59: Energy Toxicity and Insulin Resistance with Dr. Ben Bikman

Hello and welcome to the Metabolic Classroom. I am Professor Ben Bickman, biomedical scientist and professor of cell biology. Thank you for tuning in. Thanks for joining me during this discussion that we have today where the episode topic is going to be energy toxicity. This is a topic that is a bit obscure. It's certainly not one that the average person would have any, not only any familiarity with, but certainly no appreciation for the. So before we get started, I consider it quite helpful to do a little background here and even explain why this idea exists and what it hopes to explain what, what is what it's what it's attempting to, to provide an explanation for. So to answer that part of it, energy toxicity is an idea that is invoked to try to explain why a cell becomes insulin resistant. Now, this idea won for every cell. It's generally an idea that pertains to the cells that are capable of storing energy, primarily capable of storing energy as fats. And this is primarily now the liver and the muscle. So the general idea is that this condition, the idea behind energy toxicity, a certain metabolic state that's characterized by the accrual of excess energy. Um, now excess energy can take a lot of forms. It can be glucose stored as glycogen, but this is primarily focused on triglycerides. And I already mentioned the tissues that this is generally focused on muscle, on muscle becoming insulin resistant because it's loaded with energy, but it also can be used. It's often also invoked with regards to the liver. But essentially, uh, it. The idea being that as the cell becomes loaded with energy, it starts to become resistant to further energy storage. And a way to mount that resistance is to become resistant to insulin. Because after all, insulin is the definite article there, the primary stimulus to tell a cell to store energy. There are other hormones that elicit an effect, but they all pale in comparison to what insulin does. Now, as much as I'm talking about energy toxicity here, there's another term for it. A synonym for this would be lipotoxicity. You might have heard that term before if you haven't heard of any of them. Lipotoxicity is perhaps a more accurate way of talking about this idea of energy toxicity, because after all, it's generally considered that the fat that is stored is the cause of the energy toxicity. That as much as a cell is muscle and liver cell especially is capable of storing glycogen. The evidence that glycogen storage promotes insulin resistance is very, very flimsy. Now there are some lines of evidence that do support that, but primarily when people talk about Energy toxicity, whether they know it or not, they're really talking about lipotoxicity. And to be clear, that's the idea that the excess storage of lipids are causing this toxicity, which itself is a bit of a strange term because it's not like the cell is infected with energy, but it's reached a point where the amount of energy is detrimental. And that's why we bring in. That's why people bring in the term toxicity here. So the lipotoxicity is a slightly more accurate version of the same thing being energy toxicity. So to provide a little more background to this, this can apply to both glucose and fats, as we continue to talk about energy toxicity, that even when glucose is in abundance, it will primarily be stored in liver and muscles as glycogen. And then once the glycogen, traditionally, the way this will go is once the glycogen stores are metabolic, any excess glucose, which there can be in excess quite readily begins to be converted into fat, which muscle and liver do very well. And of course, fat cells do very well. Anyone who tells you otherwise is absolutely incorrect. Glucose is perfectly. A fat cell is perfectly capable of converting glucose into fat. Particularly this changes based on the size of the fat cell. The particular distribution of whether it's the fat from the plasma, from the blood that's contributing to the growth of the fat cell or glucose really depends on the size of the fat cell. But suffice it to say, glucose can contribute to the energy toxicity by nature of it being converted into stored fat. And then, of course, fat does this very well. Excess fat consumed with some important context, which we'll get to in a moment, will be stored. Now, this point is one that we will revisit because this is a. A fundamental concept of the energy toxicity idea, that this isn't necessarily fat that we're eating, but it's thought to be that we have fat that is coming from the fat cells. So, so fats that get stored as energy, stored as fat in the fat cells, then starts to come out of the fat cells and then getting stored downstream, if you will. Now it's getting stored in muscle and liver, leading to the lipotoxicity, or the energy toxicity in those tissues causing the insulin resistance. I'm going to state that again because it is a very important part of the energy toxicity model, this, this theoretical idea to explain insulin resistance, and it is one that we will revisit. So again, a lot of the idea behind energy toxicity is that you have too much energy getting stored as fat in Tissues that are ill su for the long term and excess storage of that fat, muscle and liver, and that much of that fat is coming from fat cells that are breaking down the fat. So the fat cell is undergoing lipolysis, the breakdown of the stored fat, and it is releasing these fats as free fatty acids, and then they're getting stored in other tissues. Another term for this is ectopic lipid deposition or ectopic fat storage. Ectopic being an idea where you're storing something where you shouldn't be or something is happening where it shouldn't. Like you, for example, have heard, undoubtedly you've heard the term ectopic pregnancy. That's when the pregnancy or the fetus is developing somewhere other than the uterus, maybe in a fallopian tube, or maybe it got the fertilized egg got out of the fallopian tube through some retrograde action and it's happening somewhere else in abdomen or any. Anyway, it ectopic is when something's happening where it shouldn't be happening. And in the case of ectopic fat storage, it's when the fat is basically forcing other tissues to start storing fat. All right, again, that's a fundamental concept of energy toxicity. And so we're going to revisit now, is it that simple? Is it just as simple as the, the fact or the idea that the muscle and the liver starts storing fat and then they become insulin resistant? No, it's not that simple. We need to firstly understand the role of triglycerides. And I'm primarily going to focus on the muscle because that is the heart. That is the tissue of interest primarily when it comes to energy toxicity. People will use the term energy toxicity to explain muscle insulin resistance primarily, but also liver. And some of these ideas still apply to the liver, but we're focusing mostly on muscle cells. So first of all, we have to understand how muscle cells store fat. Muscle cells, muscle cells naturally have a capacity to store fat. That's a very important point. That, and it's the type of fat that matters most here, actually, that's more important than the amount of fat the fat cell is storing. The type of.