← The Metabolic Classroom with Dr. Ben Bikman
The Metabolic Classroom with Dr. Ben Bikman
Why Some People Burn More Calories Than Others
00:28:43
More Knowledge, Better Health
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- [00:01]
Ben Bickman
What if your body could burn calories without turning them into usable energy? Inside your cells are mitochondria, tiny engines that burn fuel. Normally, that fuel gets converted into ATP, the energy that your cell can actually use. But sometimes the body lets that energy leak and it releases it as heat instead. That is called mitochondrial uncoupling. Think of it like revving a car engine while it's in park. Fuel is being burned, the engine's working, but the car isn't going anywhere. And the fascinating part is that insulin appears to make the mitochondria more efficient, helping the body store energy more easily. But when insulin is low and ketones rise, mitochondria can become more uncoupled, meaning more energy may be burned off as heat and instead of stored as fat. So calories matter, but hormones help determine what your body does with those calories. This is lecture 154 of the Metabolic Classroom,
- [01:09]
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- [01:41]
Ben Bickman
Howdy, howdy ho, and welcome to Fantasy Fanfellas. I'm Hayden, producer of the Fantasy Fangirls podcast and your resident lover of all things Sanderson. And I'm Stephen, your bookish Internet goofball, but you can call me the Smash Daddy. And we are currently deep diving Brandon Sanderson's fantasy epic Mistborn.
- [01:57]
Podcast Host
But here's the catch.
- [01:58]
Ben Bickman
Steven here has not read Mistborn before. That's right.
- [02:02]
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- [02:02]
Ben Bickman
So each week you'll get my unfiltered raw reactions to every single chapter. And along the way, we'll do character deep dives, magic explainers, and Steven will
- [02:10]
Podcast Host
even try to guess what's next. Spoiler alert.
- [02:13]
Ben Bickman
He'll be wrong. News flash, I'm never wrong. Episodes come out every Wednesday, and you can find Fantasy Fanfellas wherever you get your podcasts.
- [02:21]
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- [02:43]
Ben Bickman
Welcome back to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. Today we are going to explore one of the most underappreciated livers in all of human metabolism. That lever or lever is the question of how efficiently the body converts the fuel it burns into usable energy. And what happens when that efficiency deliberately breaks down. This is the phenomenon known as mitochondrial uncoupling. This topic helps us understand why, under certain conditions, people burn measurably more energy than their body size says they should be burning. By the end of the mini lecture, I think you'll understand that the answer actually helps us understand even the very nature of obesity. So why we get fat. All right, to make sense of this mitochondrial uncoupling, we first have to understand what it means for metabolism to be coupled in the first place. And the cleanest way I know to explain it is to think of it as an engine in a car. Think about the two things an engine can do. When you press the accelerator, there are the revolutions per minute, the RPMs, which tell you how hard the engine is working and how quickly it's burning fuel. Then there is the speed of the car, the forward motion down the road, which is the useful output, if you will. So it's the result, it's the work that we're getting as a result of burning all of that fuel. When the car is in gear or the engine is in gear, like, for example, it's in drive, if you're in an automatic transmission here, in this metaphorical car, those two things are tightly linked. You press the gas, the RPMs will climb and the car will move. The fuel you burn is converted efficiently into work. That tight relationship between fuel burned and work accomplished is what we mean by coupling. Now put the car in park or neutral and press the accelerator anyway. The engine roars, the RPMs climb, the fuel is readily burned, the engine's making a lot of heat, but you go absolutely nowhere. So you're getting a lot of fuel burning, but not much work. No motion, in this case, that is uncoupling. You've uncoupled the burning of the fuel from the work of the engine. Your mitochondria work in much the same way. They burn fuel and consume oxygen to pump charged particles across an internal mitochondrial membrane, building up a kind of pressure as these molecules are accumulating on one side of this membrane. This is kind of like the engine building up its RPMs. Normally, that pressure is released in the mitochondria through a single piece of molecular machinery that captures that energy. It harnesses that concentration of those molecules, and then it allows those molecules to come back across the membrane, but in the process turning it into ATP. So, and of course, that that's the the working molecule, it's that usable energy that the cell is going to get work done on. The molecule that gets the cellular work done again is ATP. So fuel burning is coupled to ATP production, that is the car and drive, or that is the mitochondria coupled. But the membrane can be made deliberately leaky. When a specialized protein, fittingly named the uncoupling protein, opens a channel, the pressure bleeds back across without passing through that energy capturing machinery. So fuel keeps burning, oxygen keeps being consumed, but the output is just some heat rather than a lot of ATP. So this is like when you're revving the car when it's in park or neutral. There's a lot of revving, there's a lot of fuel burning, but you're not going anywhere. There's not a lot of work getting done. Now, you might reasonably ask why the body would ever do this on purpose. The answer is probably warmth. You see, we carry two broad kinds of fat. The familiar white fat, the type of fat that you can pinch or jiggle, is built for storage. And its mitochondria are very tightly coupled. They're frugal, efficient, they're designed to hold on to energy. But we have a different type of fat. Brown fat is a very different type of creature, if you will. It is densely packed with mitochondria, which gives it its more brownish color. But these mitochondria are full, full of that uncoupling protein that I mentioned a moment ago. So its entire job is to burn fuel for heat. It's running the engine in park, but that's a feature rather than a flaw. In fact, this is how a newborn human baby keeps warm. You'll notice that a newborn baby doesn't shiver to generate heat. They don't have enough muscle to do that. So they have this fat that is designed to keep them warm instead. So uncoupling is not a malfunction, it is a built in setting, a way for the body to dispose of fuel as heat instead of storing it. And as we'll see, diet and hormones can turn that setting up or down. But adults also do have this brown fat. Just to make it clear, as much as I mentioned that babies have it, we start to lose some of it, but we still have some as well, just like we did when we were babies. And it has been shown to be more active in response to cold exposure. Now the purpose of this mini lecture is not cold exposure, but that is an obvious way to trigger the brown fat and that mitochondrial uncoupling and it has also been shown in adults that have more brown fat, they tend to be more resistant to weight gain and its consequences. Now, all of this also points to how a scientist measures coupling in the lab, in practice. And the method is pretty straightforward. I've done this a lot in my own lab. We track two numbers in a piece of living tissue or the cells. We want to measure how much oxygen the mitochondria are consuming, which is sort of the surrogate for how fast the engine is turning. But we also measure how much ATP the mitochondria are producing, which sort of stands in place for the engine actually moving the car, or the work that is getting accomplished in tightly coupled cells. Those two numbers kind of go together. A great deal of oxygen being used is going to result in a pretty good amount of ATP being produced in uncoupled mitochondria. These two numbers have come apart. The oxygen use stays very high, may even go higher, while the ATP production falls behind. It might not be going up at all, might be going down. Now, I mentioned that my lab has focused on this, and I'm going to highlight some of our work in a moment, but I want to share with you briefly how I became interested in this in the first place, because I think it's a fascinating little bit of history. So this started with an observation that was made more than a century ago, and it was never really explained. The mechanism was, of course, much too molecular to be identified at the time, in the era before insulin was available as a treatment. Two legends in their own field. These two pioneers, Elliot Joslin in the field of endocrinology, and Francis Benedict in the field of energy expenditure and metabolic rate. In fact, the Benedict equation is still used to this day, and it was, it was so accurate in order to determine metabolic rate in. In various bodies. So these two legends, Joslin and Benedict, they come together, this power couple here, and they studied diabetes or they studied metabolic rate in people with what they called severe diabetes, what we would now call, well, type one, but untreated type one. They didn't have insulin as a therapy at the time. So these are bodies that make no insulin on their own. What they found was that these patients burned energy at a rate that was much higher than it should have been, about 15 to 20% higher than it should have been, based on their body size, because body size is what largely determines someone's metabolic rate. A bigger body has a higher metabolic rate. That's no surprise. Now, these patients were wasting away. They were losing weight at an alarming pace, despite eating an excess of calories, and their engines were just running hotter than expected. Now, fast Forward decades later, 1984, to be precise, another group with far more precise instruments, of course, they found that the observation held up. So this was a careful study of patients with type 1 diabetes, who of course, were producing no insulin on their own. And they found that their energy expenditure once again was about. At the time, they found that it was precisely 20, 40 calories a day. Now, these were small bodies. They found that this was much higher than it should have been. It should have. Their metabolic rate should have been about 1700 calories. So again, once again, this was pretty close to what Benedict and Joslyn found. It was about 15 to 20% higher than it should have been based on their body type. So they confirmed these, that kind of metabolic anomaly from, from decades prior. Now, here is the thing that interested me the most. When those patients were given insulin, their energy expenditure, their energy expenditure or their metabolic rate fell. In fact, it started immediately, like within minutes of the insulin injection, and it went right down to where it should have been. What was predicted based on their body size? The variable that moved the metabolic rate up and down then was insulin itself. You take away the insulin, the body's burning too hot, you give it back, things, the burning slows back down to normal. What makes this so compelling is that it runs directly against the ordinary intuition about energy and even survival. We tend to assume that a starving body or a body losing weight uncontrollably must be conserving energy.
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- [13:34]
Ben Bickman
It's got to be banking every calorie it can against the shortage. Yet here was the precise opposite. Bodies somehow burning faster than healthy bodies of the same size. For a long time, the standard explanation of how an untreated type of diabetic was losing so much weight was simply explained by the blood sugar or the glucose that was lost in the urine. The reasoning being that uncontrolled diabetes spills glucose and therefore calories into the urine and that this lost fuel accounts for the weight loss. There is certainly some truth in that. That's going to be a couple hundred calories that's getting wasted in the urine. But it does not add up to the whole picture because the calories lost in the urine cannot fully account for the measured rise in energy expenditure. Just urinating out energy would not explain a higher energy expenditure due to a higher metabolic rate. So something else is making these patients just burn more. Of course, it has everything to do with mitochondria, including the Mitochondria in our fat tissue. All right, so let's come now to my own lab. So we're fasting. We're going forward further in time now to test whether insulin really does reach into fat tissue and change how the mitochondria behave there, my lab ran a series of experiments. All of these have been published. We started with rodents, and we gave the animals enough additional insulin over several weeks to hold them in a steady state of chronically elevated insulin, the very state that has become, of course, so common in people with insulin resistance. Then we examined the mitochondria in their fat, and we found that the high insulin levels reduced both the rate at which those mitochondria were working or respired. We call that mitochondrial respiration. That's just the mitochondria work. But we also found that, that we shifted the degree to which the mitochondria were uncoupled. So to put it in the language of the earlier analogy, insulin took the engine out of park that was revving really high, but not going anywhere. But it shifted it firmly into drive, albeit at a kind of low idling rate. So we found that insulin made the mitochondria more tightly coupled, so that less fuel was being burned off as heat and more was being captured for the cell to use. Of course, fat tissue has a very low metabolic rate, so this just meant that very little fuel was being burned and more was being stored. It accomplished this in part by turning down the uncoupling machinery itself, lowering the amount of the uncoupling protein, and dialing back the genetics of the. Well, this, this kind of genetic program that builds and activates the heat generating mitochondria or the uncoupling proteins. Notably, the effect was not uniform across every fat depot in our study, and you could look it up for more details, but it appeared that in some fat depots, but not others, we saw more of this coupling happen. In fact, we found that brown fat became much more tightly coupled and subcutaneous fat became more coupled. But visceral fat was largely just still very coupled, and it didn't shift as much, but the whole consequence that we found lined up, kind of like what you'd predict, based on what I've taught you so far, that the chronically high insulin lowered total energy expenditure. And indeed, we measured this at the level of the whole body in these animals. So the fat tissue is more tightly coupled, the metabolic rate went down, and the whole body metabolic rate went down. Now, this makes some sense, right? Insulin is the body's principal storage signal. So it makes perfect sense that alongside instructing fat cells to take up and hold on to fuel, it would also make their mitochondria more frugal, more tightly coupled, wasting less energy as heat, conserving more for storage. This also offers a mechanism for something many people who take insulin therapy come to notice, which is a tendency toward weight gain. Part of that may be insulin doing precisely what we measured in the laboratory, quietly making the body's fuel economy more efficient. Maybe quiet, but it's not very subtle. You notice this, the patient sees this. You see this not only in type 1 diabetes, where the person will start to both eat less and yet gain fat at a remarkable rate, but also even in people with type 2 diabetes. Once you put a type 2 diabetic on insulin therapy, the evidence is clear. You give that overweight type 2 diabetic more insulin and their metabolic rate begins to slow even more, making weight gain that much easier.
- [18:35]
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Ben Bickman
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- [19:46]
Ben Bickman
All right, if insulin pushes the engine into drive to be more frugal or miserly with the energy, the next obvious question is whether anything pushes it the other way, back toward being in park or neutral, where you're revving the engine but not going anywhere. And the most interesting candidate is a molecule that rises precisely when insulin falls. When insulin is low, whether from fasting, carbohydrate restriction, or of course, in untreated type 1 diabete, the liver begins burning so much fat that which it can do when insulin's low and it turns that fat into ketones, the dominant one being beta hydroxybutyrate. Of course, like the other fuels, a ketone is both a source of energy and a signal. In fact, it's more of a signal than the other nutrients are. And it was that signal role that we wanted to understand. In my lab, we exposed fat cells and fat tissue to ketones across three different systems. Cultured fat cells, so that is fat cells growing in a little petri dish. We studied the fat tissue from rodents and most importantly, at the pinnacle of all creation, humans. We obtained human fat by fat biopsies. We measured, took this from people who were in ketosis and not in ketosis. So high BHB and low bhb. The result was fantastically consistent across all three. In fact, this is one of the studies I am most proud of that has ever come from my lab in my whole career as a scientist. Ketones drove the mitochondria to respire or work much harder or faster, burning roughly 90% more energy. In the cultured fat cells we found in the rodent tissue, it went up even more. And in the human fat tissue it was the highest of all we in that. In the fat tissue from humans, we found that when the ketones were elevated, respiration climbed up by 128% higher than compared to the fat tissue from those who were not in ketosis. Now that's only one part of the story. Remember when we talk about uncoupling, part of it is the work of how quickly the mitochondria are burning the fuel. But then a part of it is how much it's using that fuel to create ATP. All of that extra fuel burning produced no matching increase in ATP. The fuel was being burned, consumed and the oxygen was being used. Yet usable energy converting into ATP was not coming out at the other end in proportion that gap. So the, the vigorous burning, with no extra usable ATP to show for it, is the unmistakable signature of mitochondrial uncoupling. Ketones had taken the engine and revved it while in park. The cells confirmed this at the genetic level as well, ramping up the very machinery of uncoupling in response to that beta hydroxybutyrate exposure. Now, we are not the only lab that has found this to my knowledge. We are certainly the only ones who've done it in humans. But earlier work from rodents found that feeding animals a ketone, a BHB supplement, also multiplied that heat generating machinery in their brown fat and modestly raised their energy expenditure. Again, this is rodents. The human piece of the part of this is what matters most to me, because human evidence, of course, is the standard. The fact that fat taken directly from humans in ketosis showed the same uncoupling signature tells us this is not an artifact of cell culture or a peculiarity of rodents. It's a real feature of human physiology. There's a deeper implication tucked inside this response. White fat, the body's storage tissue, is not locked permanently into its frugal, tightly coupled identity. Given the right signals, the white fat, specifically the subcutaneous fat, that fat that you can pinch and jiggle, can begin to take on the characteristics of brown fat, more mitochondria, and importantly, switching those mitochondria into the uncoupled state. So that's a transformation that we in the biz of studying mitochondria call browning or beiging of white fat. What our ketone findings suggest is that ketones are among the signals capable of nudging ordinary storage fat in that direction, coaxing a tissue that was built to hoard energy into behaving at least part way like a tissue built to give it off as heat. Now circle all the way back to that century old finding that puzzle Untreated type 1 diabetes is the most extreme version of low insulin and high ketones that a body can reach. If ketones uncouple human fat, and our biopsies certainly plainly show that they do, then at least part of the mysterious 15 to 20% rise in metabolic rate that the early researchers measured in that later work confirmed may be nothing more than those patients, their own fat tissue flooded with ketones and stripped of insulin's restraint, running the engine in park or neutral and just pouring fuel. Burning that fuel not for work, but just as heat.
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- [27:08]
Ben Bickman
now all of this puts us in the middle of one of the longest running arguments in nutrition science, and I think the mitochondria have something to contribute that can help us make sense of all of this. On one side, when we look at obesity, there's the view that obesity is, at its core, nothing more than a matter of calories energy in versus energy out, nothing more. On the other side sits the view that hormones and insulin above all, govern whether the body stores fuel or releases it. Those are usually treated as rival theories locked in some kind of opposition. I would suggest they are simply two halves of a single mechanism. Calories absolutely matter. The body cannot store energy it never took in, and it cannot waste energy that was never there to begin with. But the hormonal milieu, the environment, determines how efficiently a given number of calories is handled, and the hinge on which that efficiency turns is the fat cells mitochondria. When insulin is high, those mitochondria are tightly coupled and the calories are stored with wonderful efficiency. Very little of that energy is wasted as heat it's stored. When insulin is low and ketones are elevated, the same mitochondria turn leaky and wasteful, and a portion of those calories is now dissipated as heat, rather than stored in the absence of elevated insulin. In other words, the body has a harder time storing calories as fat because the very machinery that would otherwise store them with maximal thrift has been shifted toward waste. The calories don't fully count, in a sense, because some of them leave as heat. After all, a calorie is literally a measurement of heat. This is, I believe, a large part of what people are pointing at when they speak of a metabolic advantage on a ketogenic diet, it's of course not any kind of magic. But it's also not a license to ignore food or ignore calories completely. But it is measurable. Carefully controlled studies in humans have found that people burned more total energy on a very low carbohydrate diet than on a high carbohydrate diet of equal calories. In fact, it's pretty meaningful on the order of 2 to 300 calories a day. In one particular study, that is potentially an hour or more of straight exercise that's just now being wasted. Instead, you didn't have to earn it through all of that effort. So the calories out part of that equation, which is normal, normally accounted for with activities like physical activity or exercise, is now just happening in because the engine is simply idling at a higher rpm. We see some echo of the same theme in fasting. In the early days of a fast, when insulin drops and ketones climb, resting energy expenditure tends to rise rather than fall, which is what most people think happens. So it's the opposite of what you might intuitively expect. Now, in this case, some of that increase is actually driven by the nervous system and adrenaline or epinephrine. And so I don't want to lay it all at the feet of mitochondrial and coupling, but the timing is telling. Energy expenditure rising in step with falling insulin and climbing ketones. It fits the pattern of our fat tissue work perfectly, just like we would have predicted. Now, what does all of this mean for someone who's trying to manage their weight and their health? The practical thread running through all of this is that the kind of calories you eat shapes the hormonal environment those calories arrive in. And that environment in turn sets how thriftily the body files them away. A pattern of eating that keeps insulin chronically high invites the body to store fuel with a remarkable efficiency. Very little of it is lost. In contrast, a pattern that keeps insulin low and allows ketones to rise, whether through carbohydrate restriction or fasting, or maybe in some instances, just the use of exogenous ketones shifts the fat cells, mitochondria, toward the wasteful end of the dial, so that a portion of what you eat is surrendered as heat, rather than locked away in storage or waiting to be just burned when you exercise. Now, this is not a claim that calories don't matter. I want to be careful. But it is a reason to pay close attention to the hormones, the environment that those calories exist in. So when you consider this altogether, the century old observation that insulin deficient patients have excessively high metabolic rates, the finding that insulin tightens the coupling in fat and lowers energy expenditure, and the finding that ketones loosen that coupling and raise it, the concept becomes clearer. Calories provide the fuel, while insulin and ketones determine how the fuel is used. And the mitochondria of the fat cell, deciding from one moment to the next whether to store the fuel or burn it off as heat are the place where those two competing views of obesity can really come together. This is why, in closing, I'm such an advocate of the view that what matters most for weight loss is control carbs. If you control carbs, you control insulin. If you keep insulin low, you allow the mitochondria in your fat tissue to be frivol this with energy, making weight loss that much easier. Class dismissed. Until next time. More knowledge, better health.
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