156: Visceral Fat - The Hidden Fat That Drives Insulin Resistance

This is Lecture 156 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. Today we are talking about visceral fat. Now, you've probably heard that before. That is the fat that is stored deep in the abdomen, and it's tucked and woven around our organs. And among all the places the body can store fat, this is the depot that is most tightly bound to metabolic disease, and understanding why it behaves the way it does tells us a great deal about not only insulin resistance but also fatty liver disease and even chronic inflammation, these things that really run underneath so much of what we call metabolic dysfunction. Let's begin with what visceral fat is and where it's located, because the location is important. When most people picture body fat, they think of the soft layer of fat just beneath the skin that you can pinch and jiggle. And that is subcutaneous fat. That's the largest fat depot in the body. And as we'll see, it's the safe one. Visceral fat is different because it's inside the abdominal cavity. It's wrapped around and woven between digestive organs. It's spread across the intestines, or it's weaving through the gut, and it's packed around the kidneys. Now, you can't pinch this. And a lean-looking person can carry a surprising amount of it hidden because it doesn't show. This is also why body weight and even waist size can be a little misleading. A person can look lean with little fat under the skin and still carry a heavy load of fat packed around the organs, a pattern sometimes described as thin on the outside but fat on the inside. And the hidden visceral fat carries the metabolic risk. That the, the mirror or the even sometimes the measuring tape won't reveal. What sets this depot apart more than its position is its plumbing, if you will. The blood that drains from visceral fat does not return straight to the general circulation the way blood from your subcutaneous fat does. Instead, it empties into the portal vein. That is the blood vessel that carries everything absorbed from the gut directly into the liver before it reaches the rest of the body. So whatever visceral fat releases, whether it's fatty acids or whether it's other signaling molecules, the liver sees it first and it sees it at a very high concentration before that material is then diluted into the broader, wider bloodstream. That is an important point, and we'll return to it when we talk about fatty liver in, in a moment. And it's indeed a topic I've discussed recently. But this is why visceral fat earns its reputation. When researchers carefully separate the contribution of visceral fat from subcutaneous fat, comparing people matched for overall fatness but differing in how much visceral fat they carry, visceral fat consistently tracks more closely with all of the bad things: insulin resistance, abnormal blood lipids, in the general cardiometabolic risk, and that it does so at a much, much higher relevance or statistical significance than subcutaneous fat depot, even though the subcutaneous fat depot is much bigger. It's a much larger depot. Well, it's larger, but it is more benign. So it's not the amount of fat alone that predicts metabolic trouble, but where that fat is placed. And visceral fat is placed in the worst possible spot. Now, that raises an obvious question: why does the body keep fat here at all, and why do men tend to accumulate so much more of it than women? Well, visceral fat is not a mistake. It is a fast-access energy sitting right next to the liver and richly supplied with nerves and blood vessels, and it's built to be filled and emptied quickly in response to the body's moment-to-moment demands. The— this feature then that makes it metabolically active, it is— it's responsive in its direct line to the liver, but it's also what makes it kind of dangerous if it gets too big. It is useful in small amounts, but it is harmful in excess. The sex difference is striking, but it is also very consistent. Men and women after menopause deposit fat preferentially in this abdominal space, the pattern we describe as apple-shaped, while women in their premenopausal years deposit fat preferentially on the hips, buttocks, and thighs. That prototypical pear-shaped pattern. Women carry more total body fat than men on average, yet they carry far less of it viscerally And this lower body subcutaneous storage is part of why premenopausal women are comparatively protected from the metabolic consequences that the same quantity of fat would bring in, uh, man. Of course, the difference is due to differences in sex hormones. Estrogens reduce fat storage in the visceral depot and favors selectively storage in the lower body subcutaneous tissue, while testosterone kind of works in the opposite. It reduces fatty acid uptake into those lower body or even generally the subcutaneous fat, and it allows it to then be stored more, um, viscerally. So it's not to say that testosterone directly promotes visceral adipose, it's just more that it selectively prevents more subcutaneous fat. And so if the man has a greater pressure to store fat on his body because of the com— combination of elevated insulin and sufficient calories, then he's just going to be st— storing more in his visceral space. Again, it's not because of a preference per se, but rather that being the only viable alternative. The clearest demonstration of estrogen's role is what happens when it's gone. As women pass through menopause and estrogen levels drop, body fat literally redistributes away from the hips and thighs and toward the abdomen and visceral fat climbs even when total weight doesn't change so much. The pattern shifts toward the male distribution precisely as the hormonal restraint, if you will, is lifted. And that tells us that this is hormonally driven rather than a plain consequence of aging or weight gain. So the depot exists as a rapid response energy reserve And the sex hormones largely decide how much of the body's fat ends up stored there. Now let's get to the heart of why visceral fat causes harm. And it starts with how the depot grows. As you've heard me explain previously, fat tissue can expand in two ways. It can recruit new fat cells from a pool of precursor cells, thereby adding more cells to share the fat load. We call this hyperplasia. Alternatively, fat tissue can enlarge the fat cells that already exist, packing more fat into each one. We call this hypertrophy. These two routes are not metabolically equivalent, even if the scale or the body fat measurement would say that it is. When fat expands mainly by adding new But small cells, the tissue tends to stay healthy and insulin sensitive and even anti-inflammatory, literally secreting anti-inflammatory hormones. When it expands through hypertrophy, the tissue tends toward dysfunction. Visceral fat leans more toward the latter route. It leans more toward hypertrophy. It relies on hypertrophy, and people whose fat expands this way They produce fewer fat cells over time and show greater insulin resistance than people whose fat cells are expanding or the fat tissue is expanding through hyperplasia. This matters because an enlarged fat cell is a problematic fat cell. It's misbehaving. It's stressed. As visceral fat swells, its behavior changes in ways that are independent of how much total fat a person carries. In one group of people studied across a wide range of body sizes, the enlargement of visceral fat cells specifically predicted cardiovascular risk even after accounting for overall fatness and fat distribution, which means the size of the fat cell itself, not just the quantity of fat, carries or explains the metabolic risk. The most consequential change in an enlarged visceral fat cell is that it becomes resistant to insulin. To understand why that's a problem, remember what insulin normally does to fat tissue. One of insulin's most important jobs is to restrain or inhibit the breakdown of stored fat. When insulin is present, it holds the fat cell's fat or lipid in place, and it suppresses the release of these fatty— as fatty acids into the blood. So insulin here is acting as a storage signal. It's inhibiting the fat cell's lipolysis, or the breakdown of its contents. But the enlarged insulin-resistant visceral fat cell stops listening even when insulin is high, as it is, of course, throughout much of the day. And someone with insulin resistance who is eating the conventional high-carb diet, visceral fat keeps releasing fatty acids that insulin should have suppressed. Now, decades-old human work showed this directly. The breakdown of fat in visceral tissue is harder to switch off with insulin than the breakdown of fat in subcutaneous tissue. So visceral fat leaks fatty acids under conditions where other fat depots would stay quiet. Now, where do those escaping fatty acids go? They have to be dealt with somewhere. And when they aren't being held in the fat cell, they spill into tissues that were never meant to store much fat. The liver, the pancreas, and the muscle in particular. We call this ectopic fat storage, where fat is deposited in the wrong place. Anytime you hear that term ectopic, you think of something where it doesn't belong, and it can be a contributor to insulin resistance. The liver is the first and most exposed target. Of course, that's due to the blood flow. When researchers trace the actual source of fat that accumulates in people who develop— who are developing fatty liver disease, the single largest source is sugar converted to fat. It's not even dietary fat. It's the fatty acids arriving from the breakdown of stored body fat. And of course, that means the, the visceral fat. So the majority of the fat building up in the liver, it came from lipolysis of adipose tissue in the midst of elevated insulin. Now, I mentioned some plumbing earlier because visceral fat drains directly into the liver at high concentration before it goes to the rest of the body. The, the, that, that portal pathway, that portal vein explains why the visceral fat is so relevant to fat accumulation in the liver. Now, it's important for me to reiterate the leaking of fat in the midst of high insulin. When, when the liver sees elevated fatty acids, it would have the option of burning those fats. And in fact, after all, that's where ketogenesis is coming from, where the liver is seeing a lot of fat or in the form of fatty acids. But because insulin is low, the liver is able to burn those fats, and it does so very happily. And in fact, it can burn so much fat that it starts generating ketones. But if the fat is releasing fatty acids and insulin is high, the liver does not have the option of, of oxidation or burning those fats because insulin is inhibiting the fat burning. It's inhibiting ketogenesis. So the liver is being force-fed these fats and it has nothing to do but store them because insulin won't let it do anything else. All right. Now, this insulin resistance of the growing fat cell, the fat cells getting so big that it stops listening to insulin to, to ensure that it doesn't grow even bigger. That's part of the problem. But there, as I noted, is a second consequence of the fat cells getting too big. And it manifests inside the cell as the hypertrophic visceral fat cell outgrows its own blood supply. A fat cell can only enlarge so far before it pushes the surrounding capillaries, which is that smallest blood vessel. It pushes them too far away to keep the cell itself adequately supplied with oxygen. Beyond a certain size, the interior of the fat depot starts to become hypoxic, or it suffocates. It's starved of oxygen. And this is a particular problem in the visceral depot, again, because of the selective growth through hypertrophy. This was first demonstrated in animal models of obesity, where the expanded fat tissue showed clear regions of low oxygen, and the cellular response to that low oxygen has been confirmed in human fat cells as well. Now put yourself in the position of that oxygen-starved fat cell. From that cell's point of view, the correct response to running low on oxygen is to call for more blood supply. And this is exactly what it does. The hypoxic fat cell ramps up the production of signaling molecules that summon new blood vessel growth. Chief among these signals is vascular endothelial growth factor, sometimes just known as VEGF, V-E-G-F. And all of this it does in an effort to restore its own circulation. This is an adaptive move. The cell is trying to fix its oxygen problem by recruiting the vasculature that it needs. But here's the problem. That same low oxygen program that is driving the cell to try to recruit new blood vessels also switches on a broad inflammatory output. It starts to— when, when the fat cells are made hypoxic, they don't only release the vessel growth signal, they simultaneously raise the release of inflammatory messengers and turn down the production of anti-inflammatory hormones. So the cells attempt to rescue its blood supply, and it's, uh, ends up shifting the whole body into a pro-inflammatory state. So that, that call for new blood vessels is, is not only often insufficient in the first place, but the corrections in this correction. So the fat cell is growing, it's pushing itself too far and its neighboring fat cells too far from capillaries. So it starts releasing this whole catalog of pro-inflammatory cytokines, all in an effort to correct its blood flow. Even if it does correct some of that blood flow, the rest of the body is left to pay the price. So this— because now the rest of the body is flooded with these pro-inflammatory cytokines, these signals. This is a large part of how excess visceral fat produces the low-grade systemic inflammation that accompanies becoming overweight and metabolic disease. The individual cell is doing something reasonable from its perspective, but the system pays the price. Now there is one more piece to the inflammatory picture, and it comes from outside the fat cell. As the visceral fat depot becomes hypoxic and stressed, it also recruits immune cells, particularly macrophages, which then move into or migrate into that fat tissue and gather around the enlarged and dying fat cells. As the fat cells are becoming hypoxic, they start to die. Well, if a cell dies, you need another cell to come clean it up. That's what macrophages are built for. So these immune cells release their own inflammatory signals, amplifying what the fat cells have started. So the tissue shifts from a quiet, benign storage organ into an active and angry source of inflammation. The visceral depot, more— much more than the subcutaneous depot, draws this immune infiltration, which is why it contributes so disproportionately to the body's inflammatory load despite being again the much smaller fat depot. All right, now I want to get towards the end of this mini lecture on a more hopeful note, because the same feature that makes visceral fat dangerous also makes it responsive. And that responsiveness points toward what we can do about it. We've talked about how visceral fat resists insulin's signal to hold on to its fat. The flip side is that visceral fat is unusually sensitive to the signals that tell it to release its fat, namely the catecholamines, specifically adrenaline and noradrenaline, or as we would say here in the US, epinephrine and norepinephrine. And those are that, that, those are signals of the sympathetic nervous system. And these signals that come from the sympathetic nervous system are designed in part to mobilize stored energy. The fat cells of the visceral depot carry a much higher density of the active beta-adrenergic receptors. These are the receptors that these catecholamines, epinephrine and norepinephrine, or AKA adrenaline and noradrenaline, act on. And so they carry this, um, a strong signal, much more. The visceral fat is much more sensitive to the signal again than the subcutaneous fat cells are. In direct comparisons of human fat from these two depots, visceral fat breaks down its stored fat far more readily in response to catecholamines than subcutaneous fat does. And this is particularly driven by what's called the beta-3 adrenergic receptor. So it's much more active in the visceral fat depot. And earlier on, I mentioned how the visceral fat is much more innervated. It has more nerves going to it than subcutaneous fat. This is why, and this explains it. It's because with more nerves comes more nervous signaling, comes more catecholamines activating that beta-3 adrenergic receptor, which drives lipolysis. This has a practical implication. Anything that raises that sympathetic signaling, or in other words, increases the catecholamine levels, should in principle act preferentially on the depot that is most catecholamine responsive. And the most reliable, best evidenced way to do that is exercise. Every bout of physical activity produces a surge of catecholamines, and those catecholamines act most strongly on the fat that is best equipped to respond to them, which is the visceral depot. When we look at the human trials, exercise lowers visceral fat, and it does so even when overall body weight barely changes, which tells us that this is not a generic weight loss effect, but a specific mobilization of this particular fat depot. Aerobic exercise of moderate to higher intensity has the clearest effect, reducing visceral fat without requiring a calorie-restricted diet alongside it. Now, passing from that very substantial evidence into a more speculative possibility, And I do want to mention that it is speculative. That brings me to cold exposure or cold plunges and cold showers, that they've become popular and that I personally enjoy with my cold plunge every morning. This is a potent activator of that sympathetic nervous system, and it is a strong stimulus for catecholamine release. Given that visceral fat, again, is the depot most responsive to catecholamines, it is mechanistically reasonable to hypothesize that cold exposure could help mobilize visceral fat. In particular, the physiology lines up. But of course, I mentioned this is speculative. We do not have good human trials showing that cold exposure selectively reduces visceral fat mass. Most of the cold research is focused on activating brown fat and raising energy expenditure rather than on shrinking the visceral fat depot specifically. So the, the direct test that would answer this question has not been done. There's not enough evidence to support this. And so I'm not claiming this. So I do place cold exposure in the category of physio— physiologically plausible and definitely worth investigating, likely true, but needs to be proven. Exercise is the intervention that we can stand behind based on the sum of all evidence. And the cold, I think, is a reasonable hypothesis. Built on similar mechanisms. The central thought of all of this is that visceral fat is defined by its responsiveness. It is wired directly via blood vessel to the liver. It ignores insulin's signal to store fat, but it answers very readily to the signals that tell it to release. That same responsiveness, I think, is the lever we can use and physical activity remains the most dependable way to pull it. That's it. Class dismissed. Until next time, more knowledge, better health.