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Professor Benjamin Bickman (2:08)

Welcome to the Metabolic Classroom Podcast. I'm Ben Bickman. Thanks for letting me be your guest professor for the next few minutes. Don't worry about any pop quizzes. I'm here to simply make the science of metabolism clear, practical and engaging. Welcome to the Metabolic Classroom. I'm Professor Benjamin Bickman, a biomedical scientist and professor of cell biology. If you've never heard of plasmologens before, don't worry, you are in good company. These are special fats found in the membranes of our cells, every cell, but particularly relevant and enriched in places like the brain, the heart and nerves. They're not your ridge lipids, though. They help cells stay flexible because being too rigid is not good for a cell. They also protect against damage, as we'll get into in a moment, and even support energy production by facilitating the work of the mitochondria. By the end of this mini lecture, you'll understand what they are, why they matter for metabolism especially, and especially how they tie into a few subtopics that I'm going to focus on. Fat cells, mitochondrial function and insulin signaling, and even, of course, how your diet can influence some of this. Now, we're going to cover it all thoroughly, so make sure you settle in and take some notes if you need to. But let's get started by describing what plasmologens even are. As I noted, they are a type of fat, and they form some of the building blocks of our membranes or the structure of our membranes in our cells. Now, unlike regular fats, they have a unique structure, very unique compared to any of the other fats, and it makes them extra flexible and it does offer some protective roles as we'll get to in a moment, particularly with oxidative stress. Now, they are found all over the body, like I said, but especially these high demand tissues like the brain and the heart, and muscle cells, immune cells, cells that can have a potentially very large metabolic demand, are particularly enriched with plasmologens. For example, in the heart, plasmologens make up a big chunk of the fats that are in the membranes of these cardiomyocytes or the heart cells, and even more so in nerves, which are already covered with fat to help them function. The process of creating plasmologens begins in an organelle, a specific organelle or part of the cell called peroxisomes. Now, peroxisomes are interesting because they actually work kind of in concert with the mitochondria when it comes to breaking down fat. Although the peroxisomes do more than just that, so too do the mitochondria. But when we typically think about burning fat or breaking down fat through beta oxidation, we think of the mitochondria but some fats are actually too big for the mitochondria. Fats that are sometimes just referred to as very long chain fats. Well, that's where the peroxisome comes in. It's sort of a big brother to the mitochondria in that regard. So the peroxisomes can break down fats. That's also where these fats are built. So within the peroxisome, other cell parts can. Peroxisomes will start it. And then with the work of other parts of the cells, they add the finishing touches to the final lipids that are going to be called plasmologens. It is a fairly complex process, which isn't surprising when it comes to lipid biochemistry. It often is. And suffice it to say, if something goes wrong with plasmologen synthesis, if we can't make enough, there are consequences. There are even some genetic anomalies that have to do with making the cells less capable of producing plasmologens. There are consequences. For now know that plasmologens are not just fats sitting around being lazy. They are very involved in keeping cells functioning. Well, now let's talk about some of those broader functions. One thing I've already mentioned is that the plasmologians help keep cell membranes fluid. Now what do I mean by that? I mean that it helps the cell actually have some dynamic aspect to it, which you might think of some cells like muscle cells. Why would a muscle cell need to be dynamic? Well, it's not going to have the conformation demands that say a red blood cell has. A red blood cell, which also has plasmologens as it's flowing through the bloodstream, needs to be able to undergo tremendous conformational changes to squeeze through various parts of the cardiovascular system into sinuses and things, for example. Well, muscle cells don't have to do that, but muscle cells still have to be able to shift. It's almost like as much as the shape of the muscle cell isn't undergoing the dynamic shifts like a red blood cell is, it's landscape or its surface is almost like an ocean in that there are things moving around on it. No cell is ever rigid and firmly set. So when I say that plasmologens help keep cell membranes fluid, that's what I mean. It helps proteins move around, including things like the insulin receptor, as we'll come to, and that has to happen. We have to allow these proteins to shift around in order for the cell to respond to and then propagate or carry on signals like coordinating immune responses, responding to hormone signals or nerve impulses. Plasmologens also act as antioxidants, which can then soak up harmful molecules that we call reactive oxygen species, ROS or ROS that can get produced during just the normal course of metabolism. These ROS can absolutely damage cells. They can undergo force molecules like other lipids, proteins or aspects of the mitochondria to undergo this harmful oxidative damage. So in that sense, plasmologens act like a little bit of a shield protecting the cell. Now, let me expand on that just a bit because it is, it is an important part of plasmologens. So they do reduce oxidative stress and they do so by acting as a, a sacrificial shield in cell membranes. What is so unique about plasmologians is that they have a particular biochemical bond called a vinyl ether bond. That vinyl ether bond is highly reactive to ros, to oxidative stress. And so this is then going to. Whereas you'd have an oxidative stress molecule potentially bind to a protein or to DNA and damage it. When the ROS interacts with plasmologens, the vinyl ether bond can absorb that hit, then it in turn will break down. So it, it does, it is a sacrifice. You lose the, the plasmology in the process, but it's built to do that. It's better for a plasmology to take that hit and fall rather than, say, DNA. The antioxidant role absolutely is essential in helping the cell maintain normal balance of, of redox status. And again, remember where plasmologians are particularly enriched, like the brain and the heart. Gosh, we need those tissues to be working well. Thankfully, the plasmologians are there to ensure that oxidative stress isn't going too far. Now, as I noted, they're also involved in cell signaling and we are going to revisit this in just a bit when I get to insulin signaling. But that does mean, once again, that when broken down, plasmologians can release molecules that help control inflammation and cell growth. Plus they play a role in even very special processes like sperm, egg fusion or even the formation of muscle cells. Now, obviously, there's a lot I could get into when it comes to plasmologens because they play such an important role in biology. But what I want to focus on, of course, is the metabolic parts of, of plasmologens. So let's focus more on metabolism and let's start with a very kind of general overview. Plasmologens are key players in many metabolic reactions, including balancing the nature of our fat cells. And when plasmologin levels are reduced, we have metabolic consequences like an increased risk of type 2 diabetes and metabolic syndrome and heart disease. Low levels of plasmologens can also enhance inflammation and oxidative stress because they're not there to help balance those things out in. In instances, like I noted, where we have rare genetic disorders of an inability to produce sufficient plasmologens, it can be catastrophic, you know, very, very lethal and, and compromise health considerably. We just have, especially when it comes to oxidative stress, we lose this significant protector. All right, now let's really get into the fat cells now. Now, fat cells, or adipocytes, are more than just storage depots for extra calories. We've talked before abundantly about how fat cells are so involved in hormone reactions. But fat cells are very dynamic. The fat tissue is a dynamic organ. Fat cells are dynamic cells that, yes, they help regulate energy balance to ensure that we don't starve to death every time we fast for a bit. They also are important fat cells are when it comes to fertility and insulin sensitivity and the production of many relevant hormones. Plasmologens are key components of fat cell membranes, and they play a role in fascinating, a fascinating role in shaping how these cells function in particular, especially when it comes to transforming slow fat, if you will, into fast fat tissue. Now, this is something we've discussed before, so it'll sound familiar to you. But briefly, white fat and brown fat are two types of adipose tissue with very different jobs in the body. White fat found in places like your belly or your thighs, that's mostly your subcutaneous fat that you can pinch and jiggle, but also your visceral fat, the fat that is tucked deeper within your abdominal cavity. But white fat acts like you expect fat to act like. It has a very low metabolic rate and is very good at storing extra fat. Brown fat, on the other hand, is a metabolic, busy body. It is packed with mitochondria, which gives it its darker color, or why we call it brown. And these mitochondria are themselves unique because they are designed to really burn a lot of energy. This is because of the process of uncoupling, again, something we've discussed abundantly in the past. So while white fat stores energy, brown fat burns it. And some white fat can transform into a beige version that acts more like brown fat, revving up metabolism and here's the cool part. Plasmologens can help turn white fat into brown or beige fat. So it's taking a low metabolic rate fat and turning it into a very high metabolic rate fat. By increasing this process called thermogenesis, or the fat cell burning energy just for the sake of creating heat. The browning effect is like flipping a metabolic switch, helping the body just burn more fat. It increases metabolic rate. Studies in preclinical work actually show that boosting plasmologens reduces weight gain by by ramping up this heat producing activity. The thermogenesis mimicking what happens when you're exposed to cold or exercising. It is in a way like a natural fat burning boost and again, paradoxically happening in the fat cell itself. When you're a forward thinker, you don't just bring your a game, you bring your AI game. Workday is the AI platform that transforms the way you manage your people, money and agents so you can transform tomorrow Workday, moving business forever forward. Ready to order? Yes.

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Professor Benjamin Bickman (15:22)

Terms apply seecapital1.com for details. This is a moment to get a little more involved here. There is a key player in this process and it's an enzyme that is abbreviated as TMEM86A. It's a terrible name for an enzyme, but it is what it is. This normally breaks down plasmologens in fat cells and on. When you in preclinical models have animals undergo diet induced obesity, so high fat, high sugar diet, the enzyme will go into overdrive, lowering plasmology levels and making the fat cells more prone to storing fat, which of course just exacerbates obesity and subsequent inflammation and insulin resistance. But when the enzyme is blocked, plasmologen levels rise and this in turn triggers a cascade that boosts fat breakdown, heat production, and even the creation of new mitochondria within the fat cell. So really making the white fat behaving more like brown fat, or like I said earlier, it makes them beige. They never actually become full on brown cells. Brown fat cells. So we say that they've been beiged. We turn that word beige into a, into a verb. We're beiging the white fat cells. So the result of this, we have smaller fat cells, we have better weight control, we have better blood glucose control, better insulin sensitivity and reduced inflammation. There is some evidence to suggest this is relevant. In humans, low plasmologen levels are linked to obesity and metabolic syndrome, suggesting that supporting them could nudge your fat cells toward a healthier and more active state. We'll come back, we'll wrap up at the end with some tips on what you can eat in order to increase plasmologens. Now, I've already been skirting around the mitochondria when I've been describing the consequences of plasmologens or the effects of plasmologens in the fat cell. Let's just explore that with a little more detail. It is a good segue into focusing more on the mitochondria. Plasmologens are abundant in mitochondrial membranes. Not just the cell membrane, but mitochondrial membranes, especially the inner mitochondrial membrane, where they help shape the structures that make energy production continue. The unique structure of the plasmologens not only helps keep the membrane stable, but it also helps support the anchoring and function of the electron transportation complexes. The electron transport system is this series of protein complexes that pass electrons, all for the purpose of generating ATP, the main energy molecule of the cell. By maintaining the right membrane environment, plasmologians ensure that the mitochondrial complexes work well. It's like they are just keeping the gears of the metabolic machine well oiled under stress. Certain proteins can break down plasmogens to protect the cell, but this can deplete them if not replaced. There's an enzyme called tifazin. Tifazin helps reshape the plasmologens and other fats in the mitochondria. When this process fails, like in a condition called Barth syndrome, that's one of the genetic conditions I mentioned earlier. It leads to energy shortages, damaged mitochondria, much more oxid stress in turn, all of which can contribute to myriad metabolic problems. With this in mind, it's not much of a surprise that low plasmologin levels are linked to mitochondrial disorders. Alzheimer's, diabetes, insulin resistance, all of these effects. So keeping plasmologens in check is crucial for mitochondrial performance and overall health. Now, I've mentioned fat cells, mitochondria, but at the beginning I also indicated that I wanted to devote a little Time talking about insulin signaling, because insofar as plasmologens affect the cell membranes, they in turn affect those proteins that are anchored in those membranes. Imagine like a raft floating on the ocean. It can move, but it's always there. Well, plasmologens help them, help the insulin receptors be there, insulin receptors on the cell surface. So floating on the cell, if you will, actually floating through the membrane, they will bind insulin and in turn tell the cell what to do with nutrient metabolism and of course, including, and most famously regulating blood glucose. Now, it does so by, in that instance, letting glucose come into the cell. Depending on the cell, when the system fails, we get insulin resistance, where the cells ignore insulin, which of course in part increases blood glucose potentially dramatically. But as you all know, and as much of my work suggests, when the body becomes insulin resistant, you then have a greater risk of virtually every chronic disease. Type 2 diabetes goes up, Alzheimer's disease, heart disease, infertility, and much, much more. Now, the plasmologens, specialized in the cell membrane as they are, influence the insulin receptor primarily through indirect mechanisms related to the composition of the cell membrane and the movement and the dynamic response that the insulin receptor can have at the cellular level. The plasmologens, of course, contribute to the fluidity of the membrane and the formation of what's called lipid rafts. Now, I used the term raft earlier in a metaphorical sense, describing the cell membrane as like an ocean surface. But in this case it's actually a technical term, a lipid raft. These are cholesterol rich domains where insulin receptors cluster to signal. Well, when plasmologin levels are low, membranes become more rigid and that in turn impairs the insulin receptor from clumping, clustering, which they do by design, and the downstream activation of the pathways, like some of these intermediates that come later, like pi3kinase and akt, that they aren't working as well, they're not responding. You don't see them get as activated in response to insulin. And then of course, that means insulin's not working as well. The obvious effect is going to be blood glucose rising. But then there are the other consequences, like I already mentioned, chronic disease, you know, now you have less nitric oxide being produced from the endothelium, you would have a reduced ability to produce estrogens from the ovaries. This rigidity of the cell membrane can disrupt the insulin receptor's ability to activate itself. So when insulin comes and binds to the insulin receptor, the insulin receptor will go through a process called Auto or self phosphorylation it activates itself but that becomes compromised when plasmologens are down. So with lower plasmologens comes a reduction in that kinase activity, that self activating activity which leads to a weakened formation and transduction or sending of the insulin signal.

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Michelle Bernstein (23:16)

Check 12 are we recording? Hi, I'm Michelle Bernstein, an award winning chef, restaurateur and mom. I have a lot on my plate including my psoriatic arthritis symptoms. That's why I was prescribed Cosentyx. It helps me move better.

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Michelle Bernstein (24:11)

Your rheumatologist about Cosentyx.

Professor Benjamin Bickman (24:18)

Plasmologians also connect to other metabolic markers. For example, higher levels are not only linked to better insulin sensitivity with low levels being linked to less, but also other signs that other consequences you can see like blood lactate levels going up indicative of compromised mitochondrial function. Now there is decent human evidence to support all of this. In fact there is a large cross sectional study of over a thousand middle aged adults. I have this linked in the show notes for those of you who have access over a thousand adults finding that lower those with lower levels of plasmologens on average that was negatively correlated with insulin resistance as measured by the HOMA IR score, meaning that reduced plasmologens were associated with poorer insulin Sensitivity, even after adjusting for factors like BMI and other blood markers and blood lipids. So this kind of thing can matter. And if anyone's ever been able to get their plasmologians measured, that can be then a pretty reliable marker. The higher the better. Now, sometimes knowledge is valuable in and of itself, but of course, as you know, I'm one of those scientists who thinks that the best information, the best science is science that can be translated into actionable steps. So as we near the end of this mini lecture, let's talk about how diet can affect plasmologians. Your food choices can support this. So on this on the positive side, certain foods and supplements can boost plasmology levels since they often contain omega 3 fats like DHA. Eating fatty fish or fatty sources of of DHA omega 3s, but this is like salmon or mackerel is a great thing. Even organ meats like the liver or dairy or eggs can also provide plasmologens directly. And studies show that these foods can raise plasmologen levels in blood cells and even lower cholesterol, for whatever that may be worth in healthy and diabetic individuals. Now there are some supplements too. They're another option. Alkyl glycerols can help. And there there are not a lot of sources of that, but one is found in shark liver oil. But alkyl glycerols act as plasmologen building blocks like a scaffolding. And they show benefits for conditions like inflammation and even brain health. DHA based plasmology supplements can improve blood levels as well and further support tissue function. But even and unexpectedly, some probiotics may help, like inulin, a soluble fiber. This is found in foods, some foods like garlic or chicory root. And you can also get supplements. Some smartly designed supplements may have it too, but that can indirectly support plasmologens by promoting gut health and fat metabolism. So from a GI origin. Now on the other hand, there are some signals in the body that erode plasmologens. I've already mentioned oxidative stress, but that is one worth mentioning. Where when you have an increased production of reactive oxygen species, the plasmologians take that hit in a sacrificial sense, losing themselves in the process, but protecting important parts of the cell. But also inflammatory signals can do the same. When inflammation is activated, immune cells like white blood, the white blood cell neutrophils can release a powerful oxidant agent like for example hypochlorous acid. And that takes aim at the plasmologens in the very process I just mentioned. So as much as we often will just think of the oxidative stress molecules as say, coming from an over taxed mitochondria, you also can have oxidative stress being produced in response to inflammatory signals from white blood cells. To sum it all up, plasmologens are special fats that keep cell M cell membranes flexible. They protect the cell from oxidative stress damage and support optimal cell signaling, with the insulin signal being a good example. Plasmologens are critical for normal mitochondrial function in the PRODU and the production. They help the mitochondria work well in a way that we need them to be working. And of course, as I noted, they can also help your fat cells be much more metabolically active, going from a metabolically miser mode into a very aggressive or wasteful mode. Which interestingly is a good thing when it comes to the fat cells. If you've been able to confirm or you suspect that your plasmology levels are low, the good news is that you can tip that forward a little bit. You can crank it up a bit. Eating things like omega rich foods or certain supplements like I mentioned before with the alcoglycerols can help increase and then and then sustain optimal levels of plasma allegins. Until next time, More knowledge, Better Health.

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Michelle Bernstein (30:17)

MIC check 12 Are we recording? Hi, I'm Michelle Bernstein, an award winning chef, restaurateur and mom. I have a lot on my plate, including my psoriatic arthritis symptoms. That's why I was prescribed Cosentyx. It helps me move better.

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Cosentix Secukenumab is prescribed for people 2 years of age and older with active psoriatic arthritis. Don't use if you're allergic to Cosentyx. Before starting, get checked for tuberculosis. An increased risk of infections and lowered ability to fight them may occur like tuberculosis or other serious bacterial, fungal or viral infections. Some were fatal. Tell your doctor if you have an infection or symptoms like fevers, sweatshirts, chills, muscle aches or cough had a vaccine or planned to or if inflammatory bowel disease symptoms develop or worsen, serious allergic reactions and severe eczema like skin reactions may occur. Learn more at 1-844-cosentix or cosentix.com Ask.

Michelle Bernstein (31:12)

Your rheumatologist about cosentyx.

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