54: Saturated Fat with Dr. Ben Bikman

Hello and welcome to this week's episode of the Metabolic Classroom. I am Professor Ben Bickman, a biomedical scientist and professor of cell biology. Hopefully that means I know what I'm talking about. Thanks for joining me today. This is a topic that I've been looking forward to discussing in part because there is so much silly thinking and bad information when it comes to saturated fat, in particular its effects on insulin resistance. This is something you've likely heard many influencers speak about, especially those who advocate plant based diets that encourage you to avoid meat. Often they will cite studies, they will say, well, saturated fat, the saturated fat from meat is causing insulin resistance, so that's why you need to avoid it. I have been looking forward to this topic in part because it's actually one of the areas that I am most authority on or most authoritative on, having worked in this field quite substantially through my not only my PhD dissertation, but also my postdoctoral fellowship where I focused on metabolic research for a few years working with Duke Medical School. All right, so with that as the introduction, let's just dive right in. In fact, let's start with some of my own work. Interestingly enough, it's some of this work that is cited by the anti saturated fat advocates. And so in 2011 I authored a manuscript that was published in a very good journal called the Journal of Clinical Investigation. It's one of the higher impact factor biomedical journals in the field, so very well respected and very difficult to get a paper accepted to publish in that journal. This study focused on the, on the role of, of a particular receptor that is found on a, on the cell. So on the surface of cells, among the many, many types of receptors or doorways for various molecules to come and knock on, there is something called the TLR4 or the toll like receptor 4. What we found in this paper published in 2011 is that when TLR4 was activated, it would induce a series of events and steps that would increase inflammation and that this process would result in the synthesis and accrual of a particular type of lipid called ceramides. Ceramides are the main molecule within a family of lipid or fat called sphingolipids, named after the enigmatic sphinx, because for so many decades, no one knew what these lipids did. Now, part of what I helped with was identifying the fact that these lipids do have a metabolic role to play, specifically inducing insulin resistance. So ceramides are a main mediator of insulin resistance and they do so by blocking the, the, the cascade or the series of events that is Downstream of insulin binding its receptors. So an insulin comes and binds its receptor, it would elicit a series of second messenger events, we call it, in cell biology. So one thing leading to another, leading to another, leading to another. So I use word, the use, I used the word cascade a moment ago, and that's a pretty good word. You can imagine this cascade, this waterfall of events occurring. Ceramides block that up. It basically is damming the cascade up, ultimately causing the cell to become insulin resistant. Now, having said all of this, what is the role of saturated fat here? Well, we identified in this study through a experiments that saturated fats, uniquely among the family of all fats, saturated fats uniquely stimulated TLR4, thereby resulting in the accumulation of ceramides and the overall antagonism or the insulin resistance that, that we're interested in for the sake of this discussion and was the focus of that manuscript. All right, so let me say that again. So saturated fats were found to be a ligand or a binder or an activator of TLR4. And when TLR4 was activated, it would then create ceramides or induce the synthesis of ceramides and the accumulation of ceramides, and then ceramides would block the insulin cascade, causing insulin resistance. So that was all accurate. It's all true. And it's often cited. My own research by the anti saturated fat army. Now let's take a step out of this work. And I had to do this myself. As I'm telling you this. There's also this sort of undercurrent of my own journey because I got done that work with this strong conviction that saturated fats really are a problem. This was in. And we did this work over actually a couple years. It was 2008, 2009, when we were doing this work. You know, it takes so long to get stuff published. And I really was doing this work thinking, boy, saturated fats are such a problem. Now, how did we actually conduct these experiments? This is part of the evolution that I had to go through myself, which I was happy to do because it forced me to change to look at the experimental model. And by looking at the experimental model more correctly and more lucidly, you're able to challenge the paradigm. So the paradigm here being saturated fat causes insulin resistance via inflammation and TLR4 and ceramides. But how did we actually show that? Well, we did it by directly infusing lipids right into the bloodstream and by directly incubating or treating or bathing cells with these fats. So it was a direct model, we were either directly bathing the cells with the fats or directly infusing it intravenously. Can you see the problem? Is this a physiological model, these experiments that I'm very proud of. I'm very happy with the work we did, although I very much regret how misinterpreted they've been, and in hindsight, wish perhaps that we would have clarified some of this in the discussion of the manuscript. But is infusing a fat intravenously or bathing cells in a cell culture the same thing with saturated fats? Is that the same thing as eating saturated fat? Of course it's not. Of course not. Let's, in fact, just by way of a brief physiological primer, let's go through the process of getting fat from the diet into your blood and then. And then use that as a segue to, To. To then dive into the studies that actually explore the role of dietary saturated fat on insulin resistance. All right, so much of the action when it comes to fat digestion, practically all of it, is the small intestine. Yes, we've been chewing the food, yes, we've been churning the food around in the stomach, but there's nothing really happening until we get to the small intestine. At that point, the fat is interacting with bile salts from the small, from the. From the liver that have. That has then been stored in the gallbladder. So the fat is coming down, the gallbladder contracts, thereby reducing the risk of gallstones moving the bile into the small intestine. And then the bile will separate the fat all out. You know, fat wants to clump together, and so this, the bile will pull it apart into small little blobs. That's a process called emulsification. You've heard of emulsifiers or emulsification before. That's what's happening there with the bile salts. Now, the molecules are small enough to be acted on by an enzyme and a series of enzymes called lipase. So the lipase starts snipping off the individual fatty acids of triglycerides. So here's a triglyceride. My knuckles are the glycerol backbone, and then these three fingers are the individual fatty acids. So the lipase comes in and we'll snip one of them off. All right, there's one fatty acid now that's just floating. Then it'll come in and snip the other one off. And then we're left with what's called a monoglycerol or monoglyceride, where you have one fatty acid bound to the glycerol backbone. And then these are small enough to get moved in to the intestinal wall. So now they can pull in and get absorbed by the epithelial cells or the cells that are lining the intestine. Once they get pulled in, they actually get re esterified. That's the technical term to say that they all just kind of get lumped back together. So let's go back to me awkwardly acting this out here. Here's the fatty acid bound to the glycerol backbone, but you'll recall there' spot for two more. So re esterification is taking this fatty acid and boom, popping it back on. Taking this other fatty acid and boom, popping it back on. So now we have a triglyceride that's been reformed. And now within the wall of the intestine with all of these reformed triglycerides, it will package them all up with the lipids, with these, the, the fats we've eaten the triglycerides, other lipids like cholesterol and phospholipids and some proteins, and lump them together in a bigger molecule called a chylomicron. Now, the chylomicron is big, big enough that it's not easily moving into the blood, through into a capillary, into the bloodstream. And so it doesn't go into the bloodstream, it goes into the lymph system. And so the lymph system is carrying these chylomicrons and then it deposits them into the blood through this area up in the thoracic cavity. That's where lymph meets back up with blood. So lymph comes from blood, that's a topic for another time, but flowing slowly through the body, ultimately getting its way back to the blood. And so the chylomicrons, now these big fatty protein complexes come back into the blood. Then. Now the journey's not over yet. And remember, we're talking about the digestion of fats, because the idea is that if you eat saturated fats, you'll get insulin resistance. So the chylomicron now is in the blood and now it can be acted on. So now we'll have lipoprotein lipase, a different version of the lipase that was in the, the guts that was cutting off the fatty acids. We have a, now a different version through the blood vessels, through the capillaries, and they're cutting off fatty acids and now absorbing them into the cell. And so the free fatty acids will be pulled in. But at that point it's Possible that they can bind any kind of receptors like TLR4. All right, and then we have the Kylo micron remnant. Having dropped off a lot of fat throughout the body, it can go to the liver and get reprocessed. Okay, now that is the brief, as I said, primer on the digestion of fat. So it's a little bit of gastrointestinal physiology for you. So does eating fat elicit the same response as directly infusing saturated fat via intravenous or directly treating cells bathing them with saturated fat? So let's, in order to look at that, I just want to highlight a few studies. Okay. The first study is one by Volk, V O L K Volk et al. And it was published in 2014 in a journal PLOS One. And when I say PLOS, I'm not saying PLOS like a plus sign or addition, but P L O S. P L O S1, 2014. Volk et al. This is probably the single best study that looks at the idea of saturated fat in the D and then explores that effect in the plasma. So let me just, before getting into that study, let me just emphasize what I'm, why I'm discussing this this way. The, the idea. So I've shown you evidence that if a cell directly gets saturated fat, it is capable of causing insulin resistance uniquely more so than other fats are via TLR4, as I explained at the beginning of the conversation. Now then, does that mean that eating saturated fat will increase the amount of saturated fats in my blood? That is the question that we want to know. Does Eating more saturated fat increase the saturated fats that are actually being circulated around? Because if so, that could explain a mechanism. So this study by Volk et al. Was fascinating because it actually took people through a stepwise increase in saturated fats. And so it had this, this very fascinating experimental model where the amount of carbohydrates and the amount of saturated fats was being changed. And so it would go in the stepwise direction, up or down. So and, and fantastic changes. I mean it would be multiples more saturated fat in, at the end or the beginning of the stepwise change. And you would think if dietary saturated fat directly connects to or directly leads to increased plasma saturated fat, well then as they step wise increase the saturated fat, you should see a stepwise increase. If they stepwise increase the dietary saturated fat, to be more precise, you should see a stepwise increase in plasma or blood circulating saturated fats. And you didn't. It was totally a flat line. Even Though they were eating two or three times more saturated fat, which is substantial, it did not change their plasma saturated fat levels and at all. They stayed, they actually went down by about half with the onset of this ketogenic diet and then it stayed down that low even as saturated fat changed. So the stepwise changes, the study suggests that the body really has an adaptation that even as you're eating more, the body is clearly handling it. Where you're not seeing these saturated fats hit the bloodstream like you'd expect. It could be just that they're getting burned, it could be that they are getting desaturated. That happens very readily where you take saturated fats and you actually desaturate and elongate. So it's possible for the saturated fats to turn into, actually to turn into oleic acid, which is the main fat in olive oil, and then get stored in, in fat cells or something, which is fine. All long chain fats are capable of being stored. So that's not inherently a problem, remember, because the main thing we're looking at here is the role or the degree to which dietary saturated fat gets, can increase plasma saturated fat. Because if we can show that, then there's a mechanism to explain that saturated fats could cause insulin resistance. But I just highlighted the study and I encourage you to look it up. Volk et al. In PLOS One Plus One in 2014, where it looks at the stepwise change in dietary saturated fat and it had no effect at changing plasma or blood saturated fat levels. Now with that idea in mind, I just want to highlight. It's a little bit of a tangent, but it's just such a kind of funny study that I can't help but show it. By now you've likely heard of something called the DASH Diet. DASH D A S H stands for Dietary Approach to Stop Hypertension. I think is what the A is dietary approach or approaches to stop hypertension. And they identified, you know, a diet that was capable of slightly reducing blood pressure. And that was relevant because if you reduce blood pressure you can reduce the risk of heart attack and heart disease in general. The diet, the DASH diet is famous, then all you'll ever hear about is that it is low fat and low salt. That's what people want to brag about and use it as evidence. The problem is it is multi faceted. There are multiple aspects and dietary changes that go into the DASH diet, including reduced consumption of refined sugars and starches. So it's basically something like. In fact, it sounds like a somewhat Miserable diet, which is probably why so few people adhere to it. It's very low in salt, it's very low in refined starches and sugars, and it's very low fat. Well, I can get behind one of those things. I very much am an advocate of reducing dietary starches and sugars or refined starches and sugars, but that was all a part of it. There's many factors, but the only thing you ever hear about is the low salt and the low fat. Well, what if it's the low carb that's actually benefiting the people here, as modest as the benefit is. Now, with this study in mind, the DASH diet so Chew et al. C H I U in 2016 published a paper that actually looked at it compared the typical DASH diet, which is low fat, low refined carb, low salt, with a really high fat version. So very high saturated fat that people were encouraged to eat full fat dairy liberally. So they were eating substantially multiple times more saturated fat than the other group. And not only did they enjoy the same reduction in blood pressure that the standard DASH diet did. And remember, that's the main reason people do it at all. So not only did they enjoy the exact same reduction in blood pressure, but they actually had better lipid improvements. Their triglycerides went down more and their VLDL went down more while the LDL stayed the same across the two groups. That is really impactful by lowering triglycerides and lowering vldl. Those variables are much more predictive of heart attack risk than LDL is. In fact, a paper was just published in the past few weeks at the time of me recording this in May 2024 that looked at varying blood lipid categories in people with higher or lower risk of having a heart attack and the people with the lower vldl but the higher LDL had the lowest risk of having a heart attack. I'll say that again. People with the higher LDL but the lower VLDL had the lowest risk of a heart attack. That's exactly the lipid profile we're seeing changed in the high fat version of the famous and much beloved, I would say irrationally so DASH diet. All right, now let's just go with this a little further by highlighting. So in general, by highlighting a meta analysis that was published in 2020 by Choi et al. Choi et al. C H O I choy et al. 2020, published in the journal Nutrients, they did a meta analysis of 20 randomized studies looking at people who were overweight, with or without type 2 diabetes. And the use of ketogenic diets on a variety of metabolic outcomes. So again, this is a meta analysis which a meta analysis analysis which is attempting to come up with a, a singular conclusion based on the combined outcomes of every published in this case clinical study. So very, very, very relevant. Now just to reiterate, this is of course ketogenic diet and ketogenic diets by their nature are higher fat, including often much higher in saturated fat. And indeed, looking through, sorry I said 20 randomized studies, it was 14 randomized trials looking at comparing it to low fat diets or high fat ketogenic diets. And they found that for these patients that are diabetic, so that means they're very insulin resistant, These are type 2 diabetic, the ketogenic diet resulted in significant improvements in both glycemic control and insulin resistance compared to those on the low fat diet. So they found that the ketogenic diet, despite eating multiple times higher levels of saturated fat than the low fat diet, had better improvements in insulin resistance and moreover, they had substantial improvements in their blood lipids. But you can look at the other details in that study, but it directly refutes the idea in a meta analysis that, that a high saturated fat diet is going to cause insulin resistance. It directly they found the opposite, that in these studies where the saturated fat consumption was high, but with carbohydrate consumption being low, there was a significant improvement over better than the low fat diet. So that is a direct refutation of the plant based advocates who are calling for everyone to avoid saturated fat. This meta analysis directly refutes that. So very high impact. I hope that leaves somewhat of an impression on you. Now, throughout this conversation there's been one component missing. So remember, I started the conversation, this little lecture by describing to you how saturated fats are capable of causing insulin resistance. And now we've challenged the idea that dietary saturated fat is contributing to that. And even if we zoom out to the 30,000 foot view and look at just global and or certainly within the US dietary trends over the past 50 years or so, the actual amount of saturated fat we've been eating has been going down steadily. It kind of came up a little bit from the 1930s up through the 1960s or 70s and then it came down. And yet over this same time period, the amount of insulin resistance globally, certainly within the US has just been steadily going up, up and up and up. I mean substantially. Just at a surface glance at this really high level, at a population level, we can see something doesn't work here. Now, this is, of course, correlational, and I'm very mindful and appreciative of the weaknesses in this. But even if we use the terribly flawed view of a correlational study, we can see that there's just nothing to this. It doesn't work. This dog don't hunt, as they may say in some parts of the US Again, saturated fat consumption has been going down for decades. And yet, or at the very least in the recent decade, it's leveled out. But during this whole time, insulin resistance has been skyrocketing. So there's clearly another variable here. And among the many possible variables, let's just focus on carbohydrates. But even still, in the looking at them in the context of saturated fats, now you're thinking perhaps what on earth could dietary carbohydrate have to do with plasma saturated fat levels? We're not eating. You could eat. You could be eating carbohydrates that don't have a speck of saturated fat in them. How could that possibly increase saturated fat? Well, it can. And of course, insulin is very relevant to this. So we know that high carbohydrate intake, particularly refined sugars and starches because of the increase in insulin, is capable of activating a process in the liver called de novo lipogenesis. Some of you, with a little bit of kind of Latin background, you're hearing some of the words here where you're hearing that it is the synthesis of new fat. So the liver is capable of taking carbons, including those from glucose, and turning them into saturated fats and then packaging up those saturated fats and releasing them into the body being transported on vldl. So VLDL is going to be the vehicle that is transporting these fats. And the fat that the liver is making is always going to be a saturated fat called palmitic acid or palmitate. So there are a couple studies that I want to highlight. The first one is Acheson A C H E S O N atchison et al. 1988. This is old. That's the year that the Winter Olympics were in Calgary, Canada. I remember going a banner year. All right. This study found that when a person ate sufficient carbohydrates that deliver glycogen, got filled up, but then continued to eat carbohydrates, which is very easy to do. Most people are doing this all the time. Most people never are restricting carbohydrates or fasting enough to even have their liver drop down even close to being zero. So we're always Almost kind of filled up with our liver. So the study found atchison et al. 1988, that if someone ate sufficient carbs that the liver was filled and continue to eat carbs, which is virtually every person on the planet, that the liver is capable of converting the excess into fats, increasing plasma saturated fats, all just because of the the consumption of carbohydrates. Another study, this is Sevastionova Siastionova. I'm gonna say that again, Sevastianova. For a guy who speaks Russian like me, I should be able to get through that. Sevastianova is the name. S E V A S T I A N O V A Sevastionova et al. 2012 1. This was a short term study finding almost the exact same thing that the overfeeding of simple sugars increased liver fat, but also liver fatty acid saturated fat production. So this directly challenges the idea that dietary saturated fats are the problem in increasing body or plasma saturated fats. This is suggesting that you can find that effect increased plasma saturated fat without even eating saturated fats, that just overindulging on carbs can do it. And of course, the more refined, the easier it is for all of this to happen. All right, now my concluding thought, having challenged the idea that dietary saturated fat is the problem in increasing plasma saturated fats which can likely contribute to insulin resistance, I mean the plasma saturated fats, and then introducing this other idea that the excessive consumption of refined starches and sugars could increase plasma saturated fats, thereby contributing to insulin resistance. But I as a scientist have to admit that there is some human studies that challenge that suggest saturated fats may be a problem in the context of a hypercaloric high carb diet. All right, those are two very, very specific caveats here that need to be mentioned. So there was a study published in the Diabetes Journal and the lead author name, last name is Lukonen L U U K K O N E N in Diabetes Care. This was published in 2018, so not too long ago. And in this study again they had a diet but then had them overeat. So really getting hypercloric with eating saturated fats and monounsaturated fats or just unsaturated fats in general. And they found that the group that was eating hyperchloric high carb satur high saturated fat had worse insulin resistance than the group that was eating high carb high fat with the unsaturated group, that that group didn't have as bad of of insulin resistance as the high saturated fat group. So for the sake of just blunt honesty, if you are eating a very high carb diet and you're going to indulge in a lot of fat, then saturated fats might, might be a problem. Now, you've heard me before speak about the problem with high fat, high carb, those should never be mixed. That is a particularly delicious and particularly fattening mix where you have the high carb stimulating insulin, which is going to signal to the fat cells to store energy, and then you have a lot of fat for those fat cells to then store. It makes it all the easier for the fat cells to get bigger. So high fat, high carb is a particularly vicious metabolic mix and should be generally avoided. This study suggests that if that high carb is mixed with high saturated fat, it's a little worse, even with insulin resistance than high fat and high than high carb with high unsaturated fat. But again, as highlighted by that meta analysis, if the high saturated fat is coming in an environment where the carbohydrate consumption is low, then there's no such concern and that saturated fat is just going to be burned. All right, that's the end. Hopefully you feel like you are much more educated with regards to the intricacies, the nuances of saturated fat. Now you know the origins of some of the arguments against saturated fat in that there are studies that have shown direct cell incubations or direct intravenous infusions of saturated fat is capable of causing insulin resistance. However, that is not the same as eating saturated fat, particularly in the context of a low carb diet. Thanks for tuning in.