, in other words, and the inflammation happens sooner. And the metabolic consequences arrive at a weight that by say, Western standards doesn't even register as a problem. So different ethnic populations differ substantially and systematically in their capacity for subcutaneous fat storage. South Asians, people of Indian, Pakistani, Bangladeshi and Sri Lankan heritage, have been studied extensively and show what researchers have called the thin fat phenotype. At a given bmi, South Asians tend to have higher total body fat percent but higher abdominal fat and notably less peripheral subcutaneous fat compared to white Europeans. In fact, at the same body fat and weight levels, the average South Asian or Indian has fat cells that are multiples larger than the average white. The person of white European descent. These fat cells can be four or five times larger. Even though you look at the person, they step on the same scales and they weigh the same body mass. It's just this at the cellular level, a fundamental difference in how they're storing fat. The pattern actually appears at birth. Studies using whole body MRI have shown that Asian Indian newborns have higher total adiposity than white European newborns, with disproportionately more abdominal and visceral fat and less non abdominal subcutaneous fat, even when controlling for birth weight. So this thin fat phenotype is present before diet has had any meaningful influence on the individual. So there is genetic predisposition here. But of course we would have to also look at the health of the mother. Now, East Asians, this would be those of Chinese, Japanese or Korean descent, they do show a similar trend, but it's not quite as extreme compared to white Europeans. And I'm only noting white Europeans because that is the ethnicity that's on the furthest other end of the spectrum where there's the greatest potential for hyperplasia. Not too far from the white Europeans across that spectrum would be those of African descent, and then closer to the East Asian realm would be those of Hispanic descent. But compared to the Europeans at the same bmi, East Asians tend to have higher visceral fat for a given total fat mass with less protective subcutaneous fat.

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Skyrizi Patient (34:36)

My perfect day has sand, salt water and friends, but my moderate to severe plaques psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to skyrizi risen Kizumab RZA a prescription only 150mg injection for adults who are candidates for systemic or phototherapy with Skyrizi. Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year after two starter doses.

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Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.

Skyrizi Patient (35:16)

Thanks to Skyrizi, there's nothing on my skin and that means everything.

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Skyrizi Patient (35:24)

Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyrizi to learn.

Ben Bickman (35:38)

When we start to compare all of this, we see that there are fundamental differences at the level of these genes, how much they are expressed and the proteins that come from them. And here is the main point in this topic. If the fundamental problem with fat is not mass being the issue fat mass, but rather fat cell size, then the then certain ethnic groups hit the threshold of safe storage at lower absolute levels of body fat. This would happen at the lower level than those populations who have that higher potential. So across that spectrum, across ethnicities, we have very differing levels of personal fat thresholds. A South Asian person at a BMI of 24 may already have hypertrophic insulin resistant pro inflammatory fat cells and significant liver fat, or while a white European ethnicity at the same BMI remains entirely metabolically healthy because of a greater subcutaneous hyperplasia. So these more abundant but smaller fat cells, and they're operating perfectly normal. This is not just some minor obscure clinical detail. This is a fundamental difference in the relationship between body weight, body fat and the metabolic risk that's associated with it. Now this brings us to one of the most practically important consequences of everything we've discussed so far, the inadequacy of a single universal BMI cutoff for defining obesity and metabolic risk. The World Health Organization established the standard BMI cutoffs 25 for overweight, 30 for obesity, but this was primarily derived from data from European populations, although these thresholds aren't too bad either for those of African descent because of the general similarities in the way in which both ethnicities store fat. But for many decades these cutoffs were applied universally regardless of ethnicity. But research has now demonstrated unambiguously that these cutoffs are not appropriate across all ethnic groups. A landmark population based cohort study was published in a very good journal, the Lancet Diabetes and Endocrinology Journal, and it calculated ethnicity specific BMI cutoffs for obesity based on equivalent risk of developing type 2 diabetes. The findings were striking but not surprising to you at this point. For South Asian populations, the BMI cutoff equivalent to a BMI of 30 in white Europeans was only 23. For Chinese and Arab populations it was 26. This means a South Asian person with a BMI of 24, which would be classified as normal weight by standard criteria, faces a diabetes risk equivalent to a white European person with a BMI of 30. A multi country study, which was coming from the UK Biobank as well as the China Health and Nutrition Survey as well as the Singapore Chinese Health Study, confirmed and extended these findings across sexes and multiple Asian subgroups, showing that Singapore Chinese women, for example, require a bmi cutoff of only 25 to match the diabetes risk seen at a BMI of 40 in white European women. The practical implications are profound from this millions of Asian individuals are being classified as metabolically normal when they are not, simply because the measuring stick being used was calibrated on a different population. And the reason BMI fails so badly here is precisely because BMI doesn't tell you anything about fat cell size, fat distribution, or the capacity of that person's fat to safely expand. It only tells you about total mass relative to height. That is, after all, how BMI is determined. Two people with the same BMI can have entirely different metabolic fates depending on whether their fat is distributed subcutaneously in small, healthy, yet even abundant hyperplastic cells, or ectopically and viscerally because of large and maybe fewer hypertrophic insulin resistant fat cells. Some researchers have argued that waist circumference or waist to hip ratio, or direct measures of visceral fat are better predictors of cardiometabolic risk than BMI across all ethnic groups. That is a sentiment, of course, that I agree with completely. Now, how can you know whether you have large or small fat cells, sad or happy fat cells? Now, of course, in my lab, you could come in and we would take a fat biopsy, but nobody is lining up for that. And because of that, I want to leave you with two practical, accessible clinical markers, one being a little more accessible than the other, but both being a little obscure, unfortunately. So we are certainly at this point stepping into the realm of the academic mind. But come there with me anyway. The first is the adiponectin to leptin ratio. You've certainly heard of leptin. You might not have ever heard of adiponectin, although I've talked about it previously. Adiponectin is secreted by small, metabolically healthy adipocytes, and adiponectin has numerous or myriad healthy benefits. It promotes insulin sensitivity, it is anti inflammatory. Leptin is secreted in proportion to fat mass, and thus it rises dramatically as fat mass goes up, even as fat cells get larger. So in hypertrophic obesity, adiponectin falls and leptin rises. So the ratio of adiponectin to leptin drops sharply. And research has shown that this ratio correlates meaningfully with insulin sensitivity, visceral fat accumulation, and all the markers of the metabolic syndrome. And it's a much better predictor of someone's general direction of metabolic health than BMI or even waist circumference. So you're adiponectin to leptin ratio. Unfortunately, there are not clear cutoffs for that. It would just be a matter of of you getting it measured one time. If you could convince your clinician to measure either of those two hormones and then comparing the trend over time. The second marker is the adipo IR index. It's the adipose tissue insulin resistance index. And it's circulated simply as fasting insulin multiplied by fasting free fatty acids. The elegance of the formula reflects everything we've discussed today. In healthy adipose tissue, insulin potently suppresses lipolysis and keeps free fatty acids low. But when fat cells become hypertrophic and insulin resistant, that suppression fails. We've talked abundantly about this. That means insulin rises as as the body's becoming insulin resistant. But at the same time, free fatty acids are also going up because of the failure of the anti lipolytic break that insulin normally activates. The product of those two values, insulin and free fatty acids. It therefore captures, when you put it together into a single number, the degree to which adipose tissue has lost its normal insulin sensitivity. I confess the adipo IR index is perhaps my most beloved of all metabolic markers because it is such a beautiful indicator of the elegant system of the fat cell and insulin attempting to control what the fat cell is doing. But both of these measures, the adiponectin to leptin ratio or the adipo IR index, they'll tell you something about what your fat cells are doing. They'll tell you about the size of the fat cell. Now, one note on the adipo IR index, another reason why I actually adore it, is that it has very sex specific cutoffs, which is another reflection of the difference in physiology in this case between men and women. Men will show more severe adipose insulin resistance and obesity, driven in part by just the degree to which or the mechanism in which men store fat. Men will generally store fat more through hypertrophy than women. So women will have more but smaller fat cells. And because of those smaller fat cells, all of which is a result of the different, the differences in sex hormones, women naturally have much higher levels of free fatty acids than men do. Now again, I said naturally. And so an adipo IR index looking at insulin and free fatty acids in a man should not be compared to that of a woman because she just naturally has much higher levels of free fatty acids. Women, did you know that you're just releasing and burning a lot more fat than your male counterparts are at any given moment? Because of this, in women, you have an ADIPO IR index score of about 5.9. That's generally the range of what's considered a normal level. But in men it's less than 4, it's in the kind of mid threes. And again, it's because women naturally have higher levels of free fatty acids. So we have to account for that when we compute the adipo IR index. In the end, the question isn't only about how much fat a person is carrying, it's not an issue of fat mass. The question is how big are your fat cells? Well, that wraps up today's mini lecture on ethnicity, body fat and some deep dive into adipocyte biology. I hope this gives you a new lens which to view metabolic health, one that goes well beyond the scale and the BMI chart. If you found this helpful, of course share it with someone who needs to hear it, even if it's of course a friend, but maybe a clinician or a fellow patient and they've been told their labs are fine but their waistline isn't. Try to look at some of these other clinical metabolic markers and understand more of what's going on in your body. The science here is increasingly clear. It's not the mass of fat that matters most as we try to understand the obesity burden and its consequences across the globe. It's the size of our individual fat cells. Thanks for joining me today on the Metabolic Classroom. Remember, more knowledge, better health.

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Skyrizi Patient (46:32)

My perfect day has sand, salt, water and friends. But my moderate to severe plaque psoriasis can take me out of the moment. Now I'm all in with clearer skin thanks to Skyrizi Risankizumab RZA a prescription only 150mg injection for adults who are candidates for systemic or phototherapy with Skyrizi, Most people saw 90% clearer skin and many were even 100% plaque free at four months. Skyrizi is just four doses a year after two starter doses.

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Don't use if allergic to Skyrizi. Serious allergic reactions, increased infections or lower ability to fight them may occur before treatment. Get checked for infections and tuberculosis. Tell your doctor about any flu like symptoms or vaccines.

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Thanks to Skyrizi there's nothing on my skin and that means everything.

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Nothing is everything.

Skyrizi Patient (47:20)

Ask your doctor about Skyrizi, the number one dermatologist prescribed biologic in psoriasis. Visit skyrizi.com or call 1-866-Skyrizi to learn more.

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