46: Aging and the Life of Fat with Dr. Ben Bikman

Hello and welcome to this week's episode of the Metabolic Classroom. I am Professor Ben Bickman, biomedical scientist with a focus on diabetes and metabolism and fat tissue and mitochondrial bioenergetics and similar theme, if you will. Today I am delighted that we get to spend a little more time talking about fat tissue. It is a tissue that I have firmly believed over the years has not been appreciated other than the fact that it grows and shrinks. And there is so much more nuance to this tissue that I have long felt is overlooked that as I stated, I'm glad to be able to spend a little more time on that topic with you today. The topic specifically, of course the theme is going to be fat tissue as it was in the previous episode and as it will be in the upcoming episodes. But today we're talking more about the actual position of the fat where we store fat. And that includes the variables that go into determining where we store fat and how age influences some of these shifts. And then along with that we will touch on some of the impact of this fat storage and some unique aspects, unique from last year episode where it was a a bit of a different version of where and how and why we store fat. This is a little more focused on the why, as I said, and some of that has to do with this specific and unique ways in which the fat is stored. And then make sure after you listen to this that you go on and listen to the next episode. Next week we're going to be discussing the endocrinology of adipose tissue. So how fat tissue is talking to the rest of the body. And that will a little more discussion of the differences between the sexes. All right, so with today's topic, again, welcome. Thanks for tuning in. For those who are tuning in live and are members through insulin iq, please make sure you get your questions in. I look forward to going through those with you. All right, now as a brief review, last time we talked about subcutaneous fat and visceral fat, we highlighted some of the role for fat tissue and we even went over a little bit of the some of the evolutionary theoretical reasons for why humans are unique among all land based mammals in that we're the only ones that are born obese and we're pretty much the only ones that are really fat, particularly in the primate family. Even a lean human would be considered obese by ape or gorilla or monkey standards. And, and it's a unique again as the theory goes, perhaps it's a unique, a result of our unique metabolic demands with our brains. Nevertheless, fat Serves multiple functions. Most obvious and often only appreciated function being energy storage. Even a lean human has hundreds of thousands of calories stored on their bodies, ready to be used, waiting to be used when needed. Unfortunately, in our environment, that means rarely, most, because people eat so often. It also acts as a degree of insulation with regards even to heat, and as well as acting as a bit of a cushion. And then as we're really going to talk about next time, it also acts as, as an endocrine organ and produces multiple hormones and signals, dozens of them, that then move through the bloodstream and act on various spots of the body. All right, so with this in mind, let's move into just the different places we store fat. And as we do so, I need to highlight the role of a particular enzyme. Nothing. Little else will make sense when we talk about fat storage if we don't start with a discussion of lpl, which is known as lipoprotein lipase. Lipoprotein lipase, anytime you hear that suffix a, something, something, a's, that means it's going to be an enzyme. So lipoprotein lipase has a particular, a unique job because its primary function is to pull fats off as they circulate through the bloodstream on what's called a triglyceride rich lipoprotein. Now, that's a term I've used before, but a triglyceride rich lipoprotein is essentially a bus that is moving through the bloodstream that's carrying a bunch of fat. And the passengers on that bus will stop and get off wherever there is lipoprotein lipase. So lipoprotein lipase is like a bus stop for fat. And wherever there is these bus stops or lipoprotein lipase, that is going to be a tissue that is pulling in the fat to be stored. So wherever we have lipoprotein lipase, we have a potential to store fat, a, a, a high potential to store fat. And of course, where we have more lipoprotein lipase, we will selectively store more fat in that location. Now, lipoprotein lipase can't act alone, of course. There are signals like insulin that will induce the expression of lipoprotein lipase in particular places. Like, for example, if insulin is elevated, then it is increasing the expression and activity of lipoprotein lipase in fat tissue. When insulin is low, it is reducing the activity of lipoprotein lipase in fat tissue. And in fact, in that same instance, like an example of exercise, when a person is undergoing frequent exercise. It's increasing the expression of lipoprotein lipase at muscle tissue because the body is essentially being trained, the muscles are being trained to burn more fat for fuel and to pull that fat in, to burn it, it needs lipoprotein lipase again to be pulling in those fats from these triglyceride rich lipoproteins. And let me just mention what those are. That's going to be things like the chylomicron after it is fat that you've just eaten. It could also be fat, lipoprotein, lipoproteins that are being produced from the liver. These triglyceride rich lipoproteins being VLDL and then turning into ldl. So where we store fat is most heavily influenced by where we express the enzyme lipoprotein lipase. Now, one of the I mentioned the hormone a effector, insulin, that's a good example. But also in this sub topic, now, within this broader topic, let's talk about sex. Because the sex differences between male and female, of course, are matter enormously. And that is all about sex hormones. Now, you'll notice, of course, we all have noticed, we've noticed it in ourselves, but in, in children within our families that a little boy and a little girl look similar, that their body, overall body shape is generally indistinguishable. Of course, other than genitalia, they look the same. There aren't any substantial differences in their overall frame or the build of the body. But those differences start to manifest themselves as the child, of course, goes through puberty, which is a time of explosive difference and change, much of which of course, is mediated by an explosive increase in sex hormones. Of course, estrogens primarily being the influence within the females and androgens being the primary influence in males. Now, I'm using those terms because they are reflective of the general category of the prototypical female sex hormones being estrogens and the prototypical male sex hormones being androgens. Now, within those families there are more specific influential hormones, like testosterone is the poster child of the androgens, even though there are more than just testosterone. Now, unfortunately, we often will say estrogen. There is no hormone called estrogen. It is the estrogens and the main one being estradiol. That's sort of what testosterone is to androgens, estradiol is to the estrogens. But with that brief endocrinology lesson out of the way, these hormones have a powerful influence on the expression of lipoprotein lipase. Let's start with the boy. When a little boy is going through puberty, his testosterone levels climb manifold and this will start to increase the expression of lipoprotein lipase in the central abdominal region of his body. Now, that does not mean he begins to only get belly fat, because at that same time, testosterone is inducing significant growth of mass, lean mass, bones, muscles. And of course, there's IGF1, which is a growth hormone kind of derivative and growth hormone itself that are influencing growth. So as much as this boy is now giving the. The hormones are giving rise to the potential to be storing fat around his belly area, that energy is being devoted to growth. So he doesn't have the energy, if you will, to be. Well, not if you will. Literally, he doesn't have the energy to be storing fat around his abdomen. Unless, of course, there's an excess of energy, which can certainly happen. But usually as the boy begins to go through puberty, he leans out because all of that energy is being spent and devoted rather to storage, to being used to fuel growth of the body itself. Now, however, because testosterone or androgens generally are increasing the expression of lipoprotein lipase in the central area, that does include an increased expression in the visceral area. And we will talk explicitly about visceral adipose tissue in a little bit because that matters greatly, because we store fat differently in the visceral space than we do in the subcutaneous space. So within the male, there is that potential that when fat storage does start to happen, it's going to happen in a. In a more pathogenic or a more harmful way. Because storing fat centrally can be problematic. It begins to want to restrict its fat storage itself. It wants to prevent storing too much fat centrally. And that actually has some unfortunate effects. All right, now let's shift over to the girl becoming woman. In that case, of course, she has a significant increase in her estrogens. Now, just as a reminder, both sexes have both sets of these or these two primary classes of sex hormones. Males have androgens and estrogens. Females have estrogens and androgens, albeit in a slightly different proportion. Specifically, relatively higher in estrogens. And this relatively higher level of estrogens elicits substantial differences in how little girl's body is storing fat versus little boy's body. Whereas the androgens are inducing the expression of lipoprotein lipase in the central abdominal area of his, the androgens are inducing the expression of lipoprotein lipase in her body in the distinct female areas. Like breasts, buttocks and hips. Now, the, another contrast then, not only is the location different from, from a subcutaneous aspect, but. Well, it is in fact that in the female instance, it's all subcutaneous. The estrogens are not increasing the expression of lipoprotein lipase in the visceral area, the central area. It's only in this subcutaneous depose. And this is very much why the female can have more fat than a male and in fact is by design supposed to. I'll revisit that in just one second and be healthier. It's because she's storing her fat in a subcutaneous depot and that is a healthy place to get fat. Healthy for reasons we'll get to in just a moment. Now, another the, the fact, the point that I mentioned that I would revisit is that estrogens also, in addition to increasing the expression of lipoprotein lipase in these prototypical female fat depots, breasts, buttocks, hips, it also increases the, the action of storing fat. And this is a unique aspect because of the sex hormones where she's storing more fat, but at the same time she is also burning more fat. In fact, it's a pretty substantial increase. But I want to emphasize, as I did in the previous episode, that it's this turnover overall that's higher. But even still, the net effect is a body type that is storing more fat more readily and that is the estrogen that is an effect of the estrogens. Now, there are some obvious benefits to storing fat in the subcutaneous space metabolically, but of course, which I've alluded to, and I'll get to more in detail in a moment, but also just for the sake of reproduction and fertility, it doesn't behoove a woman to be storing fat viscerally if she has the potential to grow a baby in that same visceral space. And so it makes a certain amount of sense, evolutionarily or by design, to not have fat being stored in the visceral space in, in a healthy woman who hopes to reproduce, because then of course, there is a physical competition for space and she wants to devote that space, her body wants to be able to devote that space to the baby rather than fat tissue. So by storing fat subcutaneously, it moves, it literally moves it all out of the way. Now, what about when a woman is no longer fertile and has gone through menopause? There are a lot of changes, of course, that happen. And this can, this will be a focus of a Different metabolic classroom because it is a very, it's a fascinating topic to explore. But within the realm of just fat storage, when a female goes through menopause and the ovaries have run out of follicles, there's no more eggs there. Then the composition of her ovaries, the cellular composition begins to change in the relative amount and the activity of the very highly active sex hormone producing cells begin to reduce. That's the theca cells and the granulosa cells. She just has fewer of them and there's relatively just more of other cells that have kind of filled the space. But even still the ovaries have shrunk because of the loss of this mass of granulosa cells and theca cells, which itself is a product of the loss of follicles because she's not ovulating anymore. So during or, or with menopause in the, in the reduction in estrogens which very much happens, she begins to shift where she stores her fat. And it's not, it's not uncommon for the woman during menopause to find that she begins to store less fat in the breasts, buttocks, hips, and relatively more in that central region. So it's almost as if she's. Her body fat pattern storage is starting to default somewhat closer to the males now. Never completely, thankfully, you know, the body type will still obviously be female. We clearly know that to be the case. But nevertheless there is a shift and interestingly, and we're going to revisit this next week, so I'm just giving a bit of a teaser. The fat tissue becomes one of the main sources of estrogens in her body. Her ability to create estrogens from androgens becomes more relevant in her fat cells as the ovaries begin to quiet down a little bit. And, but with all that having been said, because she's storing more of her fat in that central, even visceral region, like her male counterparts have long been doing, she begins to have an increased risk or the increased disease risk that goes along with storing fat there. So she starts to become somewhat mortal, if you will, metabolically speaking, getting closer to the level of disease risk that her male counterparts have. Not totally related to fat mass, but, but more closely. All right, so that is the differences between the sexes, which hopefully by now you can appreciate is quite profound. Now let's just touch on age because it changes a little bit with age, the nature of the fat storage as well as somewhat location. So this one is a oddly placed within this broader topic, but it still Fits generally, of course, as we mentioned last time, during infancy and childhood, a child has rel, particularly infancy, much of the fat in the child, in the baby is brown fat, which is a very high metabolic rate fat, as we discussed previously, to help baby be warm when baby's generally less capable of shivering because muscles are not quite up to the job during this time of infancy and childhood, as the child is gaining fat mass, which is good and healthy, it's mostly through hyperplasia, so the multiplication or the proliferation of fat cells. So hyperplasia is accounting for the fat mass getting bigger. Now, during, as the child transitions into adolescence, the number of fat cells starts to plateau and then any further fat gain once the child has transitioned through adolescence and is now in their adult body, which is typically going to be mid teens in girls and late teens, even early 20s in boys. You know, boys are late bloomers and some even later than others. So some boys actually don't fully stop adolescence or end adolescence until they're in their early 20s, you know, 2021, that's possible. And so that is the point generally where the production or the change in the number of fat cells plateaus. That starts to curve off. And now hyperplasia is generally done. And any further growth, any further change in fat mass is going to be through hypertrophy. Now, you'll recall from previous discussions that hypertrophy is an unhealthy way for fat cells to grow. And we're going to revisit this more in just a moment because there is an influence here that's that we need to revisit with regards to visceral versus subcutaneous fat. But it's an unhealthy way to get fat as the fat cells grow. Remember, you'll recall from previous episodes that two harmful changes occur. One, as the fat cell has undergone such substantial hypertrophy so as to increase its volume by 10 or even 20 times, which is a growth that no other cell is capable of. It be to become insulin resistant to restrict its own growth. Remember, insulin is telling a cell to grow. And by becoming insulin resistant, the fat cell is becoming resistant to further growth, which is good, and it's good for the next, which is good for one reason, which is the membrane can stay intact and not burst, literally pop like an overfilled balloon, but also because it helps prevent the next consequence, which is also beginning to happen as the cell gets bigger and bigger, bigger and bigger, which is that it becomes hypoxic in, begins to suffocate, and as it as it gets pushed further and further away from capillaries, the life giving blood and all of its oxygen and other metabolites that it needs to receive and give back to clear out. As it is getting pushed further and further from capillaries, it becomes ever more pro inflammatory. Now that may sound strange, but one of the effects of activating or releasing these pro inflammatory molecules is the growth of new blood vessels. So even here, just like the overfilled fat cell becoming insulin resistant to protect itself from further growth, the hypertrophic fat cell is trying to protect itself by belching out a small catalog of pro inflammatory cytokines in order to correct its hypoxia. Now that got us into adulthood, lest it seem like I forgot the overall topic, but during this time, of course, the child or the, the adult is storing fat in the prototypical fat storage depot based on their sex. Now there's always some familial variability here. Familial variability being that which is determining LPL expression that goes a little beyond sex. It's, you know, some, some men and women simply store fat in slightly different places and that's going to be a heritage, an inherited attribute. Now, interestingly, throughout the rest of this person's life, the number of fat cells they have is going to be quite static. If a fat cell dies, which it does, fat cells are not immortal. They, they're very long lived though many years indeed, that once a fat cell dies, it's generally replaced until they get into their 60s or so. And then at that point the number of fat cells a person has starts to drop. Now that may sound like a good thing, but if a person is still eating a diet that is spiking insulin and providing sufficient energy as it did before, the body is still going to want to store the same amount of fat that it did before. Because it's diet that's largely dictating how much fat you're storing. And so if cell number is going down, how do we store that fat? Well, that means the size of the fat cell is going to go up. So the fat cells become more and more hypertrophic, and even worse, they begin to increase the potential of storing fat ectopically. So this is now coming full circle back to the topic of where we store fat. Ectopic is a word you're probably familiar with. You've heard it in other contexts. Ectopic means something is happening where it's not supposed to be happening. And if you are storing fat outside in a, in a tissue other than your fat tissue, that is ectopic. So this is increasing the likelihood of the person storing fat in their liver, or storing fat in their pancreas, or storing fat excessively in their muscles and other tissues, many tissues in the, even in their tongue and in their throat region, which is making it difficult for them to breathe when they lie down to go to sleep. So there are, there are a number of places the fat can be stored when it's not being stored in the fat cells, which again begins to be problematic as a person transitions into older age. And as a part of this, during elderly, that elderly time, it is increasing the likelihood we start to lose more and more visceral fat cells or, sorry, subcutaneous, we begin to lose more subcutaneous fat cells, increasing the likelihood of fat storage in the visceral space. Now, the next topic I wanted to get to was the difference between hyperplasia and hypertrophy. And I've, now that I'm here, I find that I've discussed it a little more than I'd intended up until this point. But let me just bring it up again. Based on the differences between subcutaneous and visceral, as I mentioned earlier, there's a problem with storing too much fat in the visceral space. Now, even men, while there is no uterus and no potential to have a baby stored within that abdominal space, there is still a lot of other important things that are stored there, like the intestines and the liver and the kidneys. I mean, all of these important organs are there. And so it stands to reason that we don't want to store too much fat there lest it become, begin to physically compress blood flow and tissue function. And so if you were to guess how visceral fat tends to store fat, which option do you think would be the most common through hypertrophy or hyperplasia? Remember, hyperplasia is the reproduction or the, the multiplication of fat cells. That of course, has an almost limitless potential if it's turned on. And whereas hypertrophy has within it a built in regulator because you're not going to make more fat cells and the fat cells can only get so big. So if you were thinking visceral fat storage promotes or tends to go down the path of hypertrophy, you, you nailed it. That is what happens. And that is generally why the visceral adipose becomes so problematic, because it's only going to go grow through hypertrophy. At the same time, it becomes, it's a part of its function beyond energy storage and insulation and hormone production. Is actually an involvement in the immune system. The visceral fat is loaded with lymph nodes, for example. And so it's no surprise to find that there are a lot of immune related cells within visceral fat, particularly macrophages. And macrophages can become highly pro inflammatory and indeed they do, particularly as they get loaded with fat that is being leaked out of the hypertrophic visceral adipocytes in those lipid loaded macrophages become what's called foam cells, because if you look at them under a microscope, it looks like they're filled with little air bubbles, but it's actually little fat bubbles. And as they get loaded with lipid, they become very pro inflammatory, compounding the already pro inflammatory environment of the hypertrophic fat cells. Now, in contrast to all of this, and the hypertrophy of the visceral fat is the hyperplasia of the subcutaneous fat. And this of course is a more female specific phenomenon driven by estrogens. But generally a woman has a greater hyperplasia at particularly the buttocks and hips. Now she may curse that, but it does mean she can store fat in a healthier way, even if it is maybe to a little more readily stored than she would like because of those same sex hormones. So the estrogens are increasing the hyperplasia capacity or the hyperplastic capacity of that subcutaneous fat. Now underlying all of this is the fact that visceral fat and its hypertrophy wants to be burned. So cell for cell, gram for gram, visceral fat will be breaking down its fat to be burned much, much higher than subcutaneous fat at any given moment. And it's much more sensitive to any of the epinephrine or adrenaline signal that may exist in the body. Whether that's coming through exercise, whether it's coming through an increase of epinephrine through cold exposure, through caffeine consumption, all of these stimuli that increase epinephrine are going to have a much greater effect at visceral fat than subcutaneous. So let me just state that again. Visceral fat burns more readily, or is more readily broken down, to be more precise in my language, than subcutaneous fat is it wants to be burned. The body doesn't want to be storing too much fat there. And this could be one of the reasons why men are able to burn fat and lose fat a little more easily than women, because they're storing fat in a place that literally wants to be burned more. Now one final discussion here, and this was actually something I just highlighted on, on social media, which is the effect of non caloric and even non overtly endocrine signals, which is signals coming from plastics. There was a fascinating study published a few years ago by a chemistry group that looked at the degree to which various chemicals and plastics are capable of inducing fat cell growth. And they found that these, so they compared it, these chemical, these chemicals and plastics. They compared these effects to a drug, a class of drugs called within the family of PPAR gamma activators. And these drugs are known to increase fat production and fat storage. And they found that these plastic, these plastics or plasticizers, these molecules like polystyrene, propyl, urethane, pvc, all of these chemicals that can be leached from plastic. And interestingly they actually obtained these chemicals from normal everyday plastic sources like a yogurt cup or a plastic water bottle. I mean it was pretty sobering. But all of these chemicals except one increased the growth of the fat cells more than the drug did. It was all equal or greater effect. And even the one that wasn't as great, it was still in the same range as the drug itself. So a pretty, a pretty shocking effect here of the plastics that just induced promoting overall fat storage. All right, so let's conclude then. So as summary we talked about just a brief primer or overview reminder of why we store fat and and how that was particularly the previous episode discussion. We focused on the role of lipoprotein lipase and its influence by hormones, even insulin and exercise, non endocrine signals as well as and most especially sex hormones, including the changes that happen with menopause and changes that occur over the life of an individual through aging. And we talked a little bit about the hyper, the differences between hyperplasia versus hypertrophy and how those differences are reflected in specific fat depots within the body, whether it's subcutaneous or visceral. And then even a little hint of some strategies which is going to be the topic of a very near upcoming in two episodes discussion of how to lose this fat, what we can do about it. But a little review, a little sort of whetting the appetite with regards to a mention of the effect of epinephrine, particularly on visceral adipose tissue. I hope that this has been helpful. I hope that you've been able to take some notes and that you can now go and share some of these ideas with another. Thank you for tuning in. Thanks for subscribing on the YouTube channel. If you're tuning in there and until next time from the metabolic classroom. Remember, more knowledge, better health.