149: The Hidden Signals That Make Fat Cells Grow

Your fat cells aren't just sitting there storing energy. They are actually listening to signals. Inside each fat cell are proteins called nuclear receptors. Think of them like switches that respond to things like hormones or fats or drugs and even some chemicals from the environment. One of the most important of these nuclear receptors is called PPAR gamma. PPAR gamma. It helps decide whether a cell becomes a fat cell and how that fat cell stores fat and even how healthy that fat cell is. But here's the key: PPAR gamma may help build the storage system, but insulin tells that system when to run. That means dietary fat alone isn't the main driver of fat storage. In a low insulin state, your body is more likely to burn fat. In a high insulin state, your body is more likely to store it. So if you want healthier fat cells, the most practical place to start is controlling the signal at the top of the stream. That is insulin. This is Lecture 149 of The Metabolic Classroom. Welcome back to The Metabolic Classroom. I'm Ben Bikman, metabolic scientist and professor of cell biology. In today's mini lecture, we're focusing on nuclear receptors and how they influence the function of your fat cells. You're going to learn about how a small family of proteins inside the nucleus reads chemical signals from inside the cell and then uses that information to decide whether a cell becomes a fat cell at all, and then how that fat cell behaves once it exists. And finally, what happens when those signals are scrambled or somehow influenced or regulated by things like certain drugs or dietary nutrients, or by chemicals that you could say were never supposed to be in the body in the first place. This is a topic that lets us connect some basic molecular biology and then connect that to some of the most, some of the most used drugs right now for diabetes. And then we'll shift into, as I noted, some of these environmental chemicals that may be doing to human metabolism what some of these drugs are doing, albeit to, to a more modest degree, but it's— they're influencing these same nuclear receptors. The fat cell, as you will see, is not a passive container. It's not just something sitting there being told what to do. It is influencing its own actions through its, these nuclear receptors, these nuclear signals. So originating from within the very heart of the cell itself, if you will. Okay. So to start as usual, let's start with the basics. Nuclear receptors are a family of. About 48 or so proteins in the human genome that share a common architecture, and they also have a common job. That job generally is that they will read a chemical signal from inside the cell, and then they translate that signal into some changes in gene expression. The signals that they read, so the inputs, the signals that are telling or activating or regulating these nuclear receptors For the most part, they're small and they are lipid-soluble molecules. So these are things that can pass through that external cell membrane. When you hear that something is lipid-soluble, know that it can come to the cell and then just slip right through. This includes things like fats, uh, some cholesterol molecules, bile acids, thyroid hormone is one of them as well, and also the steroid hormones. Um, and that includes sex hormones and it includes cortisol. Those are all built on what's called a cholesterol nucleus. So the sex hormones and even cortisol. Now we're going to talk about cortisol a lot here. It's very relevant. Um, now the genes that these signals regulate in response sit at the heart of how the body senses its own internal chemistry, and then it can adjust the metabolism accordingly. Each nuclear receptor is built around a common structural plan. There's a DNA binding domain, so it's on one end, so it can literally connect on to your DNA. And then on the other end, there's what's called a ligand binding domain. When that— when this microscopic molecule slips into the, into the binding pocket or the activating pocket, when the signal slips into that binding pocket or the activation site on the nuclear receptor, The receptor will change its shape and then it will pull in some cofactors and then to help influence its action. Then it will bind to the DNA and start kicking off or regulating the gene expression. It will sometimes turn on a particular gene being expressed or it will downregulate, turn down the expression of a gene. And then remember, of course, that gene becomes a protein and that protein then has a function. Most of the receptors that I'm going to discuss today in the mini lecture work as heterodimers. That means that they will bind with something else. So if I'm talking about a specific nuclear receptor, know that it's not acting, um, uh, solo, that it will very often pair with something called the retinoid— retinoid X receptor, RXR. Then the, the RXR is a pretty— it's a recurring theme that you see across this family, these nuclear receptors. Without the RXR partner, the receptors generally aren't going to function. No, so, all right, so keep that detail in mind. It's going to matter when we get to some of the environmental contaminants at the end of the lecture. Now, among the roughly— I said about 4 dozen of these nuclear receptors in this family— several of them matter for fat cell function. This subfamily of this family of nuclear receptors that I'm referring to now in the fat cell are the peroxisome proliferator-activated receptors, PPAR, and there's 3 of them: PPAR-alpha, PPAR-delta, and PPAR-gamma. And then they orchestrate adipogenesis, so the synthesis of new fat cells, as well as the storage function within an existing fat cell. So this lipid handling process as well. Now, other nuclear receptors do include the glucocorticoid receptor. Now, you might hear a term, uh, a sound there that sounds familiar. The glucocorticoid receptor reads cortisol, and that you'll see has an influence on visceral fat and subcutaneous. And then also thyroid hormone receptors influence energy expenditure when they influence these nuclear receptors. And even estrogen and androgen receptors can contribute to some of the sex differences in fat metabolism. Now, I'm not going to go into all of those, but I'm going to stick with the nuclear receptors. So we can't do justice to all of these things just in this one mini lecture. So today I'm going to concentrate primarily on 3 of these receptors: the PPAR gamma receptor, then the liver X receptor— to us, actually, time allowing, that will be very, very modest— but then mostly PPAR gamma and the glucocorticoid receptor. And then we'll close, of course, with a section on the synthetic chemicals, these obesogens. There's a little bit to say there insofar as some have been identified to act on through one of these receptors in particular. Now, let me start with the nuclear receptor that I had in mind when I put this mini lecture together, and that is PPAR gamma. PPAR gamma is what we call the master regulator of adipogenesis. The reason for that title is pretty straightforward. If you— you— when you activate PPAR gamma in a cell, it becomes— it allows this progenitor cell to become a progenitor cell being what's called a fibroblast. Now, you might have heard me mention fibroblasts before in the context of scar tissue, um, for example, but fibroblasts can become any number of things, including a fat cell. So with— if PPAR gamma is activated, that fibroblast, that kind of primordial or early stem cell stem-like cell, it can then commit to a big— to becoming a fat cell. If you remove PPAR gamma from a fetus, like this has been done in animal models, of course not human models, then the embryo cannot make fat at all. Um, and in fact, it can't even survive. So the baby, it will be a miscarriage, not only because of the total loss of fat, but you also actually do need some PPAR gamma in the development of both the placenta and even the heart. Now, as I noted earlier, PPAR gamma does not do its work alone. It works as a heterodimer. So two different things, that's where the hetero term comes in, but they dimerize, they come together. So PPAR gamma works with RXR and together they sit at this, um, the regulatory regions of genes that define what a fat cell is, the genes that will build the lipid droplet, helping the fat cell get more fat in it, and the genes that will transport fatty acids across the membranes to bring bringing in those fats from outside the cell. Also genes that will— that orchestrate the storage of triglycerides, so converting fatty acids into one single triglyceride molecule. But also they regulate the gene for adiponectin, which I'll come back to later. You've heard me talk about that before, but that's the hormone that adipose tissue secretes when it is healthy, when it's metabolically favorable, and helps, helps the rest of the body be metabolically functioning and favorable as well. Now, PPAR gamma also partners with another transcription factor called C/EBP alpha, and the two of them together push the developing fat cell across, uh, if you will, a commitment threshold, um, from which there's no real return. So if C/EBP alpha and PPAR gamma are coordinated, then you've really committed a primordial cell into the path of becoming a fat cell. The natural ligands of PPAR gamma— that's the molecules that activate it, uh, in normal physiological conditions— are lipids. So now, lipids is a huge term that encompasses a massive swath of molecules, but specifically fatty acids and certain fatty acid derivatives can activate PPAR gamma. And we'll come back to that point in more detail when we discuss diet, because it's one of the more interesting threads in metabolic biology that what you can eat can reach the genome of your fat cells through this receptor. Now, before we move on, one important framing point: PPAR gamma does not operate in a hormonal vacuum. The dominant systemic signal that drives PPAR gamma expression in the first place, and that drives the differentiation of pre-adipocytes into mature fat cells, is the patina peptide, the humble hormone insulin. In fact, the standard laboratory protocol for growing fat cells in a petri dish, something my lab is literally doing right now at the time of this recording, requires insulin in that medium. So in that soupy broth where these cells are sitting and living, you need insulin in order to push them into fat cell. If you deprive the cell of insulin, it doesn't matter what other signal you give it, including activating PPAR gamma, with some of the drugs I'm going to mention in a moment. It doesn't matter, you cannot do it. Insulin signaling drives the expression of PPAR gamma itself. It drives the expression of that partner, CEBP alpha, and it drives the expression of nearly every downstream gene that PPAR gamma turns on. So when I say that PPAR gamma is the master regulator of adipogenesis, the more, the more complete version of that would be that PPAR gamma is the the executor of an adipogenic program that insulin orchestrates. So it's, it's the— if I'm going to use the term orchestrate— insulin's the conductor, PPAR gamma is, I don't know, the, the, the baton, I suppose you could say, that the conductor is waving and the rest of the band start— the orchestra starts to follow. So these are not parallel systems, they are singular, and insulin sits at the top. It sits at the beginning, it sits upstream. Okay, with all of that lengthy background, let's get to something very practical, because the clinical story of PPAR gamma actually begins when drug developers discovered a class of compounds called thiazolidinediones, or just abbreviated as TZDs. These were shown and were found and continue to be known to lower blood glucose very effectively without causing hypoglycemia, but it does so without acting on the pancreas in the way that other drugs do that are the insulin secretagogues. So there's an entire different class of medications that would also lower blood glucose, but they do so by forcing the beta cells to make even more insulin. So PPAR gammas looked really good, and they still do if all you care about is the glucose. Well, that's not fair. That's not fair to say because, as you'll see, when you activate PPAR gamma, you lower glucose by improving insulin sensitivity. But this was something that wasn't discovered until the mid-'90s. That's when the target was identified as— of these drugs, the TZDs— the target was identified as PPAR gamma. What makes the, the TZD story so instructive is that the drugs do improve insulin sensitivity, but they do so in part by forcing the patient to grow more fat cells. To anyone who's trained in the modern understanding of obesity and metabolic disease, that would sound like an indictment of the drug class. But if the— if your intention is to lower glucose, if that is, say, what the clinician is focused on, then it works, uh, because you give the glucose more destination, more homes to go into, so you can clear that glucose from the blood more easily. In other words, you have more cells that are responding to insulin, because fat cells do, especially if they're small. And so what you're doing is stimulating the growth of more fat cells, so there's more places for insulin to work, more places for glucose to go, and thus you have an easier time controlling blood glucose. And indeed, the patient becomes more insulin sensitive. There were 3 TZDs that were widely used clinically. The first one is troglitazone. Um, that's largely been withdrawn because of some liver effects. And then the remaining two, pioglitazone and then especially rosiglitazone, have become some of the most prescribed insulin-sensitizing medications in the world, and they're still heavily used today. Now, as a result of the small and healthy and functional fat cells, um, plasma adiponectin goes up a lot. You make more adiponectin as you have smaller fat cells, and now you have even more smaller fat cells because you're making more of these fat cells. So no surprise that adiponectin levels go up a lot. That's a very metabolically favorable signal. Adiponectin does a lot of things to improve insulin sensitivity in places like the liver and the muscle. But remember, all of this comes at the cost of the patient gaining several kilograms of pure fat in just months. So this is actually one of the reasons why patients want to get off the drug. They appreciate that their blood glucose levels are looking good, and yet it's happening paradoxically while they're getting fatter and fatter, because remember, they're stimulating the growth of new fat cells. All right, hopefully that is interesting to you. Now let's move on to the dietary signals and leave the drug signals behind. Um, where we have the activation of a nuclear receptor by the synthetic drug, and I described some of its metabolic consequences, the good and the bad, the obvious next question is whether activation of something we eat can have similar consequences? The answer is yes, kind of. Fatty acids, the same fatty acids that arrive in the bloodstream after a meal and then get taken up by fat cells for storage, they do bind directly to PPAR gamma and to another, a sister receptor, PPAR alpha. And PPAR alpha has kind of opposite effects, burning more fat, but in so doing. There's— there— but, or with this in mind, there's a long list of these fatty acids that do this, and it's, it's complicated. Like, things like eicosanoids, even oxidized lipids, certain fatty acid esters. Polyunsaturated fatty acids will tend to bind with a higher affinity than saturated fats. This is why within the social media space you'll see people talk about how seed oils are uniquely fattening And there is some compelling rodent or animal evidence to support that view. That would be relevant here where these polyunsaturated omega-6 fats are going to bind the PPAR gamma receptor better than saturated fats and thus promote the expansion of that fat cell pool. But that's another reason why, if you'll pardon a brief tangent, I think it's so nuanced in implicating polyunsaturated fats as a cause of insulin resistance. I just got done explaining, after all, how the ability to make new fat cells helps a body be more insulin sensitive. If your fat cells are insulin resistant, they are not growing. But if the PPAR gamma activation through polyunsaturated fat is stimulating the growth of new fat cells, they maintain an insulin sensitive state, which allows them to continue to grow. So to a degree, all of this means that the composition of the dietary fat, um, can influence the environment or the activation status of PPAR gamma within a fat cell. The population of PPAR gamma molecules is not sitting empty waiting for a drug. It can be activated or regulated to varying degrees by whatever the lipid species are that are present in the cell at any given moment. Long-chain fatty acids, even beyond the ones I mentioned, like some of these arachidonic acid derivatives like prostaglandins and leukotrienes, they influence it. And then I noted oxidized fats like oxidized phospholipids. All of them act on PPAR gamma, and the integrated signal across all of these inputs can influence the transcriptional state of that fat cell. Is it storing more just to get big? Is it inducing the proliferation of of primordial fat cells to get more. All of it goes into this. So what this does and does not mean is kind of nuanced. The endogenous activation, so the internal signals, um, the activation of PPAR gamma, like with these fat molecules, is no— in no way equivalent to the magnitude of activity that you see from a TZD. Uh, it's, it's going to be much more modest. But there is, there is a second, um, question here, and it goes directly to the— those of you who are interested in this to a deeper level. If dietary fatty acids activate PPAR gamma and PPAR gamma promotes fat storage, does that mean that dietary fat drives fat accumulation? Well, the answer is no, it's not that simple. The reason is that The binding of PPAR gamma with these fatty, these lipid signals is not the singular signal. Now I've noted this a couple of times here. I think is the third time. Remember that fat storage requires insulin. In a low insulin state during fasting or during prolonged exercise, or you're on a ketogenic diet, fatty acids in circulation are directed primarily toward oxidation. By that, I mean burning. I, I should be clear. Earlier when I mentioned phospholipid oxidation, to be more precise, I should have said peroxidation. So lipids that have been modified through oxidative stress. Now I'm talking about the oxidation as in they're getting burned. Those— I, I try to be clear in distinguishing those two terms and I failed earlier, so I should have mentioned these lipid peroxides. Now we're talking about if insulin's low, any of the fats that can be burned are getting burned. They're not being directed to storage regardless of what they may be doing at PPAR gamma binding pockets, the, the binding domain. The same fatty acid that can occupy the receptor in a postprandial high insulin adipocyte does very different work in a fasted low insulin adipocyte. PPAR gamma is a— it's a permissive transcriptional input that will establish the cell's capacity to store, but insulin is the signal that determines whether stored is what the cell actually does with that, with those fats. This is why dietary fat per se, in the absence of carbohydrate-driven insulin elevation, it does not drive net fat accumulation. And it's why PPAR gamma biology is really, I think, fully compatible with the metabolic logic of a low-carb diet. Drugs are designed to be high-affinity, full-activation agonists, whereas dietary lipids are going to be a much lower affinity. They're partial agonists or activators and they exist at concentrations that fluctuate with feeding and fasting and whatever the overall metabolic milieu of the body is. But the, but the qualitative point stands. The food that we eat is, through this pathway, a transcriptional signal. The composition of dietary fat in the metabolic state of the cell that determines which lipid species accumulate inside it modulates the activity of a receptor that then decides what kind of fat cell exists and how that fat cell functions. Now, One other point on that is that the, the most common fats in the fat cell are unsaturated fats, including monounsaturated and polyunsaturated fats. Uh, so that's something relevant to keep in mind. And there's very compelling evidence to show that as humans eat more polyunsaturated fat in the diet, you get more polyunsaturated fat in the fat cell. You do not have something equivalent with saturated fats where you eat more saturated fats. You do not see an enriched pool of saturated fats in the fat itself. And again, it's a lower affinity binding of PPAR gamma anyway. All right, that's a lot of PPAR gamma. And there was another main receptor I wanted to talk about, uh, in the time we have in this mini lecture, and that's the glucocorticoid receptor. So that is the one that responds to a hormone you are already familiar with, and you probably already associate with belly fat, and that hormone is cortisol. The glucocorticoid receptor is a nuclear receptor like PPAR gamma, and it binds cortisol. No surprise. In adipose tissue, glucocorticoid signaling is a powerful driver of adipocyte differentiation, especially in the visceral depot specifically. And chronic glucocorticoid, uh, excess, or just elevated levels of cortisol, can start to produce a body composition that changes in a way that is Uh, it's called Cushing syndrome, and when it's really extreme, so someone has an endocrine defect and their cortisol levels are really high. Now this goes beyond just sleep deprivation and feeling stressed because you're worried about something. That, that's all in a physiological range. What we're talking about now is much, much higher, but you start to see a very particular phenotype or body type where the person starts to get very obese centrally, abdominally, but they get very thin on their extremities. Now that's a complicated kind of metabolic dynamic, right? Uh, but what may— that's what makes this receptor especially important in the context of the fat cell function. It's that adipose tissue does not just respond to circulating cortisol, that some adipocytes will actually amplify the cortisol locally. Inside the fat cell, there's an enzyme that actually regenerates active cortisol from an inactive precursor metabolite called cortisone. Effectively, it allows the cell to top up the cortisol concentration within the fat cell itself, so not relying on the adrenal glands to create more cortisol. And visceral adipose has particularly high activity of this enzyme. So that means that even when systemic cortisol levels are maybe normal, the local concentration of cortisol inside the visceral fat cells can be substantially elevated. And remember, that matters because the glucocorticoid receptor is in the fat cell. So it doesn't have to rely on an external cell surface signal. If the glucocorticoid receptor was on the surface of the cell, then the fat cell making more cortisol within itself wouldn't activate it because it's not necessarily coming out then coming back in what's called an autocrine activation. No, this is the fat cell makes more cortisol. The nuclear— the glucocorticoid receptor, that nuclear receptor, senses its own-made cortisol, so amplifying this effect. Okay, now the final thing I want to talk about here before wrapping up are the obesogens. Everything I've said so far has involved molecules that the body knows, you know, very fats, different types of fats, and different types of hormones. But things get a bit wild when we consider what happens if molecules the body has never encountered get into the cell and find themselves binding the same receptors. And that is where we bring in the term obesogen. You've probably heard that term before. Much to my delight, it's gotten some attention. The term describes the environmental chemicals that promote fat accumulation through some of these endocrine disrupting mechanisms. The list of suspected obesogens is long But it includes some compounds that you probably have already heard of. For example, phthalates. Yes, that's an awkward word to say where it's two consonant sounds together. Phthalates, P-H-T-H there at the beginning. Phthalates are plasticizers used to make plastics flexible. So think of something like your squishy, flexible plastic bottle. But they're present in food packaging, like I just noted. They're present in vinyl flooring and a lot of other personal care products and even medical equipment. The major phthalate metabolite found in human urine. So measuring that— so thankfully it can be excreted, that's, that's good news. But it is a direct activator of PPAR gamma. It binds that same pocket that the diabetes drugs that I mentioned earlier bind, and it can push these pre-adipocytes toward becoming mature fat cells in the way that the drugs do. To a lesser degree, bisphenol A, or BPA, also appears to have some similar effect, but nothing— not as strong. And the evidence, the, the mechanism and everything is a little more diffuse, and there may be multiple nuclear receptors there rather than just PPAR gamma alone. Nevertheless, it's known to bind and activate PPAR gamma. All right, let's bring all this together. My hope is in the process of listening to this you've had a little bit of a picture emerge, and that's that the fat cell is we could say transcriptionally dynamic. So it's regulating gene expression that's influencing whether it's burning, whether it's dividing, whether it's growing. So this, this conversation of expansion of the fat cell pool or fat mass, and it's all regulated by a small little family of nuclear receptors that can read any of these lipid— not any, many of these lipid-soluble signals from within the fat cell itself. It doesn't need to rely on a signal just in the blood. As, as I mentioned, PPAR gamma can read the fatty acids depending on the type of fat and then decide whether the cell is a fat cell at all. It helps determine whether it becomes a fat cell. The glucocorticoid receptor can respond to cortisol, including cortisol that has been generated internally, and that will shape the visceral fat depot in particular. And these same receptors can be triggered by the TZDs and some of these obesogens these molecules from outside the body that also fit this PPAR gamma binding domain and turn it on. Now, what does any of this mean for the person who's trying to live a good metabolic life? The honest answer is that you can't really avoid every chemical that fits a nuclear receptor binding pocket. And even if you could, you would still have to contend with the receptors that listen to your own internal hormones. But there is one input that sits upstream of essentially all of this, and it is one you have considerable control over. Insulin is the dominant systemic signal that drives PPAR gamma expression in the first place, that orchestrates adipogenesis, that determines whether the storage program PPAR gamma enables actually is running. Cortisol-driven visceral fat expansion is amplified by insulin, and even the obesogen story is at the level of whole body fat accumulation gated by whether the metabolic environment is one of storage or one of mobilization, and that environment is set by insulin. Controlling carbohydrate intake is key to keep insulin low and stable, and that is the most practical and rational strategy a person has for keeping the nuclear receptors of adipose tissue in a healthy and well-regulated state. You cannot escape the receptors, but you can, to a very meaningful degree, decide what hormonal context they operate in. Class dismissed. Until next time, more knowledge, better health.