158: Why Some People Stay Thin No Matter What They Eat

We all know someone who seems to eat whatever they want and never gains weight. But there isn't one explanation for that. There are a few, and they don't all mean the same thing. For some people, the fat from a meal goes into muscle and gets burned instead of going into storage. Your body has a system that decides which of those happens, and it works differently in different people. For others, the extra energy simply gets burned off through everyday movement they don't even realize they're making. Fidgeting or standing or pacing, for example. That alone can account for a surprising amount. And then there are people who really are storing fat. They're just storing it where you can't see it— in the liver, the pancreas, and around the organs. Two people can be equally lean on the outside and have completely different metabolic health on the inside. So the mirror and even the scale don't tell the whole story. Fasting insulin or triglycerides and HDL levels and visceral fat can reveal risks that appearance alone may completely miss. Being lean can be healthy, but it isn't automatically proof of metabolic health. This is Lecture 158 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Everyone knows someone who eats terribly and stays lean, and that person is usually presented as some kind of evidence against a lot of what you might have heard me talk about on this show previously. The fundamental rules of metabolism— are some people breaking it? Well, there is in fact something real here, but it isn't a single cause that's driving these sorts of differences that you might see between people. In fact, as I was exploring this topic, I think that there are 3 different things that can be going on, and they have very different implications for any random person that they're happening to. All right, so let's get started. There is more than one answer here when it comes to explaining why some people can be thinner than other people despite seemingly— emphasis on seemingly— eating the same way or having the same habits. When we call someone thin, we are obviously just describing the fat that is sitting in the subcutaneous layer, that fat that's just beneath the skin, what the fat that we can see it, we can pinch it, we can jiggle it. But that's really just the fat that's kind of on display, if you will. It tells us how much fat a person stores in the one place we can look and nothing about how much they store anywhere else. Of course, subcutaneous fat isn't the problem when it comes to health in the right amounts and in those right places. It's actually part of optimal metabolic health. It's the tissue that is built to hold fat safely, and it keeps holding fat, and it allows that fat to not be circulating in the blood. But also, that healthy fat storage depot will, will release favorable hormones like leptin and adiponectin. So when someone eats poorly and stays lean, we shouldn't leap to any kind of single conclusion or single explanation. The energy or calories from a meal, it has more than one destination. It can be pulled into fat tissue and stored. It can be pulled into muscle and burned, or it can be burned or dissipated through movement that the person might not even know they're making. And it's only really the first of those that results in fat accumulating, and it's the one everyone assumes is happening. So I want to start with the other two that I just mentioned of the three, because they're both not only very real, but they also have an enormous variety between individuals. The most important variable is not how much fat someone eats, really, but which tissue claims it. And that comes down to a single enzyme. When you eat dietary fat that comes in, the diet is then packaged in the guts into these really big lipoprotein particles like chylomicrons, and then it's released into the bloodstream. Those particles are too large to enter tissues on their own. So any tissue that wants that fat that was just consumed has to reach out and grab it. And it does so through the actions of an enzyme called lipoprotein lipase. And that lipoprotein lipase, or LPL, is anchored on the inner surface of capillaries. Now, you'll recall capillaries are the smallest operating unit of the blood vessels. It's the, the blood vessels that are actually penetrating and permeating through all of our tissues. And this enzyme, LPL, will cleave the triglyceride molecules in that passing lipoprotein particle, thereby liberating the fatty acids. So it's pulling off the individual fatty acids from the triglyceride that's in the lipoprotein, and then that tissue where the LPL is residing, is able to pull that fatty acid into that— into itself. Now, fat tissue has that enzyme, of course, but muscle has it too. In fact, other tissues do too. Um, but I'm going to focus on these main two tissues because they're so different in their function— fat tissue and muscle tissue. So the fat in your— from your bloodstream can end up wherever the enzyme is most active. Fat tissue uses those fatty acids for storage. Of course, muscle, not surprisingly, will mostly burn that fat tissue. The relative activity of one enzyme in these two different tissues is sort of a switch that will determine whether the fat from your last meal gets stored or gets burned. And it won't surprise you at all coming from me to learn that insulin heavily controls that switch. In fat tissue, insulin increases the enzyme's activity, opening the door for storage. In muscle, insulin tends to do the opposite. Human studies that have used control ins— controlled insulin infusion show muscle enzyme activity dropping by roughly a third within hours of increasing insulin, and the size of that drop tracks with how much glucose the muscle was taking up at the same time. That makes some physiological sense. Insulin is essentially announcing to the muscle that glucose is available and the muscle shifts its fuel preference toward glucose and away from fat. That's, I think, just further evidence of the insulin control over the Randle cycle. That's a bit of a tangent though. So the rise that we see, the increased activity of LPL on the fat tissue side is slower than, than we might often consider it to be. So these same kinds of studies that these clamp studies, it's called, where they're infusing insulin during that acute state of just a few hours, the insulin isn't really affecting LPL and fat tissue, but it does later. So this operates kind of across a whole meal and even between meals rather than within the meal itself. Now, importantly, back to the topic, um, that balance between LPL activity and expression can differ The, the balance between muscle and fat tissue will differ between people. That, that's a ratio of how active is LPL at the fat versus how active is it at the muscle. But that ratio isn't fixed, or it's not set. Um, one particular study, these, that I want to highlight is one where the researchers had 16 trained runners and they had them stop training for 2 weeks. And they did a biopsy of their fat and a biopsy of their muscle before and after the cessation of training. Muscle LPL activity dropped sharply. Interestingly, fat tissue LPL enzyme activity went up. The ratio of fat activity to muscle activity went from about 1/2 while training to roughly 4.5 after 2 weeks off. So that's an 8-fold shift toward storage rather than burning in the same 16 study subjects. Now, resting muscle activity varies between people in ways that do show up in whole body fuel use. In one particular study found that in patients who spent a full day in a metabolic chamber and they measured— in the study they measured fuel burning or fuel oxidation, uh, continuously during this period of time. Those with lower muscle LPL activity burned proportionally less fat across 24 hours. And in the same population, a low ratio of fat to carbohydrate burning has been shown to predict weight gain years later. This is— this happened independent of how much energy the person was expending in total. Now, building on that, the responsiveness of the switch tends to predict long-term fat accumulation. In another study, investigators took 39 adults through 2 weeks each on a higher carbohydrate and a higher fat, lower carbohydrate diet, but matched in calories. They biopsied fat tissue, they biopsied muscle, both in a fasted state and 6 hours after a meal, then they tracked body composition annually for 4 years. So they were looking over time at how much fat these people tended to gain or not gain. Interestingly, what predicted the 4-year fat gain wasn't the fasting enzyme level, but the change after the meal. People whose fat tissue enzyme activity climbed after the carbohydrate-rich meal gained more body fat over the following 4 years, and people whose muscle LPL enzyme activity fell after that same meal gained more, um, gained more fat mass. So, uh, interestingly, neither of those changes in muscle or fat enzyme activity were different after the higher fat diet phase. So we could have two people eat an identical meal. In one, that meal could flip the LPL activity in fat tissue, so flipping the storage switch. In the other, it may barely move. In that fat tissue storage switch. So this kind— this is kind of a partitioning phenotype or, or body that's shaped by, yes, genetics, but also by insulin responses, but even by how much a person moves, which is the next thing I want to get into. So the second explanation for why some people seem to not gain as much weight as other people despite eating the same is that some people dispose of surplus energy unconsciously rather than storing it. So let's start with, um, sort of as I, as I generally talk about the ability of a person to burn off that excess energy before I get to the physical activity component, I just thought it would be prudent to mention thyroid hormone. Thyroid hormone is a very popular topic and rightly so. Thyroid hormone is indeed a strong metabolic signal. Among healthy people whose thyroid labs are entirely normal, there's a lot of variation, and it does relate to metabolism. In a study of 89 euthyroid adults— so people with normal thyroid levels— that were in a metabolic chamber, those with higher free T3, which is the main active form of the thyroid hormone, people with higher levels of free T3 had higher sleeping metabolic rates and burned more fat, and those with lower free T3 went on to gain more weight over time with follow-up studies. Interestingly, free T4, which is the less active version of thyroid hormone, is sort of the pre-activated version. Unfortunately, that's the number that most clinicians actually measure. They don't often measure T3 for some bizarre reason. They measure T4, but the T4 levels didn't have any kind of relationship with any of this at all. But I should note, in this study, even though the thyroid— the free T3 levels were statistically related, it wasn't, it wasn't overly meaningful. It was a small effect. So I don't think it can feasibly account for the difference between the friend who eats whatever he seems he wants to versus the one who can't. The variable that likely matters most when it comes to burning off excess energy is actually more boring, and some may say it's controversial. In a study of 16 non-obese individuals, they were overfed 1,000 calories a day above maintenance for about 2 months under strict supervision. Fat gain varied more than tenfold between these people as they looked at all the variety of these humans. Some gained barely a third of a kilogram over these 2 months despite eating 1,000 calories over their baseline, while others gained more than 4 kilograms with the same additional calories. So where was that fat going in those who gained less than a half a kilogram? Two-thirds of the increase in total daily energy expenditure came from movement that isn't exercise. So this is things like fidgeting, or just moving, shifting their posture a lot during the day, or standing more frequently, or even pacing. All of these activities that the people wouldn't have even accounted for and weren't even mindful of. What's important here is to you, for you to appreciate the magnitude of this. That component, that, um, unaware activity rose by nearly 700 calories a day in some individuals, and in others it fell, and it alone predicted this, this degree of resistance to fat gain with a correlation point, uh, correlation statistics that were very, very high. So let me just reiterate that point because it actually does seem to be among the biggest and thus most relevant points when you're trying to understand why is it that this person can't seem to indulge as much as another person. Well, a lot of that indulgence appears based on their movement. They're not tracking it. They can't really, uh, they wouldn't be conscious of it. They're just, they're fidgeting more, they're moving more. And again, in some people that went up by over 700 calories a day, and some people that went down by a couple hundred calories a day. So as they started eating more, they were less mobile and less active. And again, not in a way that your exercise tracking watch would necessarily be detecting. Okay, now still before I leave this subtopic of just people who burn more energy, I thought it would be helpful to just explore the question of how much of this may be inherited. We, we are able to answer a little bit of this because of identical twin studies. So a similar study to the one I just mentioned with the overfeeding, it, it looked at this same overfeeding strategy in 12 pairs of identical twins. Weight gains ranged from 4 to more than 13 kilograms, and twins tended, no surprise, to resemble their own sibling far more than anyone else. So roughly 3 times as much variance was between pairs as within the pairs. And when you looked at the visceral fat specifically, it actually went up even more. And we're going to talk more about visceral fat, but then there 6 times as much variation between the twins, the sets of twins, rather, rather than, or when compared with the twins, twin to twin within the same little pair of twins. I hope I've explained that in a clear enough way. So in other words, this does suggest that it is, uh, it does seem to be an inherited pattern, that if one— although of course with identical twins they're closer genetically, they're identical, than siblings are— but even still, it would suggest this familial pattern that the— a sibling and a sibling are— if one sibling tends to be kind of lean, so too is likely the other sibling. Then compare that family of siblings to a different family of siblings, and you're going to see much more variety between those two families than you would see, say, within the same family. Now finally, in this subtopic, there's also the least glamorous and maybe most anger-inducing explanation of all: our perception of what we eat is unreliable. My old dad, old Papa Bikman, once told me that humans are great self-deceivers. I think you see that in a lot of ways in life, including when people are reporting what they eat or what they think they eat. Using doubly labeled water, which is the gold standard for measuring metabolic rate, in people that are free living, so not getting them locked in a metabolic chamber. A group reporting around 1,000 calories a day was measured taking in roughly twice that. So they were underreporting their caloric intake by, by about half while their metabolic testing came back totally normal. This is a very inconvenient truth. The person that you watch eating an enormous lunch may be eating very little at any other time of day. I mean, they're not thinking about it. Conversely, someone that you may see who's nibbling through the day may be more than making up for it, so making up for it and then some, every single evening. But they might not be able to even articulate those kinds of differences. So I'm not necessarily presenting this that a person is deliberately deceiving themselves or deliberately deceiving the scientists who are attempting to track what they're eating. It may be operating kind of below that level. They're not consciously eating more than they think they are, or the other person's not consciously actually eating less than they think they are. But it is something that is real and probably matters more than most people would like to think. Now let's move on to the next explanation. Some lean people genuinely aren't accumulating fat. That, that's true. So they're partitioning it towards burning, sending it to the muscle, or they're just sort of twitching more of it off with this, this level of physical activity that they're not really tracking, or they're just not eating as much. But of course, some people are storing the fat. They just may be storing it where you can't see it. Imaging work out of a group in London measured separately the fat inside the abdomen, so that visceral fat, surrounding the organs versus the fat in the subcutaneous layer and the fat stored inside liver and muscle. Then they compared people matched for age and sex and body mass index, and in many cases even comparing for total body fat percentage. The variation between where these people were storing fat was enormous. For example, two men of the same age with the same body mass index and the same body fat percent could differ by several kilograms in the fat that is packed inside the abdomen. So that visceral space— from this work came a phenotype that the researchers named thin on the outside, fat on the inside. And they— this was defined by an unfavorable ratio of internal abdominal fat to subcutaneous fat in someone whose body mass index may be within the normal range. In their cohort, roughly 1 in 7 study subjects and 1 in 8— so it was actually 1 in 7 men and 1 in 8 women with a normal BMI met that definition where they were excessively fat on the inside versus the outside. So take any— now that matters again because this is someone that you could look at and think that they're leaner than someone else. So take any group of normal weight adults And somewhere between 12 and 15% are carrying their fat burden internally, which of course carries a much higher metabolic risk. So they might not look like they're as fat as the next guy. So no one is necessarily going to tell them, hey, you need to, you need to lose weight. No one's going to order all of these better blood tests like fasting insulin or look at the triglyceride to HDL ratio. Because they look like they're metabolically sick. So the, the physician will see a normal BMI and just move, move on and, and sort of give the study— give the patient a clean bill of health. So this is what I mean when I say that not being able to pinch it or jiggle it doesn't mean you aren't storing it. But again, please appreciate why I am mentioning this here, because the overall topic right now is why is it that some people can eat whatever they want and stay lean? Well, maybe they aren't staying lean. Maybe you're just not able to pinch it or jiggle it or see it as easily as you think. Maybe they're just storing it somewhere else. All right. Now, why would fat end up in these other places like the liver rather than under the skin? This is a concept that we've discussed previously, but it is appropriate to mention it again, which is the personal fat threshold. Every individual has a ceiling for how much fat they can store safely in their subcutaneous fat. Below it, below that threshold, metabolic health is preserved. That whatever amount of fat they're storing, it's not gonna be adversely affecting their health. But the moment they start to surpass their ideal threshold, which is very individual, then those fats are spilling out of the fat tissue. But remember, all in the midst of elevated insulin. That's the critical thing. When fat is releasing its fat, yes, it could be burned by the muscle very happily. Or burned by the liver or burned in the pancreas or any tissue that wants to burn fat. But when insulin is high, those tissues cannot burn that fat. It's locked in. So the tissues are force-fed that fat and they can't do anything but store it. Now that ceiling, that threshold is, is, is personal. That's why that adjective is used in describing the personal fat threshold. So it's not like you can make population descriptions or, or general ratios here.. It's not a body mass index cutoff. One person will cross that threshold at a body mass index of 38 and another one, say, at 22. This is a lot of the difference when it comes to ethnicity. Whereas you could have a white European Caucasian who is designed genetically to store more fat in a healthy way. They may be the one whose optimal kind of threshold happens at their BMI of 38, whereas you have someone of East Asian descent. Who has a very low threshold, they get to that BMI level of 22 and now they've already reached their threshold. Of course, much of what determines that threshold, that ceiling, is how their fat tissue grows. And I'll be brief here because it is something I've discussed in much more detail previously. There are two ways to accommodate fat storage. The existing fat cells can swell, each taking on more lipid and getting larger. That's hypertrophy. Or the tissue can recruit new cells. So they expand the adipose capacity, um, rather than stretching each cell, just rather than by increasing the number. So both can produce the same number on a scale, but you can get radically different metabolic outcomes. A fat cell that keeps enlarging will eventually fail. And this is again, part of the topic where some people can appear to be leaner. Uh, if you have someone, and this is a paradox, so I wanna try to explain it clearly. If you have a person whose fat tissue grows primarily through hypertrophy, they will actually have a lower cap on how much fat they're going to be storing. So they— this is the person you could look at and say, well, that's not fair, they're leaner than me and they're eating the same way I am. It's because if their fat cells are only growing through hypertrophy, they actually have a limited capacity. But again, the consequence of that is that while they may not be storing their fat tissue, their fat in their fat cells, now they're storing it somewhere else, um, even in the visceral space or in the other tissues that I've mentioned, like the liver. You can even store it in, in, in muscle. You can store it in the pancreas. Your kidneys can get fat. You're storing it elsewhere. And of course, that's, that's the phenomenon of ectopic fat storage, and it is not ideal for long-term metabolic health. We do have direct human evidence that this, that these, that the differences in fat cell size really do matter for long-term health. Studies that have looked at fat biopsies have measured the size of these fat cells, and they found that even after adjusting for age and sex and total body fat percent, average fat cell size was about 20% larger in those with diabetes and in similar range in those with prediabetes or early insulin resistance. And, and similarly, when you look at, um, these— the fat cell size, if these— when these scientists followed the normal glucose group for an average of more than 9 years, the fat cell size is largely what predicted who had an adverse change over time versus not. Now remember, that is not That is not something that a measurement of body fat percent is going to tell you. You have to know the specific size of the fat cells, which of course the average person can't know. All right. And this is— here's the final thought for why someone seems to be able to indulge more than someone else and not gain the fat. Maybe. But, but when you can't see it, though, it's very possible that the friend who is indulging is actually storing fat. So just to wrap up this thought, but they're not storing it in their subcutaneous fat tissue. In fact, I'll never forget the conversation I had with a friend years ago, always a very lean person, and he would always drink a lot of sugary soda. And his wife was bemoaning the fact that he was able to indulge in this very unhealthy habit and still stay lean. And I said, the bill comes due. That you might not be storing it in your subcutaneous fat, but you are storing it somewhere else. And of course, fast forward a few years and he was diagnosed with fatty liver disease. So you're going to store it somewhere in some of these people. All right. In closing, as you can tell, there's no single reason a person eats badly and stays lean. Some are sending some of that excess fat to the muscle to be burned instead of for storage at the fat tissue. Some are burning off. Surplus energy through movement they don't even know they're making. Some are actually eating less than they think they are. Conversely, some are eating more than they think they are. And some are lastly just storing that fat in a place nobody can see, so they look leaner. The problem, of course, is that all four look the same from the outside. If you're the lean person eating whatever you want, your appearance isn't necessarily giving you a clean bill of health. So you cannot rely on the obvious signs of body fat as your metric of health. You gotta do some of the things like I mentioned earlier, get your fasted insulin levels checked, look at your triglyceride to HDL ratio. And if you're the one who is watching a friend eat whatever she wants while you feel like you gain weight from just smelling a freshly baked loaf of bread, what you're seeing is maybe just a difference in fuel partitioning and storage capacity, or even something as boring as some unintentional movement. Class dismissed. Until next time, more knowledge, better health.