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Great, all right. So let's do this. Let's move right into the metabolic classroom. And I mentioned that the topic today is, "Do you make your fat cells hungry?" Yeah, thanks so much. This is a study that I've actually had in the back of my mind for years, and and I would, I would remember it and then forget about it, remember it and forget about it. And then with the new year, and knowing of course, a lot of resolutions will be based on controlling body weight, as they should be. That's a good, just, that's a good New Year's resolution. It's also more timely than ever as we are worried about COVID-19 and the obvious data that suggests that having too much body fat is the single greatest or most relevant pre-existing condition in determining who has a very serious reaction or who doesn't. Of course, there's a lot of nuance there, but nevertheless, that's what the best available data in the U.S. suggests. So as people are making efforts to lose weight, this study, uh, really serves as a sobering reminder to not attempt long-term weight loss through caloric restriction.
Now, let's, let me kind of set the stage here. So this study, um, involved a really mix, a good mix of of human subjects and human intervention with some really cool, um, biochemistry. And on the biochemistry side of this study, they looked at the expression and activity, and that's the most important variable, really, how active this particular enzyme was. And this enzyme is called lipoprotein lipase. This is the main, the main enzyme that will pull fats from the blood, whether it's fat that is being, um, released from the liver when the liver is making new fat, or whether it's following a meal, um, when the fat gets packaged into what's called triglyceride-rich lipoproteins. So this, this enzyme, lipoprotein lipase, will see the passing triglyceride molecules, the main form of passing and storing fat around, and it will pull the fatty acids off of it, if you will, and then allow them to be transported into the cells. This is the main mechanism whereby fat cells get big and stay big. In the earliest stages, this might be a topic for another time, when a fat cell is really small and just growing, if you will, it uses, it makes its own fat from from glucose. And then once it gets to a bigger size, now it's growing and maintaining by just pulling in fat and storing the fat, not making it from scratch, but pulling it in. So lipoprotein lipase matters for the growth, maintenance, and shrinking of fat cells. Of course, because in the end, you'd want to be pulling in less than you're letting out of the fat cell if you want that fat cell to shrink.
So they had these ladies during the course of this study, they pulled fat biopsies, some things we do here as well in my lab, but then they measured the the activity of this enzyme, lipoprotein lipase, to just see how busy are these fat cells and pulling fat off during the course of this intervention. And the intervention was a low-calorie weight loss study. So they took these overweight women, all of the subjects were women, and then they had them go on to a very low-calorie diet over the course of three months. And of course, as you might expect, when they were eating about a thousand calories a day, which is very low, they lost a lot of weight. And then for the following three months, they kept them there on a very low-calorie diet to maintain that that state of weight loss because, of course, if you, whatever dietary intervention you do to lose weight, you need to keep doing it to keep the weight off. Generally, when you start to go back to the way you're eating, you'll go back to the way you were weighing.
So they had three time points. They took a fat biopsy at the beginning of the study, a fat biopsy at the end of the initial period of weight loss in that kind of three-month window, and then a fat biopsy three months later with the sustained weight loss. And then, um, in this, what they did, if someone has access, if they're looking at the study, in in figure one, they they looked at this in different conditions. And the first was they looked at it in fasting conditions. So the women came, came in fasting, and then they pulled these fat biopsies and measured the activity of lipoprotein lipase. And it kind of went something like this, where at the beginning of the fast, at the beginning of the study, before the weight loss, these, um, LPL was active at the rate of of these units were, you know, five, basically sort of a rate of five. Well, I just, I'm giving it that value, that's the value, but it's these equivalents of activities. So it was giving this activity score of five at the initial time of weight loss. So right after the weight loss was achieved in this fasting state, lipoprotein lipase had gone down by about half, in fact, almost exactly half. And then as this weight loss was sustained, LPL during a fasted state, LPL went back up to where it had been, even though they weighed less. So there was this period of time during the immediate weight loss where LPL was less active. So the fat cells were physically pulling in or pulling in less of the fat that was flowing by and then dumping it in, you know, allowing it to be stored into the fat cell. Now, that's interesting. Again, that is in the fasted state, but that's where, that's where the the nice side of this ends because you'd say, well, that's benign enough. LPL activity went back up to where it had been, uh, in a fasted state. I agree. In a fasted state, it looks like they just got back to where they were.
However, things really get ugly, um, in two other follow-ups. In a subsequent study, they gave the people an infusion of insulin, just to mimic as if they'd eaten an insulin-spiking meal. This matters because for LPL to be turned on, insulin must be elevated. This has ramifications, of course, within the low-carb or low-fat diets. All the more reason we focus on insulin with Insulin IQ. Insulin is a necessary stimulus in in activating LPL. So in these ladies, they gave them this insulin infusion, and then, then things really took off where in the state of immediate weight loss, the the activity, so the first weight loss state, the activity of LPL went up a little bit. It was a very modest, uh, marginally significant change. However, as the weight loss was continued over the following three months with that insulin infusion, lipoprotein lipase was now eight times more active in response to that insulin and than it had been before. So the efforts of these women to sustain their weight, their weight loss with very low-calorie diets, their fat cells had become eight times more sensitive to insulin turning on LPL. In other words, insulin was eight times better at telling those fat cells to store fat. It's almost like the fat cells were hungrier, they were more eager to pull in this fat.
And if that wasn't bad enough, in figure five, they showed what happened when the, when these women just ate a mixed macronutrient meal. So the first part of it was just infusing insulin. This follow-up was just giving them a meal and then looking at after the meal, to pulling fat biopsies and measuring the rate at which LPL was acting. In this time, whereas insulin alone bumped it up to about eight times higher than normal, now after the meal, in this now kind of chronic, several months into sustained weight loss with low calorie, it was now 12 times higher. LPL was 12 times better at pulling in fat from the blood and storing it in the fat cell. So that's my my comment about the fat cells being hungrier. In this state, of course, I'm using that term to be a little provocative, but I base it on these findings, on these last two observations in in figures three and five, which was, you know, especially five, after the meal, just a normal mixed macronutrient meal, carbohydrates, proteins, fats, the fat cells were 12 times better than they were before, even though they weigh less. They weigh less, and now their fat cells are hungrier, you know, 12 times hungrier than they were before, 12 times better at pulling fat in from the blood to store into the fat cell. And that, that's the gist of the study. Um, but hopefully, a bit of a sobering, um, uh, not reminder, because some people wouldn't have known this, but, uh, a sobering lesson, uh, where we need to be careful in how we're losing weight. And if we're, if we're trying to reach sustained weight loss by following the old maxim of "eat less, exercise more," we really are following the pattern outlined in this study, which explicitly found fat cells become 12 times better in these ladies at storing fat. We don't want that to happen. We want the inverse.
And as the follow-up to this, I'm not going to cite the studies. There are other studies that have done this. We want to turn down the activity of LPL in the fat cell, but that fat has to go somewhere. You can't just turn off LPL at the fat cell, otherwise your triglycerides in your blood start to climb, and that's, that's not good. That's atherogenic, I'm very likely contributing to the development of atherosclerotic plaques. So you want that fat to go somewhere. And if you can lower insulin, like say through a low-carbohydrate diet, you selectively turn down the LPL in the fat cell, and you turn it up in the muscle cells. Your muscle cells start to express more lipoprotein lipase, and they become the new sink, if you will, or the engine that is that is that you can pour that fat into, uh, to be burned. So we, and I'll do that as a follow-up sometime, I'll highlight that specific study. It's by a scientist with the last name of Greenwood, but it's pretty compelling. Back to this study, don't make your fat cells hungry by starving the body. In contrast, let the, let the fat cells naturally just start while they become less relevant. You just simply aren't depositing fat in them. And that best happens when insulin comes down, rather than just trying to deprive the body of energy overall.
Wow, interesting. Yeah, pretty neat, huh? Yeah. Who would, who would have thunk that, uh, fat cells were so darn smart, huh? Yeah, that's right. Yeah. Yeah. So there's a study, I think I've mentioned it on here before, but there's a study where they took a group of women who severely restricted calories, same thing, a thousand calories. They did it for eight weeks and looked at their ghrelin hormone a year. They did it in certain increments, but including a year after this severe caloric restriction. And same thing, even a more direct making your fat cells hungry. They, they said that the ghrelin hormone was higher a year after the caloric restriction than it was when they started. So it just goes to show, once you've gained weight, this is kind of a sad fact, but once you've gained weight, you will be fighting that weight for a long time. Um, yeah, especially if you try and get rid of it through caloric restriction. And we're, we're hardwired to survive the next famine. So that, you know, in in any other society that isn't full of gluttony and the ability to, you know, get our hands on whatever we want, this would, this mechanism or these mechanisms that our body, you know, is utilizing would be a good thing. But in our society where we just have too much abundance, we see it as a bad thing. And mind you, Carly, not just our society, it's a global problem, right? Right, right. If it started in the U.S., we are so good at exporting all our vices and virtues.
And the comment you made about muscle, this might explain, you know, most people who've gone to school, who've studied nutrition and exercise and all that, I think would tell you, oh, you can't gain muscle without exercising. Exercise is the means to gain muscle. But in our, um, with our clients, we always, we often will see people gain muscle over the course of say, three months, six months, with even without exercise. We watch that. Do you think that's a, uh, you know, product of what you're saying? What a, what a great, um, observation. I, I will say, if, if assuming what you're seeing is real, there is evidence by, um, Jeff Volek, um, when he was at Connecticut, uh, where they published a paper reporting an increase in lean body mass following a low-carbohydrate diet. So exercise was not part of the intervention. So I'd say there's a precedent for that. It's hard for me to imagine the mechanism other than there must be some rebound increase in growth hormone, which which certainly can happen in low-carbohydrate diets. Um, but I, I'd say there is a paper that's been published on that exact topic. Well, you should expect the opposite. When you're lowering your insulin, you should expect to see, you know, your muscles shrink, as far as, yeah, yeah. Well, that's debated. Yeah. The role of insulin as a genuinely anabolic hormone at the muscle is a little unclear. I heard someone once say it this way, and I'm quoting whoever it was, insulin, rather than being anabolic at the muscle, is better thought of as being anti-catabolic. It simply defends the muscle proteins rather than force, rather than promoting their synthesis. I don't, I don't really know how accurate either of those views is. Um, but I would just say, I actually, I lean into it, um, simply because I hate the idea of people abusing. I'd rather have a bodybuilder abusing testosterone than insulin, frankly. Yeah, interesting. Ben, thank you for for that, uh, discussion. Any other? Yeah, the more the more you know. Yeah, yes, exactly. We have a few people that have asked questions specific to what you've been talking about. We take a couple of those. Yeah. From Edith. So what happened? So you made mention about the fat that doesn't get stored. So Edith is asking, so what happens to the fat that doesn't get stored in those fat cells? Yeah, yeah. So it, there, it has to be accounted for. This is why I wince a little bit when I hear people only talking, for example, I was talking to people who were saying, um, we just, in order to prevent insulin resistance, we simply need to make sure fat cells can't grow. And I said, oh, well, that would probably, um, prevent insulin resistance at the muscle, but then what do you do with that fat? It's got to do something, and it's got to go somewhere. It must be accounted for. And so I, I think I addressed that at the end by noting that, um, if insulin is low, LPL expression at the muscle is up, and and so the muscle becomes the the user of that fat. And indeed, if insulin is low, the muscle isn't storing it, it is burning it, because it, low insulin state facilitates the use of fat as a fuel, not only the mobilization of the fat, but the use of the fat as a fuel. So it's not like the muscles are just pulling it in to store it. Nope, that's not the case. Just pulling it in to burn it.
Follow up. Can I ask you a follow-up question? Could fat cells do the same thing? You've talked before about how our, our white adipose tissue kind of acts like brown brown fat. Could that be contributing there? Yo, certainly. Um, I don't know the degree to which newly pulled in fat would be fueling this shift, but you're right. Um, in a low insulin, higher ketone state, uh, the metabolic rate in our white fat cells, namely our subcutaneous fat cells, the fat beneath our skin that we pinch and jiggle, we we reported a study last year that metabolic rate increased by two to three times in people that were in ketosis. And in fact, Rich contributed a fat sample to that study. Rich, bless your heart for being such a brave study subject. Awesome. Um, Jack was going to, but he didn't have enough fat. We had to turn him down. Yeah, right. And he didn't want to. Jack actually, the truth is, Jack declined because he didn't want a scar to to interrupt his Speedo season coming up. No, no, no. That won't, that'll look terrible on my calendar of myself. Yeah, right, right, yeah. Anyway, uh, Carly, I actually really forgot what I was intending to say, but yeah, oh, fat cell. Yeah, the fat cell could be a, a more, more readily, more readily burning its own fat. But, but nothing, nothing to the degree that the muscle would. It would be orders of magnitude difference between them. The muscle would really be the main place.
Okay, there's a follow-up to that that question. Ben, is what you're referring to the same effect when one does intermittent fasting or fasting? Um, yeah, probably. I don't know of a of a study that explicitly looked at fasting changes, but yeah, I would think insofar as insulin really dictates these, um, people may think, boy, Ben, get a new hobby, but when it just comes to human nutrient metabolism, insulin just really is the king. Not that there aren't other players, there are, but when insulin is low, lipoprotein lipase activity and expression and every other enzyme related to fat uptake and fat storage in the adipocyte will simply be turned off. There's, there's just no way around that fact. Insulin is absolutely essential to those processes. So yes, with an intermittent fast, I, I would suspect that's the same case. In fact, let me, let me go off on a moment with that. Carly had mentioned ghrelin, which is this, the prototypical hunger hormone that promotes hunger. A study was just published, I think within the last week or two, that compared two groups, intermittent fasting versus chronic low calorie. You know, these two different diets where again, the chronic low calorie would be like the average person who says, I need to lose weight, I'm gonna start, you know, a low-calorie, low-fat diet. And then they looked at this intermittent fasting group, which was calorie unrestricted, but it was eating windows as people would typically think of, or multi-day fasts like every two weeks or something like that. Um, and and they found that in the, the fasting group, they had significantly lower ghrelin. And then to say that in a different way, the chronic low-calorie group had significantly higher ghrelin levels than the fasting, the intermittent fasting group, suggesting that these are people who are going to have to be fighting with hunger much more than the fasting group. And hunger always, almost always wins, I would say. But all the more reason to kind of do low carb where, where the maxim, the adage, right, Rich? It's, it's eat when you're hungry, don't eat when you're not hungry. That was the foundation of our program. It's liberating.
All roads always seem to point back. No matter how many times we discuss the variations on this topic, it seems like all roads point back to the same few answers, don't they? Yeah, yeah, that's right. I know.