When Fat Turns Toxic: What Really Causes Lipotoxicity | Dr. Ben Bikman

You hear the word lipotoxicity and it sounds kind of scary. But eating a ribeye every night isn't automatically going to cause this, right? What's the difference between that and when fat actually does become a problem?

There is absolutely a mistaken view when it comes to the role of dietary fat and what the body does with that fat, let alone storing it in a way that is harmful. But the, the mistaken view might be that eating fat leads to lipotoxicity, and that is not necessarily the case.

Hey, friends, welcome back to Meet the Truth. I'm Lauren Johnson. Today we're diving into a word that sounds a little intimidating. Lipotoxicity. Don't worry, by the end of this chat, you'll know exactly what it is, why it happens, and how to keep it from messing with your health on a carnivore diet. Joining me today is Dr. Ben Bickman, a biomedical scientist, professor of cell biology, and author known for his research on insulin resistance and metabolic health. Today, he's here to break it all down for us in plain English. So grab a coffee, get comfy, and let's dive in. Dr. Bickman, thank you so much for joining us. You hear the word lipotoxicity and it sounds kind of scary. But eating a rib eye every night isn't automatically going to cause this, right? What's the difference between that and when fat actually does become a problem?

Oh my gosh, what a great question, Lauren. And I appreciate just us hitting the ground running here. Yeah, there is absolutely a mistaken view when it comes to the role of dietary fat and what the body does with that fat, let alone storing it in a way that is harmful. Now, a lot of my postdoctoral work, in fact, indeed my entire fellowship years was devoted studying lipo to studying lipotoxicity. And so if I'm going to claim any kind of authority in any topics, this would be one of them that I would humbly plant my flag. But the mistaken view might be that eating fat leads to lipotoxicity. And that is not necessarily the case. I would say that it would depend what else you're eating with that fat. And by that I mean you can't ignore the degree to which hormones are telling the cells of the body what to do with that energy with that fat. So the whole idea of lipotoxicity is, at least from the perspective of a scientist who studies human metabolism and someone else may define it differently. But to me, the term lipotoxicity and how I've described it in my peer reviewed studies in scientific journals is That a cell will accumulate certain fats and these fats then contribute to the two things I've studied insulin resistance and then mitochondrial dysfunction, although that's a bit of a vague term. But briefly, what we have found is that when a cell accumulates a certain type of lipid, and I'll come back to that certain type of lipid in a moment, but I don't want my answer question to be so long and tedious. But the insulin resistance happens when the lipids block the ability, when these particular fats, and of course that's where the term lipotoxicity is coming from, that fats are becoming harmful or toxic to a cell. It's that the cell is accumulating enough of these fats or lipids that it's blocking the insulin cascade. When insulin, as a hormone comes and binds to its receptor, it will then initiate a series of events. One protein activating another protein, activating another protein in turn. And then these lipids will come in and block that. It's sort of like the stick going into the spokes of a bike and then jamming up the bike, stopping the bike, breaking the bike from its movement. The same thing happens here where these lipids will come in and block the signal. Now, at the same time, my lab published work finding that these same lipids that antagonize or block the insulin signaling cascade also disrupt mitochondrial dynamics. A little known fact of the mitochondria within the cell is that mitochondria are constantly in a state of flux. They're very dynamic. They're fusing into these long stringy structures and then they're pulling apart or undergoing mitochondrial fission. These lipids force the mitochondria to stay in a state of fission, so they're pulling the mitochondria apart. And we found that that results in a much higher degree of oxidative stress being produced from the mitochondria. So the mitochondria are just a little dirtier. There's more, there's more kind of pollution or exhaust coming from these engines now, if you will. And then to get right to the, the heart or the meat of the matter here, if someone's talking about lipotoxicity, they need to then be discussing the right type of lipid. And that lipid is ceramides. And that stands separate from how most people might be thinking of lipids that are maybe causing harm. But when you can cause a cell to start accumulating, making more and accumulating this type of fat called ceramides, now you're doing everything that I just got finished Artic. You're causing insulin resistance, you're forcing this sustained mitochondrial fission and the net result is a pretty disruptive environment to normal metabolic function within the cell. But then back to the finishing my answer to come directly back to your question. Eating a rib eye or any amount of these natural fats, that does not necessarily equate, in fact not at all. Does that mean you have more ceramides in your cel? Because when you're eating that fat you would just be burning that fat, especially if it's just in the form of a ribeye. And so maybe the final answer to this already too long of final bit to this excessively long answer is that a cell can choose what to do with the fat that it has access to. It can store it or it can burn it. And if insulin is low, the cell is burning that fat. It's not storing it, it's not turning it into ceramides. But even how a cell stores fat can differ. But that's almost another tangent here to my already long answer. So eating a ribeye does not necessarily lead to lipotoxicity. If we define lipotoxicity as the degree to which a cell is accumulating ceramides, which is the lipid that matters most when it comes to these harmful metabolic consequences, then there's, there's no connection there.

I'm sure that makes a myself doing carnivore relieved. So thank you for explaining that very thoroughly. Why do some people see opposite results than what they hope for on carnivore like weight gain or higher blood sugar? What could be causing those in those cases?

Yeah, I, I'm actually, I'm not familiar with instances of, of weight gain. Now of course this, the question puts me in a little bit of an awkward space because there's not a lot of peer reviewed studies I can refer to or, or any that, you know, there's no large scale trials that have been done on carnivore diets. So I have to sort of and then rely on anecdotes in answering that question. I'm unaware of people gaining weight on a carnivore diet. I've not seen that or heard that. And if that is happening, at the risk of taking the easy way out, I would just wonder how diligent or strict the person's actually being. But that's a little bit of an offensive answer because I don't want to discount someone's experience, but I've not seen it. But the second part I have seen, in fact even attempted to answer this question, namely, how can someone be reducing their consumption of carbohydrates or indeed putting it to zero and still and find that their glucose levels are either stubbornly elevated, that they've not come down, or in some instances they've actually gone up, I actually think that's probably a result of an excessive or rather a more dramatic glucagon response. In effect, that's what our evidence suggests. We've not published this yet, but we did a human study looking at people across a spectrum of type 2 diabetes and pre diabetes or no evidence of it whatsoever. And we found that people who tended to have the higher glucose levels and they were wearing CGMs, we didn't do carnivore, but on a very low carb diet, it was ketogenic, pretty close that they, these people who, some people who tended to have the higher blood glucose levels on this diet had the highest glucagon response to dietary protein. And so what's funny now is that even though your first question was talking about the consequences maybe of eating too much fat, and I hope I've alleviated some of those concerns, I don't think that's a problem in this instance. I think it might be where you have people who see an increase in their glucose levels, it may be a consequence of them being having a bit of an exaggerated response to the protein. So they eat protein and then protein is eliciting a more dramatic glucagon response. And this is something that is known to happen in people with type 2 diabetes. They eat protein, they see a bigger glucagon response, and then that is driving up their glucose or keeping their blood glucose elevated. So that might be one part of the answer, that if they're actually measuring their fasted glucose levels and seeing that their glucose is going up, it might be that they're a little glucagon dominant here, where they're getting a bit more of an exaggerated glucagon response to the protein in particular. And glucagon is insulin's opposite. I am mindful of the fact that people might not know what glucagon is. It's insulin's opposite. Insulin wants to lower glucose, glucagon wants to increase glucose. So that's one part of the answer. But the second part, I'm cognizant of the fact that some people might be basing their thoughts on an elevated hemoglobin A1C. They might have found that their A1C started at 5.5 and now it's 5.9 or it's 6%. So it's gone up. I actually, I detest A1C, if I'm being honest. I think it is a clinical marker that has broken our ability to measure proper human health and it's disrupting better measurements. Where nowadays a clinician can tell a patient, hey, you don't even need to come in fasted. We're just going to measure your A1C. Well, that's fine for A1C, although I'm going to revisit that and express a concern with a 1C as a marker in just a moment. But that means you can't measure any other marker. You can't get any hormone measurements, you can't get any of the blood lipid measurements, because if you don't come in fasted, they're all going to be screwed up. And so A1C, you don't need to be fasted to get that. And so the clinician is thinking, well, A1C is the best marker anyway. I don't need anything else. And how convenient that you can come in unfasted so it's easier for you to come in patient and you're not going to complain about being hungry. Unfortunately, though, it prevents us from getting all these other markers like insulin or triglycerides, because they're going to be very responsive to what the person just ate. But the other concern I have in people who've adopted a carnivore diet who are relying on A1C is that we forget that hemoglobin A1C is sure A marker of glucose, although maybe a poor one, but it also is a marker of how long lived your red blood cells are. That A1C is actually a measurement of both of those variables, glucose and red blood cell longevity. Because if you have red blood cells that live longer, the likelihood of them simply getting glycated is higher because the red blood cell just is lasting longer. And so it's just more. It increases the statistical likelihood that it is just going to get glycated. That is something that happens, and it does happen naturally. And what if some people who adopt a carnivore diet are, now they have so much good iron, heme iron, now they have a lot more good Omega 3s and fewer Omega 6s. And so their red blood cells are simply more resilient, they're going to live longer. They may just be more likely to get glycated in the course of that longer life. And so now we have the risk of A false positive where the A1C looks problematic, but in reality they're perfectly healthy. That's just an artifact or a consequence of them having long lived red blood cells. So ultimately a person who is on a carnivore diet and they know they're being clean and good about it, if they notice their blood glucose levels have climbed a bit, I actually think it is nothing to worry about. I also think that we've become as a medical realm, in a medical realm, we become too strict on blood glucose levels. I think it's helpful for everyone to appreciate that if you attempt to find over time the ideal cutoff levels for glucose, they've been slowly getting lower and lower and lower. In other words, like nowadays we say a glucose level of above 110 is pre diabetic and if you get to mid 120s, then you are full on diabetic. Those same ranges used to be about 20 or 30 points higher, even just as little as 30 years ago. And then before that it was even higher, although not even immediately defined. But we've slowly been lowering the threshold of what's considered a good glucose number. And as a scientist who's a little bit, who errs on the side of being a little cynical about these kinds of things in modern healthcare, my personal conclusion is the reason we've been lowering the threshold for considering glucose levels problematic is because then more people are going over it and then we can diagnose more problems and put people on more drugs and earlier. And so it becomes a very effective way of making money, even if it doesn't become a very effective way of actually helping the health of the patient.

So is there a way to know ahead of time before starting the carnivore diet, if you are more at risk of lipotoxicity, are there markers to ask for or to look for?

Yeah, that's a great question. Unfortunately, there would be none that would be easily measured in a clinic. You know, like looking at say circulating levels of ceramides. That would be the best way that you can do that. But it's. Most clinics couldn't do it. That's more of a kind of science lab realm. But I would say it might be prudent for a person to monitor their insulin. Now, most people can't monitor insulin. There's no way to do it at home, really. There's no way to do it in real time. Certainly there's no continuous insulin monitor. But insulin is going to be the deciding variable that determines whether the body is storing that fat and thereby Increasing, say, the pool of ceramides within cells or whether it's burning that fat. But let's say. Let's say a person knows, okay, I have really, really high insulin. It might be worth starting on slightly lower levels of fat, possibly. I mean, I'm trying to really be generous to the view that eating fat in any way contributes to lipotoxicity. And that's hard for me because I don't believe it does. But it might be a reason for someone if they're starting a carnivore diet with very dramatic hyperinsulinemia, meaning the body's going to be more inclined to store fat, that might be a reason to start a little slower on the fat level, perhaps just with the risk of if I'm eating too much fat while my insulin's still high, I'm going to be storing a little more of it. Yeah, that would be true. And with more of it potentially becoming ceramides, but I am speculating on that. I don't know if that's true, but maybe that might be the only reason. Start a little lower on the fat, maybe leaner meats, and then you could get more comfortable with fattier meats, which are going to give you more satiety. But also, Lauren, I feel inclined to mention that even some people still don't even understand lipotoxicity from the level of ceramides. Many people want to define it based on just the amount of fat that is in the tissue itself and most of the stored fat that is in tissues. Like if you look at fatty liver or fatty pancreas or fatty muscle, those are not ceramides that are being called the fatty part of the tissue. Those are triglycerides. And triglycerides are in an entirely different pool of fat. Triglycerides are the kind of poster child for the glycerolipids of the family. There are hundreds of thousands of different types of lipids. So it's a fantastically complicated realm of biochemistry. And I don't claim authority as a lipid biochemist, but ceramides are in the family of sphingolipids, named after the enigmatic sphinx because we didn't know what they did for so many decades. Now we do. But if a tissue is considered fatty, like fatty liver, someone may call that lipotoxicity, and I'd be fine with that definition. But the triglycerides are not inherently harmful. In fact, triglycerides are metabolically inert. So people need to be careful that they're not mistaking Stored fat with lipotoxicity. Because after all, if you want to find people with really, really fat muscles, look at very lean marathon runners. Athletes, very well trained athletes have a lot of fat stored in their muscle. Indeed, they have as much fat in their muscle as obese type 2 diabetics do. And yet the muscle of obese diabetics is profoundly insulin resistant with mitochondrial dysfunction. And yet the muscle of the lean marathon runners is exquisitely insulin sensitive with exceptionally well running mitochondria. And so people who are attempting to define lipotoxicity based on the amount of triglycerides in tissue, they have to reconcile that view with what is called the athlete's paradox, which is the paradox I just articulated, that you have a lot of fat in the muscle of athletes and yet their muscle is working exceptionally well.

You talked a lot about insulin resistance in your work, but also a little bit today. Can you explain a little bit more how lipotoxicity ties into that and, and blood sugar and how. I know you went over a little bit how blood sugar can go up, but can you go into that just a little bit more?

Oh, yeah, for sure. Yeah, gladly. In fact, this right now is perhaps my strongest topic of all, namely the way lipid induced insulin resistance. That was my. Both my dissertation work and my postdoctoral. Yeah. So lipids do matter, fat does matter, but not dietary fat. That's the great conundrum. That's the great conflict that some people have to reconcile. In their minds, eating fat is not the same as storing fat, and that's not the same as accumulating the particular, most toxic of all the lipids, namely ceramides. Because again, it's that particular type of fat, the ceramides, that actually disrupt these processes, including insulin resistance. So to maybe go into a little more detail than my long winded answer at the beginning, when insulin binds its receptor on the cells of the surface, it's sort of one step, then two step, then three step. And mind you, there's a lot of branch points. It's not one kind of single line of signaling. One will signal down and then branch out, and then those branch out and then those branch out. So it becomes like this very complicated genealogy biochemical cascade. And the ceramides will block, not right up at the start, but it'll block a little further downstream. So some of the effects that insulin is attempting to do are now lost. And my lab published a report finding that too much insulin to a cell will promote the accumulation of ceramides to cause insulin resistance. So ceramides become the great mediator of insulin resistance. Almost, I'm gonna say almost just to account for an instance that I might not be able to think of in real time, but in. In almost every instance. So I typically will describe three of the. Of the canonical causes of insulin resistance, or what I increasingly call. What I increasingly call fast insulin resistance. And in fact, this is going to be my topic at the meat stock meeting next year. Fast versus slow insulin resistance. You have three of the fast causes where you could take a human, I could take Lauren, you could come into my lab, and I could make you insulin resistant in just a few hours by either boosting up your insulin. So too much insulin drives insulin resistance, increasing the level of inflammatory signals in your body. So inflammation causes insulin resistance, and then lastly, stress. The big stress hormones, cortisol and epinephrine also drive insulin resistance. And what they all have in common is, yes, insulin resistance can be a consequence, but ceramides is the mediator in all of them. So if I can block the formation of ceramides, even in the midst of those three noxious stimuli, those cardinal causes of insulin resistance, we would prevent the insulin resistance. It wouldn't have happened. And so we have ceramides being the great mediator. All of those signals that are causing insulin resistance have to run through ceramides. And again, the mistaken view might be that, or at least the incomplete view might be that eating dietary fat is directly contributing to those ceramides. That's not the case.

Okay, so it's more of a ceramide issue at the heart of it is what I'm saying.

Yeah. And ceramides are a lipid. And so I don't mind at all. In fact, I indeed have used the term lipotoxicity. But it's not going to happen automatically. It's not going to happen in isolation. There must be signals. So it's one thing to say, all right, I'm supplying the. The building blocks, the substrate. I'm giving the cell the building blocks that it would need to create ceramides. But that's not so, in other words, fat, because ceramides are a type of fat. Ceramides are built from fat. And so it would be one thing to say, okay, I'm supplying the building blocks for ceramides, this lipotoxic molecule, but it's another to direct those building blocks into the formation of ceramides. And that's where you need the signal. Like the three that I just mentioned, chronically elevated insulin stress or inflammation. Those all provide the Signal to tell the cell, hey, cell, you have access to some fats right now, Turn it into ceramides. It's not something that's going to happen in the absence of those signals. But then someone could say, well, if you do have those signals, and indeed, Lauren, you even kind of articulated a question earlier that touched on this. Should there be someone who's a little more careful with their fat consumption when starting Carnivore? Maybe if a person knows, well, I do have really high levels of cortisol or I have high levels of inflammation, I measured my C reactive protein and it was through the roof, maybe then a person could say, well, eat some, eat a little less fat until we get that under control and then we can start transitioning into more of an ad libitum or, you know, eat whatever type of meats you want and it doesn't matter if it's fatty. But as much as I'm willing to admit that could be a rational line of thinking, it's still not one I necessarily agree with. But I wouldn't begrudge someone to, to embrace that or articulate it or even promote it. But I personally have a very favorable view of dietary fat. And, and, and I wouldn't embrace that view, but I could see how someone might and it would make a certain amount of sense.

It does, and I think your viewpoint makes a lot of sense too. And I think it's really important to get multiple viewpoints as well. And then that way you can make your own informed decision and totally take the route that you want to. Can you touch a little bit on heart health and how Carnivore might affect it, or perhaps even I've heard before that someone's CAC scores have gone up with Carnivore. Can you explain how that would tie into it?

Yeah, yeah. So that would be, that would be something that actually I think mattered. So I appreciate the question, and you mentioning cac, I actually think that should be relied on before anyone considers any conventional heart health therapies like drugs. Lipid markers are terrible predictors, especially the much adored ldl. I would even say apob. I would even say lp. There was a study done in women that documented the degree to which those kinds of markers, like a bunch of blood markers, the degree to which they correlated with the onset of heart disease. And I'm sort of acting this out because along the X axis they had right in the middle the kind of neutral score. And then they looked at a certain number of variables like high ldl, high apob, high lp, all of these again much adored lipid markers. And they found like if you looked along that zero line they barely would move it maybe like 1.5 or 1.6 in the case of APOB. And then they looked at having type 2 diabetes and it like went up to 10. They looked at having metabolic syndrome, it went up to 8. And so you're talking almost, almost a 10 times greater, not quite like 7 times greater increased predictive power that type 2 diabetes would have in, in predicting or correlating with a woman having type 2 diabetes as opposed to these lipid markers that we care about so much, all again in the context of heart disease. And so I have a very cool view, or not apathetic, but limited. My enthusiasm for these lipid markers is very low when it comes to heart disease risk. I very much favor looking at CAC because that's actually a marker that you're actually looking at the degree to which the coronary arteries have blockages, at least calcified blockages or the hard plaques. And there is evidence to show that in people with elevated CAC they do have a mortality benefit with a lipid lowering medication. As much as it pains me to say this, I have to admit the evidence is what it is and those are very convincing studies. The lipid studies don't convince me in just looking at lipids alone, but when you look at the cac, it does suggest there might be something. So people who find on a carnivore diet that their CAC is going up, I do think that's important to pay attention to. Now I've not seen that, but I want to acknowledge when you asked the question, Lauren, you stated that people do see it. So I assume that is something that's happened. Those might be people that are mindful more of the composition of the fats. While I'm a great defender of saturated fat, and as an important note, just so people are aware, meat is never all saturated fat. In fact, it would be uncommon for meat to even be 50% saturated fat. It's a mix of saturated and monounsaturated with a very little bit of polyunsaturated because that just exists in all sources of fat. But it's a mix of saturated and mono. But maybe that's an instance where they want to be a little more mindful of their saturated fat and focus a little more on monounsaturated. And that might be a reason to look for the free range eggs or the, the grass fed beef which is going to have a little more of the monounsaturated, although to a very modest degree. But that also might be an instance where they want to eat more like Omega 3s as well, like fish and stuff, but. Or at least supplementing, you know, cod, cod liver oil or other kind of less conventional sources. But I don't think that's something the average person would need to worry. But there might be some people, maybe they have an APOE 4 genotype and that is resulting in a bit of an uncommon response to saturated fat. But I guess my, my general view, not being a lipid biochemist or of course a cardiologist, because I'm just a scientist, might be that if someone notices their CAC going up, I think that is something to pay attention to and it might be worth, you know, scrutinizing just what you are eating.

I think this conversation is really important because it'll help empower those that are concerned about this sort of thing happening or any of these things that we've talked about, so they can take this information and, and use it to do whatever they want if they decide to do the carnivore diet or a higher fat diet. So, thank you, that was so good. And thank you for breaking down lipotoxicity in such a, in such a simple and clear way that we can actually understand.

Yeah, good. Well, I hope that nothing thrills a professor more than hearing that his ideas have resonated.

Well, thank you and I look forward to meeting you at Meat Stock and that's in Tennessee on May 2nd.

That'll be great. I'll be there with bells on. I'm excited. Thank you so much.

And friends, if you learned something new today, tap that like button and hit subscribe so you don't miss future chats with top carnivore doctors and health experts. Drop your questions or comments below. I'd love to hear em and maybe we'll tackle them in a future episode. Thanks so much for hanging out with me today. I'll see you next time.