The sugar diet is taking the health world by storm, but does it actually work and should you try it? I'll be answering that question in today's episode of the Energy Balance Podcast, a podcast where we explore health and nutrition from the bioenergetic view and teach you how to maximize your cellular energy to maximize your health.

Today's episode is part one of a two-part series discussing the sugar diet, and in today's episode we'll be discussing what the sugar diet is and what the related diets look like, including the honey diet, very princess diet and fruit till noon diet. We'll also be discussing whether FGF 21 is responsible for the weight loss seen on these diets.

We'll discuss the effects of the sugar diet on muscle mass. We'll discuss whether FGF 21 really extends lifespan, and we'll also talk about how to maximize FGF 21 levels and whether you actually should to improve your health. As always, to take a look at the show notes, welding to the studies, articles and anything else that I referenced.

Throughout today's episode, you can head over to jay Feldman wellness.com/podcast. And with that, let's jump right in.

Alright, so these diets are blowing up right now if you haven't seen largely spearheaded by the Sugar Diet as well as a few others, and they're coming from different places. So within the bioenergetic sphere, we have the honey diet, the fruit till noon diet, and the Fairy Princess Diet.

Those all really started within the bioenergetic sphere. And then separately from that, we have Cole Robinson who used to promote what was called the Snake Diet, which was basically a low carb keto type diet with a lot of fasting. And he was promoting that for many years. Seems like he seemed to come around to Ray Peat and then created the Sugar Diet as a product there and has been posting about his results and encouraging other people to try it.

And that caught the attention of Mark Bell of the Power Project Podcast who's been doing the diet for a little while. He talks about how he's feeling really good. He is losing body fat on it. And he's talking a lot about it. And that's been spreading. And now we have lots of other people commenting on the sugar diet either warning us against its dangers or actually, suggesting that it could be beneficial or maybe won't be particularly harmful, maybe if it's only done for a certain period of time.

Thomas DeLauer recently made a video and I'm sure there will be a lot of other people making videos before this episode comes out. But, he made a video talking positively about it as a short term experiment, but certainly not advocating for it in the long term. And yeah, I'm sure it's going to continue to spread. It seems like it's really gaining a lot of traction right now.

So let's start by talking a bit about what these diets are. They're all very similar. There are some nuances between them. And I'll be honest, I don't spend a lot of time in the places where these diets exist, so I might not have all of the nuances down. Exactly right. And feel free to correct those in the comments if there's anything important that I'm missing here. But. We essentially have the honey diet, which seemed to be started from Anaology on Twitter or X, which is very similar to the Fruit till noon diet, which was started by Noah Ryan as a part of his shred maxing protocol. We also have the Fairy Princess diet, which was started by Celestial being. And then we have the Sugar Diet, as I mentioned from Cole Robinson. And so the central tenets of these diets involve eating mostly carbohydrates or all carbohydrates with no fat or protein early in the day, at the very least.

So with all of them, the idea is basically that you're only eating sugars, whether that's honey juice, maple syrup, fruit table sugar or other sources of sugar until either the middle of the day or until the afternoon and you're not eating any fat or protein during that time. And then with the honey diet, at least, the idea is that from around 3:00 PM until 7:00 PM you fast. You don't eat anything until you have your dinner, which is just protein and fat without any carbs. Again, there are some differences here. So on the fruit till noon diet, there doesn't seem to be an emphasis on this sort of a fast, and there seems to be a bit more of an emphasis on whole fruit as the sugar source.

And then on the sugar diet, there seems not to be an emphasis on consuming fat at all with [00:04:00] dinner. He seems to recommend just protein, lean protein with a lot of sugar as well. And it seems he's going, Cole has been talking about going for periods of time without any protein at all, several days at a time or longer.

And in addition to basically saying that we should be fully avoiding fat, he's advocating for very little protein at all. Whereas the other diets seem to incorporate at least one meal of protein with dinner. And then the idea being then after dinner, at least within the honey diet, you're supposed to fast for at least 12 hours before eating carbs again so that the protein and fat that you consumed don't interfere with your ability to utilize those carbs.

And so the general idea is that by avoiding the protein, you're going to be upregulating something called FGF 21, which is. Essentially a metabolic hormone that increases energy expenditure when we're not eating protein. And then the other rationale being that we shouldn't be consuming fat and carbohydrates together due to the Randall cycle.

And so based on those two things, that's where these diets were created. And I know Anaology mentioned that it was, his idea for the HONEY diet came solely out of this idea of trying to upregulate FGF 21. And the idea basically being that you would be upregulating it up until you have dinner.

And then once you have dinner with the protein in there, it would down-regulate FGF 21. So you would have increased energy expenditure earlier in the day, then it would go back down to a normal level starting from dinner and then through until the morning. Now he also mentioned with that afternoon fast that it's not necessarily obligatory, it's optional, but he does recommend it in most cases.

And he also mentions that you might be extremely hungry during that time. So just a nuance there. And with the fruit till noon diet, I've heard maybe there's some allowance for some coconut oil instead of just the fruit, earlier in the day. But yeah, so there, there's some small kind of nuances between them, but that's the broad picture where more than anything these diets are oriented toward trying to increase what's called FGF 21, which we'll be talking about a lot today.

And that being something that will increase our metabolic rate, increase energy, expenditure, [00:06:00] and lead to fat loss. That's really the kind of broad picture of what these diets are. Again, with the idea that you're hacking the system, you're trying to trick your body into burning more than is coming in.

And we'll be looking at studies that dig into whether that's actually the case and how it all works. And we'll also be talking about. The R cycle and whether it actually means that you need to be consuming carbs and fats separately. But before we dig into all of that, I do want to just talk broadly about these diets and the, what's going on in the health space, what has been going on for a long time and what I think we want to be aware of and careful with these sorts of diets.

So for one, as someone who's been eating a high sugar diet, that includes fruit, juice, honey maple syrup, table sugar, and then also other forms of carbohydrates, starches like potatoes and white rice. For over 10 years, I've been eating a diet containing those things, 400 grams or more of carbs per day, for the most part, for over 10 years, and using it for my clients to help with energy, improving sleep anxiety, losing weight, improving libido, and tons of other issues.

I'm definitely happy to see that this is gaining traction. I think that through so much. Of the time. Definitely over this last decade or really couple decades, the orientation in the alternative health sphere has been toward low carb diets. And so I, I think this is, we've already been seeing that start to fade away slowly, and I think this is just a next step there that might speed that process up quite a bit, which I think is on the whole, very much a win.

I think to be able to start to see people dispelling or not dispelling, but to see people who are, watching content, listening to content in the health space. Become comfortable with the idea of eating carbohydrates and recognizing that the carb insulin model of obesity is not actually valid and that carbs don't actually cause insulin resistance.

I, I think that's on the whole, a great thing to see and especially with some of the people who are doing this diet. As I mentioned, go Robinson was advocating for a low carb diet for many years, so it was Mark Bell. He even wrote a book called The War on Carbs. So to see these people be open-minded and shift their views, I think is fantastic.

And I mentioned Thomas DeLauer earlier as well, and he's definitely become more open to including carbohydrates over the last couple years as well. So that's all great to see. And I did talk with Mark Bell on his podcast a couple years back, talked with him about the benefits of including carbs in the diet, how it does increase your metabolic rate, the concerns with low carb, the stress that it causes the downregulation of thyroid and steroid hormones and on from there lowering the metabolic rate.

So I'm really glad to see him heading in this direction as well. And I do think everyone here has good intentions. I think people are just trying to help themselves and the people around them mostly, oriented toward weight loss in this case. But, I think everybody who is, advocating for and supporting these diets is coming from a good place.

However, I think there are some caveats here and some things to be really careful with. And for one, just talking about it in a broad sense, we saw what happened when  carbs were demonized and considered to be the enemy and not really with solid physiological understanding behind it. And we want to be really careful not to do the same here with fat or with protein.

And we don't want to see unintended con consequences that come about over many years and affect hundreds of thousands, millions of people in these audiences as a result of kind of skipping over the physiology or not. Understanding it to the depth that I think is important to understand it. And I wanna make sure that people are not making that same mistake twice, like was made with low carb diets.

And so I think we wanna be really careful when it comes to these sorts of extreme diets, the low fat and low protein together. And this is really the case with any extreme, anytime we're talking about an overly simple prescriptive, one size fits all, extreme diet, it's extremely attractive, especially with the idea that you're going to lose a lot of weight in a short period of [00:10:00] time.

And it's, on the flip side, nuance and understanding of physiology and tailoring a diet to your individual needs, and it's not an extreme diet, it's not something that's going to lead to dramatic short-term weight loss is not as attractive. That doesn't gain as much traction. And I think that's understandable.

People have dieted their whole lives. They're just wanting to get something that works. And if they're able to do something, even if they don't like it, even if they have to be really hungry in the afternoon, or they have to avoid fat and protein entirely. For a short term result. I think most people would say that the, that's worth it.

But there's a cost to that over simplicity. And we saw that happen with the low carb space. We saw that advice harms a lot of people. So we just want to be careful when it comes to swinging the other way without acknowledging the need for nuance, the need for understanding the physiology, considering that it may lead to more unintended consequences.

And so that's really what the series is gonna be focused on. And today, and specifically, we're going to mostly talk about FGF 21. As I mentioned, FGF 21 is the kind of magic weight loss factor that's being pointed to as the reason why these diets work, the reason why they cause fat loss. So we'll be digging pretty deep into the research on FGF 21 and determining whether that's actually the case whether, it is actually something that's supporting our health and what else it might be doing to our physiology. If you're not interested in digging deep into that research, then I'd recommend you just skip ahead to part two of the series. In part two, we'll talk about how these diets actually work the potential side effects of the sugar diet and how to modify the diet to prevent those side effects, the effects of these diets on testosterone, digestion, bone health, and other aspects of our physiology.

We'll talk about whether you actually need to separate carbs and fats, whether you actually can't eat them together due to the R cycle. And then we'll also talk about whether you need to be concerned about losing muscle on these sorts of low protein diets. So all that will be in part two won't be quite as research heavy.

If you're not interested in the FGF 21 research, then you can skip ahead. But if you are I'd highly recommend listening to this episode because I think it is a really [00:12:00] important frame for what's actually going on physiologically when we're eating these sorts of diets. Let's talk on the whole about what FGF 21 actually is, what leads to its production and what the effects are physiologically, how our bodies interpreting this.

So as I mentioned, FGF 21 is a hormone. It stands for fibroblast Growth Factor 21, and it's triggered under particular circumstances. It's different from a lot of other stress hormones. And we'll talk about whether FGF 21 is actually a stress hormone, but in this case it's mostly triggered by protein deficiency, very low protein diets and it lowers appetite for sugar and carbohydrates, increases appetite and hunger for protein and increases energy expenditure.

And so those are some of the main effects that are pointed to. There are also circumstances where it can be triggered by a very high carb diet. So we'll talk about that. And there's also circumstances where it can be triggered by a high fat diet. So we'll talk about that. And then also some other factors too can trigger its production and it has a number of other downstream effects that are really important to understand.

When it comes to the question of whether we wanna be orienting our entire diet toward increasing this hormone. So let's start with just a broad picture here of what triggers the release of FGF 21 and some of its effect. So taking a look at this study titled Fibroblast Growth Factor 21, and the Adaptive Response to Nutritional Challenges, we'll take a look at figure one here where we can see that FGF 21 is largely produced in the liver and is driven by a handful of different inputs.

One is we mentioned is a low protein diet, another is carbohydrates in certain contexts. Another is a high fat diet or a ketogenic diet In a certain context, we'll talk about those. And then also fasting. And all of these work through mostly different mechanisms. There is some overlap, but they all trigger the release or the production and release of FGF 21 from the liver.

Which then has a number of effects. They're pointing to the brain and the white and brown adipose tissue here, and you can see some of those effects listed in terms of insulin sensitivity, energy expenditure, glucose [00:14:00] uptake brown adipose tissue activity. We'll be talking about all of that. Now, as a caveat here, just because something leads to weight loss doesn't mean it's healthy.

We know that just because, and I should say also doesn't mean it's going to work long-term and doesn't have long-term consequences. The same goes for something that improves insulin sensitivity. We'll be talking about that or something that increases energy expenditure. We can be increasing energy expenditure by upregulating our metabolic rate in a healthy way, or we can do it by triggering stress.

We'll be talking about all that here. All of that is really important to consider when it comes to FGF 21. Now, as we'll discuss in part two, I alluded to this, there are certain modifications that I'd be making to these sorts of diets. Now, if you want to take a look ahead at the foods that I would recommend including in an optimal diet, and that includes sugar, it includes sources of sugar.

But it also includes other foods as well. So I'd highly recommend you go ahead and download the Free Energy Balance Food Guide. The Food Guide will help you determine exactly what to eat to optimally support your metabolism, and it'll help you lose weight, improve your digestion, get amazing sleep, boost your energy, and so much more.

The Energy Balance Food Guide is a one page infographic that organizes foods on a spectrum based on how effectively they support your metabolism. And it also has a separate spectrum that helps to adjust the scale for you If you're dealing with various digestive issues. Food Guide makes it extremely easy to get started with a bioenergetic approach to optimizing your health.

So head over to j feldman wellness.com/guide to download your free energy balanced food guide. Alright, so let's dig into the first of the pathways that we're gonna focus on, which is how low protein diets trigger the release of FGF 21. And again, it's important to understand how these different diets, these different.

Interventions are actually triggering the release. 'cause it tells us a lot about the context here. If we just look at the endpoint of, if we just say low protein diet, increased energy expenditure, and miss everything in between, we could be increasing energy expenditure at a major cost to our health.

So it's really important that we understand how these things are going on. And as I mentioned, a low protein diet or just a lack of protein in general is the strongest way to trigger FGF 21, at least in humans. So we're going to start there. And as you can see in that same diagram, there's a few different pathways that can be activated.

We have the ATF four pathway, which goes hand in hand with a different factor called GC N two. We have the PERC pathway, we have the IRE alpha pathway, and then there's another one too, which has to do with mTOR. So we'll be talking about that too. But the strongest one, the primary pathway here through which low protein diets trigger the production and release of FGF 21, is through this A TF four pathway.

So essentially what happens. Is when we don't have enough protein coming in. There's a lack of amino acids, obviously. Amino acids and protein. They're the structure of every cell or the primary component of the structure of every cell, every organal in our bodies. Some of them have some fat as their structure, some of them have a bit of carbohydrate as their structure.

But for the most part, protein is the primary structure throughout our whole bodies. It's not just muscle mass, it's also bone. It's also every single organ. Everything, every single cell depends on protein in order to have structure. So when we don't have enough protein, there's a number of things that happen.

The first is that basically our cells don't have the amino acids available in order to produce more protein. So we see that happening here. We see protein restriction and then a limitation, specifically they're pointing out of the essential amino acids. And what this leads to is what's called uncharged.

T-R-N-A-T-R-N-A is what basically binds with the amino acids and. Brings them to the ribosome to be able to produce proteins. So when you have a lot of these uncharged tRNAs, it activates this factor called GCN two. And then we can see that GCN two phospholate, the ELF two alpha, which then leads to the activity of a TF four, a number of obviously acronyms and very specific proteins, enzymes, factors here that you don't have to worry about.

But the important part being that when you don't have enough protein, there's not enough aminoacids to produce the proteins that we need for every enzyme, every tissue in our body, every cell. And so as a result, we activate this pathway, which is this ATF four pathway. So that's the first one here.

Now there are those other pathways that I mentioned, and I'll just touch on those real quick, but then we'll talk about the downstream effects of each of these pathways. So as I mentioned there's two other pathways. There's PERC and IRE Alpha. Those are both triggered by stress in the endoplasmic reticulum.

This is one of the organelles inside our cells and is involved with the utilization of proteins as most are. And when there's not enough AM amino acids there, it leads to poorly structured proteins. We're not able to properly structure those proteins because they're all made of amino acids, and so it causes what's called impaired protein folding that triggers stress in the endo puzzling reticulum, which activates these pathways, the PERC pathway and the IRE alpha pathway, which there's some overlap.

The Perk actually activates ATF four, whereas the IRE Alpha actually works through a different pathway. But it's important to note that all of these are triggered. One is triggered by the lack of amino acids available for producing protein. The other ones are triggered by stress and the endoplasmic reticulum.

And then I mentioned mTOR as well. So mTOR basically inhibits FGF 21 activation and mTOR is increase when we eat protein. If we're eating a lot of protein, that'll be one way that this is suppressed. And this is part of why when we don't eat a lot of protein, we see an increase in FGF 21 activity.

So with those pathways in mind, let's talk about the context of FGF 21 activity on low protein diets and why it's actually produced. What does it actually do here that helps us deal with the lack of protein. So we're gonna be looking at a study titled Homeostatic Sensing of Dietary Protein Restriction, A Case for FGF 21.

They state here more recent work provides clear evidence that protein restriction increases whole body energy expenditure, both at room temperature and thermo neutrality. And that these effects are associated with activation of brown adipose tissue increases in uncoupling protein one and the browning of white fat.

Although the physiological reason for this energy expenditure is unclear, it could be argued that the increase in energy expenditure allows the animal to burn off excess calories in an effort to procure the missing amino acids. So just to explain that real quick, what they're basically saying is that, it's interesting that a low protein diet increases energy expenditure.

It seems like the reason for this biologically is that if we're eating a lot of calories, a normal diet, but it's very low on protein, we need to be able to get that protein. It is essential for producing all of, a number of essential amino acids and then all the proteins that we need in our bodies.

Our bodies are basically saying we need to eat more in order to get those amino acids in, but we already have all this extra fuel in here, so we have to burn that off so that way we can eat more without adding all this extra body fat. So that's the essential idea that they're suggesting here and they go on to state.

However, we recently demonstrated that preventing hyperphagia is excessive eating, which happens as a result of FGF 21. It increases the desire to eat but tends to decrease the desire for sugar, but preventing hyperphagia in protein restricted mice, increased weight loss, and did not block the increase in energy expenditure.

While deletion of uncoupling protein one blocked both the increase in food intake and the increase in energy expenditure during protein restriction taken together, these data not only suggests that increased energy expenditures independent of hyperphagia, but that increased energy expenditure may in fact drive food intake.

But the pointing out here because there was a dis, some discussion in the research is all that happening, all that's happening is this is increasing hunger. You're eating more and then you're getting more energy expenditure because our body's trying to burn off all the extra. But the reality is, no, this will happen just from the lack of protein.

Even if you're not eating extra food, that'll increase the energy expenditure via brown adipose tissue activity and uncoupling protein one. So we'll be talking about those, but that's what they're pointing out here. They go on to state as expected dietary protein restriction also influences metabolism within multiple tissues, including muscle fat and liver.

The liver in particular, response to reduced amino acid intake by inhibiting protein synthesis and amino acid metabolism and increasing amino acid biosynthesis effects, which buffer against dramatic or persistent falls and circulating amino acids during protein restriction. So this is really key here.

So some of the other effects of FGF 21 are that it's going to lower protein synthesis because we have a lack of amino acids here. So it's basically saying we need to conserve these just if we have a lack of some other nutrient, if we have a lack of calories. There's all sorts of defensive adaptive processes that go on to help us deal with that.

This is one that's specific to amino acids and protein. So if there's a lack of protein, our body inhibits protein synthesis, tries to reduce amino acid catabolism as well, and increases the production of amino acids. We can produce a lot of amino acids endogenously, but there's a number that we can't produce.

So this is trying to deal with the lack of protein, trying to adapt to it properly. That's something that's important here for FGF 21. Now we will discuss this, but in case it's not clear, inhibiting protein synthesis chronically is definitely not a good idea. I know with some of these diets, they're only talking about doing it for part of the day, where then you have your protein later.

So we'll discuss that too. But the idea of just universally wanting to inhibit protein synthesis due to a lack of amino acids certainly has some costs to it that we'll discuss. They then go on to state, this study provides strong evidence that low protein and high carbohydrate independently increase FGF 21, but energy intake itself does not influence FGF 21.

Taking together these observations suggest that FGF 21 is primarily regulated by an imbalance between protein and carbohydrate intake being particularly increased when protein intake is restricted and carbohydrate intake is excessive. The important point here being that protein restriction especially increases it, but so will excessive carbohydrate intake.

And we'll talk about some studies actually looking at this in more detail, but I just wanted to point that out here, that low protein will increase FGF 21 and so will extremely high carbohydrate intake. That's where these diets are coming from. Alright, and then the last quote from this study, they state FGF 21 therefore responds to a nutritional state that's different from leptin and other energy balance signals.

Two alternative nutritional scenarios can be envisioned, which highlights these unique rules. The first one is one in which food is generally scarce, resulting in the restriction of energy intake. And this scenario, classic energy balance signals including leptin, insulin, ghrelin, et cetera, govern metabolic and behavioral adaptations to dietary energy restriction.

There's a number. They didn't mention here a number of hormones and signals they didn't mention. We know that in this first scenario they're talking about where there's just a lack of calories. We increase stress hormones like glucagon, adrenaline, and cortisol. We reduce the active thyroid hormone T three by reducing T four to T three conversion.

We lower steroid hormone production like testosterone, progesterone there's all sorts of effects that happen to turn down our metabolic rate. Now, they're talking about here that is one scenario and FGF 21 is involved in a different scenario. So they state here. The second scenario is one in which low protein, high carbohydrate foods are readily available, but protein rich foods are scarce.

In this case, energy balance signals are not engaged because energy intake is sufficient. But FGF 21 is specifically  increased because protein intake is too low, but carbohydrate intake is high. It is thus attractive to hypothesize that the induction of FGF 21 in the state provides an endocrine mechanism to coordinate adaptive responses to imbalanced protein poor diets.

So that's essentially what we have here, what's considered an imbalanced protein deficient diet, and this is a part of the response to that, and it'll have a number of effects. We've talked about some of them already, like reduced protein synthesis and increased energy expenditure via uncoupling and brown fat, which we'll talk about here in a bit as to whether that's actually a good thing.

Let's move on here and talk about what sorts of things in the diet most strongly influence the FGF 21 production and what some of the effects are looking at especially in animals. And we'll look at this in humans as well as to what actually happens when we're increasing FGF 21 via low protein diets or via other diets.

And whether you know what exactly is necessary to increase FGF 21. So this is a study titled, defining the nutritional and Metabolic Context of FGF 21 using the geometric framework. They state, although protein had overwhelmingly the strongest effect with no other term in the three nutrient generalized additive modeling, reaching statistical significance, it was apparent from the response surface visualization that the highest levels of circulating FGF 21 were associated with a combination of low protein and high carbohydrate intakes.

So we're just confirming here, protein has the strongest effect. Low protein diet has the strongest effect on FGF 21, but when you combine that with high protein, it seems to be slightly stronger. But we'll see as well that in cases of low protein, high fat diets, you do still get about equivalent amounts of FGF 21 activity, at least in other studies.

They go on state. Although glucose significantly influenced FGF 21 protein expression, maximal levels were only found when there was a combination of low BCAAs and high glucose levels. As we had reported previously in vivo, mTOR activation was greatest with the opposite nutrient ratio IE, high BCAA with low glucose.

So reporting to that here about the mTOR factor being involved. But there's those other pathways too that we discussed. We'll come back to mTOR later, but in short, they're just going on to explain how the combination of low protein and high carbs is the primary trigger. But of course it's not the, that alone is not quite as strong of an effect.

You're not gonna have quite as strong of an effect as pairing that with a high carb diet. They then go on to talk about some of the results of this study where they had basically looked at. Tons of different diet variations in either mice are about to some sort of rodent, I think it was mice actually.

And they talk about what happens when you have a low protein diet with enough calories or allowing the mice to eat as much as they'd like versus a low protein diet with not enough calories. And this is really important here because it tells us a lot about the practical situation of what happens if you're actually eating this diet in a way that's causing you to lose weight.

And what happens if you're eating this diet and you're eating tons of calories and gaining weight? What are the effects in each different scenario? So they state there were two contrasting circumstances in which [00:28:00] protein intake was low. One, a low protein, high energy intake, or two low protein, low energy intake in the first condition.

Low protein diets, fed ad libido, meaning that the mice could feed, could eat as much as they want. Drive compensatory feeding for protein terms, protein leverage, resulting in hyperphasia in an attempt to reach a target protein intake and promoting adipogenesis and increased fat mass while leaving the animal.

Still somewhat protein deprived. And they described that this was seen in phenotype one and also on low protein, high fat diets. So what they basically found was on these low protein, high carb or low protein, high fat diets where the mice were allowed to eat as much as they wanted. They eat way more food in order to try to get enough protein, so they're just going to keep eating and eating to get enough protein, and that's driven by FGF 21.

And as a result, they mentioned this promotes adipogenesis and increased fat mass. So they're putting on body fat in the process of trying to get enough protein. So if just left to their own devices on this very low protein, high fat or high carb diet, they're going to [00:29:00] eat massive amounts and increase body fat to try to get enough protein.

They then go on to state the increased food intake on lower percent protein diets is reported to be accompanied by increased energy expenditure, presumably in part through diet induced thermogenesis. In the short term, up to eight weeks, increased energy expenditure protects mice against gain and fat mass, but it is unable to prevent increased adiposity in the long term.

So this is key because we're talking here about FGF 21, increasing energy expenditure, and the idea being that this is always going to either at least meet the amount that's coming in, meaning that if you're eating a low protein, high carb diet and you're eating increased calories, let's say, but you're increasing FGF 21, you're going to have more energy expenditure and you're going to ideally lose weight, that energy expenditure is going to outweigh the amount coming in.

What they found is that in the short term, in these mice that are eating as much as they want to try to get enough protein, that is the case that and at least meets the re the [00:30:00] amount of calories coming in. The increased energy expenditure at least protects them from that fat gain initially for eight weeks, which for humans would be quite a bit longer.

But they're then going to say it's unable to prevent increased adiposity in the long term. So when you then look past that point, there's a certain point where the body can't keep compensating and we'll talk about that. It's give you a hint here, it's because it works through stress systems which have negative consequences.

You can't rely on stress forever. We saw that on low carb diets. We see what that leads to. And you're actually doing a very similar thing here. Not exactly the same, but very similar. And it'll work for a period of time until it won't, and there will be increased adiposity in the long term. That's what they're finding in this study.

And again, giving you a hint, that's one of the major concerns with relying on something like FGF 21 to increase energy expenditure due to a low protein diet. They then go on to stay and they will take a look at what goes on in the opposite situation where you don't feed ad libet, so to speak, where you have some sort of limitation.

You're not eating just a free amount of calories. They state Earlier we reported that the low protein, high carbohydrate condition phenotype one is associated with favorable late life health outcomes, such as increased lifespan, improved insulin sensitivity and glucose metabolism, increased mitochondrial function and better blood pressure and lipid profiles despite increased adiposity.

So again, in contrast to some other ways of dieting that could lead to a lot of problems health-wise, they're actually seeing improved health outcomes, but increased body fat. They say under such circumstances circulating FGF 21 levels were elevated as they were on low protein, high fat intakes, a phenotype with less favorable metabolic outcomes than low protein, high-carb intakes.

So both of them increased FGF 21 really to the same extent, but the high carb, low protein had better health outcomes, which is important to note. Again, this is not just all about FGF 21. We don't want to be overly obsessing on just one particular pathway. 'cause there's so many other things that go on with our diet, so many other factors to consider.

And one of them is the fact that there's a big difference between low protein, high fat and low protein, high carb. So they were seeing that here with the low protein, high carb had better health outcomes, even though there was still high body fat, still increased fat gain. These results explain reports that circulating FGF 21 is elevated under obesity.

So they're suggesting that maybe this is actually the state that goes on in obesity. I wouldn't fully agree with that, but we'll come back to that later. We'll talk about the fact that FGF 21 is actually seen in. Obesity, diabetes metabolic syndrome, cardiovascular disease. So we'll come back to that later.

They then look at basically phenotype two. So this is the mice that were restricted in terms of their calories, and they state by contrast and the low protein, low energy condition phenotype two, circulating FGF 21 was also elevated, but mice were both protein and energy restricted, equivalent to the starved condition.

This nutritional context is associated with leanness insulin sensitivity. A net catabolic state reduced reproduction and decreased energy expenditure consistent with the findings that FGF 21 acts via the brain under such circumstances to reduce energy, expenditure and stimulate fatty  acid oxidation and ketogenesis.

There's a lot here to unpack and we'll continue unpacking it throughout this episode. But first thing to mention is that we saw that in the state where the mice were eating, we. Less and they were able to actually get really lean instead of gating body fat like the other mice. There was a consequence.

They did, they were lean, they did have insulin sensitivity, but they mentioned there was a net catabolic state, meaning you're breaking down muscle bone and other tissue reduced reproduction. So we're basically reducing fertility, reducing the reproductive steroid hormones and decreased energy expenditure.

So it actually decreased the metabolic rate in contrast to the other circumstance where it increased the metabolic rate. We'll be talking about how this happens later, but again, they say this is consistent with the findings that FGF 21 acts. Via the brain under such circumstances to stimulate fatty acid oxidation and ketogenesis and reduce energy expenditures.

So in this scenario, you basically have the exact same thing that goes on a low carb diet in the long term, which is that the accumulated stress [00:34:00] over time will lower the metabolic rate and shift everything over to fatty acid oxidation and ketogenesis, which is the state of hibernation. It's the state of starvation, it's the state where we lower our metabolic rate so that we can survive.

And I've talked about this in a number of previous podcasts, so I'll link to those for more details there. But we're seeing that play out here. To summarize this study, a really important one, eat if we eat a high calorie, low protein, high carb diet and increase FGF 21, and let's say we're maintaining our weight.

Because the FGF 21 is really increasing our energy expenditure and we're eating a ton, but we're about maintaining our weight, then that'll work for a period of time, but then the stress will catch up with us and we're going to have weight gain later, along with other negative consequences that we'll be talking about.

Or you go the other route, which is that you're eating less and you're actually getting leaner, but then you're going to be downregulating your metabolic rate, downregulating reproduction, leading to a net catabolic state, and all the consequences there, which we'll talk about as well. So that's the two different phenotypes they identified in the study, and it's [00:35:00] really relevant to how people are using these diets.

Let's move on. There's some other things that we want to talk about here, and I'm just gonna talk real briefly about the fact that, as I mentioned earlier and as they point out in the study, there's not really much of a difference in terms of FGF 21 in terms of a low protein, high carb and a low protein, high fat diet.

So this is, and this was in humans, so we actually see this play out. So as opposed to sometimes the rodent studies don't directly play out in humans. But this study is titled Dietary Protein Restriction elevates FGF 21 Levels and Energy Requirements to Maintain body weight in Lean Men. They state here we show in lean healthy men that a protein restricted diet meeting the minimum protein requirements for five weeks necessitates an increase in energy intake to uphold the body weight regardless of whether proteins are replaced with fats or carbohydrates.

We also show that fasting plasma FGF 21 levels increase during protein restriction. And in this study they looked at low protein, high carb, and low protein, high fat diets. There was no difference in FGF 21 increase between the two of them. Both of them increased FGF 21. They also looked [00:36:00] at it the diets had different levels of protein and they also looked at FGF 21 levels after particular meals.

What they found was that getting around 15 to 20% protein didn't lead to any increase in FGF 21, but if you got that number to around 8% protein, then you did see increases in FGF 21. So what we're also noticing here, starting to realize or seeing these studies is what level of protein is needed to start to increase FGF 21?

What we're basically seeing is less than 10% especially is needed, whereas when you're getting above 10%, you're really not seeing such an increase. And we'll be going through some other studies looking at details here. Now, as I touch on, as I was pointing out some of those other studies, the main things that are increasing the energy expenditure from FGF 21 were brown adipose tissue activity and uncoupling.

If you're not aware, these are both aspects of our sympathetic nervous system, our stress s system, and increased energy expenditure. They don't just do it from FGF 21, they do it from [00:37:00] cold exposure. They do it from fasting. They'll do it from any of those kind of hormetic inputs, and they're working via the stress system, working via the sympathetic nervous system.

And so they study that specifically in these next couple of studies. We'll go through the first one titled, low Protein Diets with Fixed Carbohydrate Content Promote hyperphagia and Sympathetically Mediated Increase in Energy Expenditure, and they stayed Low Protein diets promote hyperphagia.

Again, remember, this is excessive eating, excessive hunger, and sympathetically mediated increase in energy expenditure, prevents gains in tissue reserves and concurrently upregulates hepatic and intestinal amino acid sensing intermediaries and thermogenic markers and brown adipose tissue. So we're pointing out a couple of things here.

One is that. We're seeing a sympathetic activation of the stress system via the low protein diet in order to increase energy expenditure. We're also seeing a prevention of gains in tissue reserves. This is, we're talking about they're talking on one hand about body fat that it prevents gaining body fat, but it [00:38:00] also causes reduction in body weight and lean as they'll discuss here.

So they state protein restriction, enhances energy expenditure that is partly attenuated by propanolol which is a beta blocker. So Propanolol is a medication that blocks the sympathetic nervous system. Basically it brought, it blocks the beta adrenergic receptors, which are activated by adrenaline one of our main stress hormones.

And so they found that was able to block the energy expenditure, but not on centron, which is an anti serotonin medication. They go on to state moderate to severe protein restriction, decreases gains in body weight, lean and fat mass, decreased postprandial, glucose and leptin, but increased fibroblast growth factor 21 concentrations protein matching retains lean mass, suggesting that intake of dietary protein but not calories is important for preserving lean mass.

So the important part here that I wanted to point out again, a couple one is that is finding the level where this was a concern. So what they found was that in the 5% and 1% protein groups, there were decreases, major decreases in [00:39:00] body weight and lean mass. I wanna say it was between like 30 and 60% decreases in lean mass and body weight to basically impaired growth.

And this, I believe, was in rats. And again, so we're seeing that even if there's an increase in energy expenditure and maybe some other benefits that we'll talk about later, benefits in quotes, there is certainly a cost here that we want to be aware of and we'll continue to dig into that. But they also noted, and this was important, that protein matching led to retention of lean mass, but not calories.

So increase in the calories, but keeping the fat the protein really low didn't actually lead to retains lean mass When the protein was low enough in the groups of, 10%, 15% protein, the lean mass was preserved. But when you got below that, you started to see loss of lean mass and reduced growth, reduced body weight, and eating enough calories was not enough to prevent that.

So that's a really important point here as well. So the last study we'll go through when it comes to low protein diets and driving FGF 21 is pointing out some details here in terms of the sympathetic activity [00:40:00] and how that is being driven by FGF 21 and increasing energy expenditure. So this is a study titled Influence of Carbohydrates and Fat Intake on diet induced thermogenesis and brown fat activity in rats Fed low protein diets.

They stayed. The thermic response to the standard meal was also comparable for these two groups, but the mass. Mitochondrial puria nucleotide binding of brown fat were significantly greater in the high fat group than in the high carbohydrate group. Thus, the results for the two low protein groups suggest that the thermogenic effects of protein deficient diets cannot be directly related to the amount or proportion of energy derived from carbohydrates.

So in this case, they're actually seeing that there was a stronger thermogenic effect when on a low protein high fat diet versus the low protein, high carb diet. And another way of phrasing that is that the low protein, high carb diet was less stressful than the low protein, high fat diet. It was still stressful.

It still increased energy expenditure via the stressful mechanisms the sympathetic activity, but it was less stressful than the low protein, high fat diet. Which [00:41:00] again, I'll link back to those studies where we've talked about how low carb diet induces stress and it's one of the major concerns with it.

But we can see that here. So table five is basically looking at brown adipose tissue mass and activity. And if we look at the low protein, high carb diet, which is the third column on, second from the right and then a low protein, high fat diet, which is the last one on the right, we can look at the mass which, there was a significant increase in both of those over the control, but the low protein, high fat was greater.

And then you also saw, a greater mitochondrial GDP binding, so greater activity there as well. So this is just reinforcing what we're seeing here, which is that, A, this is driven by stress and B, if we're doing other stressful things as well, like avoiding carbohydrates, it's going to further increase energy expenditure on these diets.

As I've talked about before, as we'll be getting into here, inducing energy expenditure via increased stress comes at some major costs and is not, in my opinion, the best way to be losing fat. And instead it's actually a way to lose fat, which will lead us to be prone to regaining body fat later on. So just to summarize here, we [00:42:00] have a.

These mechanisms. We talked about where low protein diets increase FGF 21. As a result of those, we have a couple of things from one, we have reduced protein synthesis and increased amino acid synthesis. So we're using other substrate to produce amino acids, and we're lowering protein creation because we have a lack of amino acids for the production of protein.

At the same time, we see increases in sympathetic or stress activity, which increases energy expenditure via uncoupling, which means that we're not actually producing the a TP from the substrate. We're just basically burning it off and producing a lot of heat. So we're not actually increasing the energy available to our bodies to function.

We're just burning off the extra fuel. And then also brown adipose tissue activity, which again, is just burning off the extra fuel. And mostly that's happening via uncoupling. We also see an increase in hunger, which is seemingly a mechanism to encourage us to eat more protein, but ideally not as much carbohydrates.

There tends to be a reduction in cravings for carbohydrates. So that's the first driver of FGF 21. We're going to talk about a couple others, and again, it's important to understand all the physiology here [00:43:00] because it really gives us a full scope of what actually happens on these sorts of diets and what actually FGF 21 is and whether it's actually something we wanna be producing.

So let's talk a bit about how stress and energy depletion induces FGF 21 activation. And they touch on that in that original figure. They show fasting and a high fat keto diet, both of which are stress inducing, but there are other things as well, like cold exposure is another way to increase FGF 21 by creating energy, stress by depleting energy.

Alcohol is another way to do that, but fasting and keto are really primary ones as well. Now, when FGF 21 is induced in these conditions in rodents and especially mice, it's produced right away. It's very quick. In humans, it's much later. It's actually a part of the energy conservation response where as we talked about one of those early studies.

When they put out the two different phenotypes in kind of the leaner phenotype, you basically had a starvation state, an energy depletion state, and you get FGF 21 produced much later as a way to conserve energy, as a way to [00:44:00] reduce our energy production and conserve as much fuel as possible so that we don't die so we can survive.

FG 21 is really central to that. It actually drives a form of hibernation, which we'll be talking about as well. So let's dig into that a little bit. We're gonna look at figure two here, which is from a study titled Regulation of Ketone Body Metabolism and the role of P par r alpha. So as we saw in the original figure, PPAR alpha is central to FGF 21 activation via the high fat ketogenic diet and fasting.

So we're gonna be focusing on that and the question of how is PR alpha activated? What kinds of things that activate activated? And then we can figure out what kinds of things will activate FGF 21. And when we see the types of things that activate PPAR R Alpha in general, it'll lead us to be a little bit.

Weary of trying to increase FGF 21. So we can see that here where they state fasting and energy stress will lower the amount of a TP. It increases the a MP to a TP ratio, which is basically just saying it lowers a TP. It'll normally also increase reactive [00:45:00] oxygen species. Both of those will increase what's called a MP kinase, which is one of the main energy sensors and our bodies.

It basically is produced when we have a lack of energy that then goes on to activate PGC one alpha and then PPAR alpha, which then activates FGF 21 which then as a result, drives gluconeogenesis, lipolysis, torpor, fatty acid oxidation, and ketogenesis. We'll talk about all of those things. Now, you can also see here on the left that am PK AMPKinase will inhibit mTOR.

And we know that protein is one of the main things that increases mTOR. And we see the mTOR interferes with PAR Alpha signaling. So what this tells us is one of the other reasons why the protein restricted diets are helpful here, because if you don't have a protein restricted diet, mTOR will be higher, which will impair PPAR alpha, which will then impair the activity of FGF 21.

So we just see that coming in here as well. We're gonna read a couple of quotes from this study that give us some more context as to what's going on with FGF 21. So they state the negative energy balance that [00:46:00] develops during prolonged fasting also includes an endo pericrine response that drives the systemic energy conservation program.

The chief player in this process is Fibroblast growth factor 21, FGF 21. The studies on mice revealed that FGF 21 is mainly produced in the liver and its expression is strongly upregulated by PPAR alpha. So the key point here is that FGF 21 is the primary driver of the systemic energy conservation program.

Meaning that, yes, in the short term, if we're eating a lot, it will increase energy expenditure, but in the long term it's going to have the opposite effect of energy conservation. They go on to state FGF one activates hepatic lipolysis and ketogenesis and hepatocytes. These things go hand in hand with an energy conservation state, a low metabolic state, a starvation state.

Those and what I'm referring to here is the fatty acid oxidation, lipolysis and ketogenesis. And in various mammalian species is the chief endocrine factor driving metabolic reprogramming during torper, which includes inhibition of cell growth and size and cell proliferation to preserve [00:47:00] energy reserves.

Torper is a kind of pseudo hibernation state where the animal doesn't go into full hibernation, but it basically doesn't move, it's physically inactive and they really severely lower their body temperature. FGF 21 is the chief factor driving this. So this is basically the hibernation state that an animal goes into in order to conserve energy.

So it can survive maybe, let's say a winter where there's not a lot of food available. Now, as a result of that, you have not only the reduced protein synthesis we talked about earlier, but of course they talk about reduced cell growth, to preserve energy, which totally makes sense. And this does also come into play with humans, and they state that here they say in contrast to mice, in humans, FGF 21 does not regulate an immediate starvation response, and its blood level does not rise until seven to 10 days of fasting when beta hydroxybutyrate plasma levels are already 70 fold higher than in the Fed State.

And this is what we see as well, right? Short term fasting, we actually see an increase in energy expenditure due to all the stress. But if we continue with that stress, whether it's due to [00:48:00] fasting or a keto diet or something else in the long term, we'll upregulate FGF 21 and we will upregulate other factors as well while we decrease thyroid hormone activity and all the other things that regulate our metabolic rate.

In order to get into the energy conservation state, that is one of the primary rules of FGF 21. In animals, including in humans. So again, something we wanna be really careful about upregulating, especially in a chronic sense, upregulating it in an acute sense. It's just getting us toward the chronic stent sense.

It's one step closer toward this sort of effect. It doesn't mean that you're going to notice it after one day, but just like fasting or keto diet, it takes time to build in that direction. But everything that we're doing here, if we're increasing FGF 21 and increasing stress drives us in that direction.

So that brings us to a relationship that I want to talk about, which is the relationship between FGF 21 and glucocorticoids, which are our primary driver of the stress response. Cortisol is our primary glucocorticoid, which I'm sure you're familiar with, and that actually goes hand in hand with FGF 21.

They talk about that here in a study [00:49:00] titled Glucocorticoids Regulate the Metabolic Hormone, FGF 21 in a Feed Forward Loop, and they state hormones such as FGF 21 and glucocorticoids play crucial roles in coordinating the adaptive starvation response. Something we've been talking about here. It was previously shown that FGF 21 induces corticosteroid novels and mice by acting on the brain.

We now show that this induces the expression of genes required for glucocorticoid synthesis in the adrenal gland. FGF 21 also increases corticosteroid secretion from the adrenal in response to A CTH. We further show that the relationship between FGF 21 and glucocorticoids is bidirectional glucocorticoids increase FGF 21 expression in the liver by acting on the glucocorticoid receptor.

So there is a, basically what we're seeing is that FGF 21 is working hand in hand with glucocorticoids, we'll just call it cortisol, even though it also includes corticosterone and other very similar hormones that are on the same pathway. But basically what we're seeing is these two things go hand in hand.

Cortisol will trigger the [00:50:00] release or production. The activity, the expression of FGF 21 and vice versa, FGF 21, will increase cortisol. We already saw that this is something that's acting in the sympathetic nervous system, which involves cortisol as a way to upregulate energy expenditure. And we're seeing here very clearly that both of these increase together.

So we are very much hammering the stress system when we're activating FGF 21 and they go on to state, we conclude that FGF 21 and glucocorticoids regulate each other's production in a feedforward loop and suggest that this provides a mechanism for bypassing negative feedback on the hypothalamic pituitary adrenal axis, the HP axis, to allow sustained gluconeogenesis during starvation.

So I do wanna mention a caveat here, and we saw this when we were looking at low protein, high carb versus low protein, high fat diets. These sorts of pathways, like the glucocorticoid specifically, will probably be much less active, especially early on a low protein, high carb diet versus a low protein, high fat diet.

Because the presence of the carbs themselves and the presence of the insulin helps to [00:51:00] lower glucocorticoids. The presence of the A TP itself from the carbohydrates help to lower the glucocorticoids. So this is something that would be more at play later on after we've driven a lot of stress, which over time interferes with our ability to produce energy, leads to low A TP and will start to lead to this kind of energy conservation state.

So that's an important caveat. This is not going to be as much at play on a low protein, high carb diet early on, but it certainly will be later. And it's important to recognize that this is. Eight, and this is innate to FGF 21. It's trying to activate the stress system to the extent that it can. But luckily when we have a lot of carbs available, at least we're blocking that to an extent, but it's not going to fully block it.

We still see all the other sympathetic activation, just not exactly the cortisol early on, at least and early on, we talked about eight weeks on in the mice diet. That's a pretty long time a human. So just like fasting and low carb diets, this is something that would take quite a bit of time to really get to this point.

Now it's also worth mentioning, cortisol is one of the stress hormones that gets produced from more intense stress. We talked earlier [00:52:00] about epinephrine and adrenaline and the beta adrenergic system, which is activated by FGF 21. It's also worth noting that an even more mild stress hormone, which is glucagon, also triggers FGF 21.

So even more mild stress is activating on the same pathway and is working through these same mechanisms. So it's something that really goes hand in hand with our stress system that FGF 21 does. So we. Again, this is reason to be extremely cautious with it, and we'll get to this in a moment. I know I was saying, Hey, on a high carb diet, this might not be as bad.

And that's true. I do still agree with that, but we'll get to this in a moment with carbs that when we're producing FGF 21 on a high carb diet, when it's not driven by the protein itself, but when it's driven more by the carbs, it actually goes hand in hand with fat production at the liver and elsewhere, which is something that obviously we don't want.

So we'll talk about that as well. But just to wrap this up here, when we're talking about the effects of FGF 21 as a result of stress, we're seeing that it basically functions [00:53:00] in that hormetic pathway and in the classic hormetic pathway. I'll link back to the episodes, did a whole series, and I've written a couple articles about hormesis and why it's not actually something that is a good thing.

It's actually something that detracts and degenerates our health and FGF 21 is central in that, and we see that here in this figure. In this study titled Therapeutic Role of Fibroblast Growth Factor 21 and the Amelioration of Chronic Diseases. They're of course talking about it as a positive thing, as I've talked about in that hormesis series.

I don't agree with that, but we see some of the effects here that are classic hormetic effects. We see that it increases a MP kinase. We see that it increases SER twos. We see that it increases PGC one alpha, and of course PPAR Alpha, which we had talked about earlier. We see that it increases nitric oxide.

Syntase increases the production of nitric oxide, which is also not a good thing, and interferes with mitochondrial respiration. I can link back to episode where I've discussed that as well. We also see a shift tor fatty acid oxidation, gluconeogenesis, glucocorticoid production, torpor, ketogenesis, uncoupling, all [00:54:00] things that go hand in hand with hormesis.

They go hand in hand with the adaptive response, which is good. It's good that we have the adaptive response. If we didn't, we wouldn't be able to properly adapt to a bad situation, to an energy depleted, stress induced state, which we have to face those all the time. So it's good that we have this system.

But it doesn't mean we want to be activating it. And in fact, activating it comes at a long-term cost, including things like a decreased metabolic rate gaining body fat over time, decreasing metabolic function, decreasing thyroid function, decreasing reproductive activity. This is why we don't want to be mimicking fasting.

We don't wanna be mimicking stress. And even though this is going to be happening less so on, or it's gonna take a longer period of time on a low protein, high carb diet to induce this, it's still a part of that a part of the effects of that sort of a diet. But as I was saying, stress is not the only issue when it comes to increasing FGF 21 using a high carb diet.

And if we're not, independent of the protein, which we know protein or lack of protein will activate FGF [00:55:00] 21. We look back at our original figure here. Where we were looking at the overview, we see that the mechanism through which the carbohydrates alone activate FGF 21 is through ch we'll call it kreb.

But there's also kreb h but basically it's the carbohydrate response binding element. We'll talk about that in a moment here, because that's not something that we wanna be activating. As I was saying, in order to activate Rgf 21 via carbohydrates, we have to be activating the carbohydrate response element, binding protein.

It's C-H-R-E-B-P as I was alluding to. This is not a good thing. It's actually something that occurs as a part of producing fat from carbohydrates. That's what's going to trigger an increase in this binding protein. It's not necessarily a bad thing, as I was saying, we wanna be able to adapt to suboptimal situations, and one of the things that it does here is it helps to clear out the excess carbohydrate that we don't need since the.

This is going to happen when we don't actually need to carbohydrate, we have excess. We'll talk about that in detail. It doesn't just mean we're [00:56:00] overeating carbs, but we'll talk about that. And it actually helps to protect the liver. So this is in some ways a good thing because if we don't have this process, this pathway going on, it'll cause fibrosis in the liver and inflammation in the liver.

And we'll talk about that. But that doesn't mean we want to be activating this process. It doesn't mean we wanna be encouraging a state where this is happening because it also goes hand in hand with increased fat production at the liver, and it increases the fat more than it increases the clearance. So again, the idea with these diets and people promoting them are, they're often saying that the increase in energy expenditures going to outweigh, it's going to increase beyond the fat production.

And on the low protein side, that'll happen at least short term until the metabolic rate is depressed. But on the carbohydrate side, if you're eating enough carbs to trigger FGF 21, that's actually not going to be the case in order to eat enough carbs to trigger FGF 21, there's going to be fat production going on at the liver and elsewhere as well.

So this is not something that we generally wanna be driving. Now we'll talk about this with some diagrams here, [00:57:00] but the, this binding protein is produced when there's basically a backup of metabolic byproducts of glucose and fructose. And when ideally we want these the glucose and fructose to be stored as glycogen to be used for fuel.

But when either the mitochondria are inhibited or when there's just so much that we've already produced a lot of energy and we don't have any more to produce, then we're going to get a backup of all of the intermediates and we'll look at a diagram of this in a moment, and that's what's then going to lead to this activation of these pathways that say, okay, if we're not, if we've already produced all the energy we need, we've already stored this as glycogen, everything is full, then let's start converting it to fat.

And that's where you start to get this activation. So we're going to look at this here, especially in the context of what's called reductive stress, which any of the people here from the bioenergetic sphere might be familiar with reductive stress. And interestingly, if you want to increase FGF 21 via high carbohydrate intake, you have to activate [00:58:00] the carbohydrate response element binding protein.

And in order to do that, you have to drive reductive stress. As I was saying, there's two ways we can do this. One is by blocking our mitochondria from functioning properly. The other is just having so much fuel coming in that you've produced enough a TP, and then you get it back up as a result of that, which drives reductive stress.

So we'll look at this abstract, but this graphical abstract from a study titled carbohydrate Response Element Binding Protein is activated by reductive stress and mediates GC KR associated metabolic traits. So we see this here where they're showing this specifically with glucose and ethanol, but we will talk about this.

The same applies for fructose. They just didn't look at it in the study, but that those can drive reductive stress, which is a high NADH to NAD ratio, or is the way I often phrase it, a low NAD plus to NADH ratio that drives the carbohydrate response binding protein and the liver, which then increases FGF 21 and also triglycerides.

You can see both of those on the right of this diagram here. So this, again [00:59:00] the supposed good thing here being FGF 21 requires reductive stress in order to be activated by carbohydrate intake, not something that we want. Pretty much everything we want to do is to do the opposite. We don't want to be in this state of reductive stress.

I'll look back to episodes where we've talked about this more specifically and the NAD 10 a DH ratio and what it represents and all of that. If you're not familiar, we will look at it very briefly here in a moment. Just for anyone who's needs to be brushed up on it. But just to share a couple of quotes here from this study, they state, we show that increased cytosolic, NADH to NAD plus, is sufficient for carbohydrate response element binding protein activation, and necessary for its activation by ethanol glucose and the inhibition of the GK rrp GCK interaction.

We then go on to say, we extend our observations to human disease showing that hepatic reductive stress reflected in the blood levels of the hepatic NADH to NAD plus biomarker, alpha hydroxybutyrate, and the transcriptional signature of reductive stress or metabolic features of [01:00:00] patients with non-alcoholic fatty liver disease, suggesting reductive stress dependent carbohydrate response element binding protein activation as a cardinal feature of common human metabolic disease.

That sounds like a mouthful, but what they're saying is basically that in fatty liver disease, non-alcoholic fatty liver disease, reductive stress, which we know. We did a whole series talking about fatty liver disease that I'll link back to where we talked about reductive stress and detail and all of these other factors and what's actually driving fatty liver disease.

But they're alluding to it here that basically you have reductive stress that leads to the activation of the carbohydrate response element. Binding protein, which drives fat production at the liver, causes fructose or glucose conversion to fat. And it also, therefore drives fatty liver disease, but it also increases FGF 21, which is involved in that fat production.

And actually increasing FGF 21 increases that fat production further despite the idea that it's supposed to reduce the fat production. But in this context, we're driven by carbohydrates as opposed to low protein or both. If you have both of those going on, you're going to see [01:01:00] this phenomenon going on.

So just to touch up real briefly on what reductive stress is, we're looking at the electron transport chain here. Where we see that at Complex One, right in the middle left, N-N-A-D-H being converted to NAD plus because it's dropping off an electron. When this is impaired, when you're not producing a TP here, when this electron transport chain is being blocked or if you've produced so much a TP that it basically reduces a T pase activity because you have excess a TP to a DP ratio, then what you'll see is you see less drop off of NADH.

NADH is electrons at Complex one, so you see less conversion to NAD plus. So the NADH levels build up relative to that NAD plus. So this is that reductive stress. We're seeing it here at the electron transport chain. That then will affect the citric acid cycle, where we have a few different enzymes within the citric acid cycle that are reliant on NAD plus and impaired or reduced by a buildup of NADH.

And you can see these here on the right we have iso citrate dehydrogenase. Below that, we have alpha [01:02:00] ketoglutarate dehydrogenase. And then on the left we have mallay dehydrogenase. So each of these three really important points in the citric acid cycle will be impaired when we have a buildup of NADH to NA plus.

And then we also see the key enzyme. That ties glucose or glycolysis the production of energy from glucose to the citric acid cycle. In the electron transport chain is an enzyme called pyruvate dehydrogenase. When you don't have enough of this, pyruvate from glucose will be converted to lactate. You're not able to produce energy effectively from glucose.

This is impaired in insulin resistance and diabetes and fat liver disease. And it is also dependent on this NAD plus to NADH ratio. So when you have this reductive stress, you have a buildup of NADH, it impairs pyruvate dehydrogenase as well. Then it will also impair enzymes in glycolysis two. Buildup of NADH 10 80 plus happens when there's mitochondrial impairment or excess a TP, which is not necessarily a bad thing, it's just a way to say, basically in both cases, it's a way to turn off energy production because we're basically either doing it really inefficiently or we [01:03:00] have enough a TP.

And so in both of those cases, we see a reductive stress component. We basically see that there's the shift toward productive stress shift toward a high NADH 10 80 plus ratio in order to turn off energy production. This happens in a starvation state to conserve energy when we're producing energy from fat.

It also happens in these states of me, of metabolic or mitochondrial impairment, or if we basically have access fuel that's already converted to a TP. And this process was something that I actually talked about in recent podcast episode discussing why fructose is not a poison, and going through Robert Lustig's perspective on that.

And I can link back to that episode here. In the show notes, but we're going to take a look at one of the diagrams that he shares from his presentation, fat Chance Fructose 2.0, where you actually see these pathways and I think it's really helpful to see it laid out by this. So you, he's showing this specifically from fructose, but it happens with the glucose as well.

We're looking at the liver here. You can see fructose is converted to fructose one phosphate and then gets [01:04:00] converted to various intermediates including go glycerol, dehy three phosphate, which then goes on to pyruvate and then goes into the mitochondria. As we said, once that's overwhelmed, there's a, if there's impairments in the mitochondria or we just have tons and tons of fructose, more than we can stores as glycogen, more than we can convert to glucose and lactate and send out more than we can convert to energy, which as I noted in that presentation, is basically never going to happen on a typical normal diet.

But if you want to increase FGF 21 via fructose and glucose, it has to happen. And so when that happens, you see a buildup specifically of the Glyceraldehyde three phosphate. It's just written as glyceraldehyde here. And then also a fructose one six bi phosphate, which you see a little bit below that in orange.

Both of those then go on to activate the carbohydrate response, almond binding protein, which as you see, and I know it's a little small, but as you can see, it activates a few different enzymes and activates A-C-L-A-C-C and FAS. And this is a TP citrate, lyase acetylate, carboxylase fatty acid synthesis.

And then you [01:05:00] also have increases in SC D one, which isn't actually shown here. But all of those are enzymes that increase fat production from carbohydrate. And so in the process of activating those and producing more fat driving de novo lipogenesis, you. Are also going to have that other effect of the carbohydrate response element binding protein, which is activating FGF 21.

So in order to have an increase in this pathway, you have to be producing more fat. And as we'll talk about here in a moment, the production of fat at the liver and FGF 21 go hand in hand. They're very directly correlated and FGF 21 actually increases the fat production as well. It's an integral part of this pathway, which is not one that you wanna be activating very often.

And so we see that here where we're going to look at the relationship between FGF 21 and de novo Lipogenesis. And a study titled A Critical Role for Carbohydrate Response Element Binding Protein Mediated FGF 21 Secretion in Hepatic Fructose Metabolism And what they state here. Is that in human subjects serum FGF 21 correlates with de novo [01:06:00] lipo rates measured by stable isotope tracers consistent with conservation of a carbohydrate response element binding protein FGF 21 interaction.

And we see that here, this kind of straight line basically between the percentage of de novo lipogenesis going on and the activity of FGF 21. And this is why we see this in various disease states. It's because this is a marker. This is elevated when there's insulin resistance, when there's fatty liver disease, when there's cardiovascular disease.

That's not something that we want to be doing. We don't want to be increasing FGF 21 by excessive carbon intake. This is independent of those effects from a very low protein diet. This is just talking about the carbohydrate driven, but we already talked about some of those negatives of driving it via protein.

But to continue on here. The state and point out that the FGF 21 actually increases fat production further. They also point out that this is a part of the adaptive response. So they state induction of carbohydrate response element binding protein beta, and its glycolytic, fructo, litic and lipo [01:07:00] gene targets were attenuated in FGF 21 knockout mice fed high fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis.

That's fat production in this case from carbohydrates, a 30% reduction in VL DL secretion and a 25% reduction in liver fat compared to fructose fed controls. So when they took out FGF 21 via knockout, there was no FDF 21 there. There's 50% less DNL de Novo lipogenesis, 30% less VLDL, and a 25% reduction in liver fat from not having FGF 21.

So the FGF 21 is actually increasing liver fat when it's activated in these states. They go on to state after eight weeks of high fructose diet livers from FGF 21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation. Whereas this did not occur in controls.

So we talked about this in the that fatty liver series where fat accumulation in the liver is a part of the protective response. We don't want it to happen, but that happening is better than it not [01:08:00] happening. 'cause if it doesn't happen, you get inflammation. In this case, atrophy like degeneration of the liver and fibrosis, which are much more severe cases.

So the FGF 21 is a part of that adaptation to this negative state and it increases that production, which is actually a safer way of utilizing the excess carbohydrate. So it's not causing these other problems, but obviously we don't want to be in a state while we're driving fatty liver. So they summarize that here where they state in this setting of high fructose feeding.

SGF 21 protects the liver against inflammation and fibrosis again at the cost of producing liver fat. So again, like we talked about prior, with this being produced in as a typical hormetic pathway, there's major negatives to not having it. We wanna have FGF 21 there. It's great that we have cortisol.

It's great that we have all of these stress induced pathways. They help us deal with whatever suboptimal situation we're in. But that doesn't mean we want to be in a case where we're increasing this activity, these pathways, we don't want to be in a case where we're increasing cortisol. We know that comes at a cost even though if we didn't have cortisol, it'd be way worse.

We need to [01:09:00] have cortisol, but it's not something we want to be increasing and activating. And so we see that here with some studies looking at carbohydrate overfeeding in humans without restricting protein, showing that it still increases sympathetic activity and obviously is increasing all of these the production of fat, which we don't want in the liver.

So we're going to look at a study here titled Fibroblast Growth Factor 21, and the Adaptive Response to Nutritional Challenges. So what we're seeing here, and this is some of the basis for these diets, at least the honey diet, as Anology mentioned, that carbohydrate overfeeding leads to less fat gain than fat overfeeding because of FGF 21 because it increases the metabolic rate and energy expenditure.

And that's true, although there is still fat gain. And again, it doesn't mean that it's something that we want to be activating. It doesn't mean it's something that's supporting our overall health. But of course, it's better to be driving that with carbohydrate than it would be to just over feed fat. They go on and state that here in this study where they state carbohydrate overfeeding, but not fat led to market increase of serum FGF 21 in humans.

And an [01:10:00] acute response is found with a fructose load. The expression of carbohydrate response element binding protein mRNA in liver and brown adipose tissue was increased and high suc gross fed mice. These results indicate that FGF 21 participates in resistance to weight gain by a high sucrose diet.

And this is important here because we see that this is still happening by increases in brown adipose tissue activity. So when you get the FGF 21 activation by overfeeding carbohydrates, you're still activating the sympathetic nervous system, albeit less than if it's on a low protein, high fat diet. But you're still getting that activation to help deal with some of the excess carbohydrate while you're also still getting liver fat accumulation.

It's also worth mentioning because I've heard some of the people supporting or advocating for these diets, suggesting that it needs to be sugar intake. You can't get the same effects from starch, but the human overfeeding study was mostly starch based. They were mostly consuming starch. So there's obviously still FGF 21 activation from starch but it's not going to be as strong because fructose is going to go to the liver and overwhelm the liver when we're having [01:11:00] insane, massive amounts to a much greater extent than glucose.

Glucose will go to the whole body, whereas fructose gets processed by the liver first. So you will have a stronger activation of FGF 21 in the liver, which is the main side of its production from overfeeding fructose containing carbohydrates versus starch, which is just glucose containing.

But again, it can still happen with starch and was shown in that study. They then go on to say, it has been described that in response to carbohydrate intake, the hepatic production of FGF 21 suppresses the sugar preference through a mechanism that involves hypothalamic signaling. Hepatic FGF 21 suppresses the consumption of simple sugars by acting on the para ventricular nucleus of the hypothalamus in a negative feedback loop.

So they're touching on something that hasn't been touched on in the prior studies that we went through, which is that FGF 21 suppresses the preference or appetite for sugar. It actually reduces our desire for sugar, which makes sense because this is a state where our bodies are saying, eat more protein, eat less sugar.

We either have too little protein or too much sugar, and so it makes sense that it's driving us in that direction. So our kind of overview here, [01:12:00] just talking about all these effects from increasing FGF 21 from carbohydrate, is that we're seeing this happen in a state of increased fat production at the liver from carbohydrates.

It still involves increased sympathetic activity, but increased stress at the same time to increase metabolism in the I periphery to try to utilize extra carbohydrates. Mostly that's going to be glucose metabolism in the states versus in the other states where it's largely going to be related to, when it's stress induced, it's mostly fatty acid metabolism.

But here because of all the glucose, fructose and insulin will mostly be increasing the con, the metabolism of those carbohydrates. We also see that it reduces the appetite for carbohydrates and sugar. So that's our overview here as far as the carbohydrate induced increases in FGF 21. So we have our overview here of increasing FGF 21 from low protein diets where we have basically all the concerns related to a lack of protein decreased muscle mass, and increased stress.

And we will talk about that even more in a moment. We've talked about the increases in FGF 21 in typical stress states where it basically works hand in hand [01:13:00] with hibernation and lowering our metabolism and all of the other hormetic effects. And then we talked about FGF 21 in the case of a high carb state where basically it goes hand in hand with liver fat production.

So generally, in all of these contexts, something that I would say is not something we wanna be increasing and definitely comes with some major costs, but there are some other things that are pointed to here when it comes to FGF 21 that I want to touch on. Briefly. The first is the idea of FGF 21 resistance.

So people will talk about or acknowledge that yes, this has increased in these degenerative states, chronic disease, fatty liver disease, but it's actually because we're not responding properly to that FGF 21. And so it's not driving that state. It's a part of the response to that state. And on one hand that's true.

It is a part of the response there. Just like cortisol would be, just like glucagon would be, that doesn't mean that they're the good guys or another way to say it is it doesn't mean that we wanna be doing things to increase those. But it's true that those are a part of the adaptive response to a negative situation, to a bad situation.

And over time, they're not going to be effective because other [01:14:00] signals are going to outweigh it. And basically say we've been trying to deal with the stress, it's chronic, it's causing a major problem. We can't keep responding at the same rate. It's just not sustainable. So then we will get some form of resistance to it.

That's true. And the resistance. Sometimes happens due to a cellular response. Sometimes it happens to other competing factors, but that doesn't mean that it exonerates FGF 21. They state that briefly here, or, talk about the FGF 21 increases in disease states, and this is from a study titled Fibroblast Growth Factor 21 in Heart Failure, and they state in humans circulating FGF 21 levels are elevated in metabolic syndrome, obesity, cardiovascular disease, diabetes, non-alcoholic fatty liver disease, mitochondrial myopathies, and cold exposure.

It's funny to see cold exposure lumped in there as something that activates the same things that all of these other disease processes do. Obviously, no surprise there, just like fasting and low carb diets. These are things that we talked about a lot in that hormesis series. [01:15:00] They go on to say, given the beneficial effects of FGF 21 that have been demonstrated in vitro, the paradoxical increase reported in these conditions is thought to be due to an FGF 21 resistant state caused by the impaired FGF 21 signaling, which results in the need for a higher FGF 21 level to exert its beneficial metabolic effects.

And as I was saying, there's truth to that. But to say that this is beneficial and the problem is our resistance to it is kinda like saying cortisol is anti-inflammatory, but we keep giving cortisol forever and it stops being anti-inflammatory. The problem isn't the cortisol or what caused the increase in cortisol in this case, we're just giving it.

But the problem is' that the cortisol, the problem is the state. The reality is this is a part of the stress system. So yes, it's not going to work as well over time, but it's not helping. It's not causing beneficial effects through good mechanisms. That's why we need to understand the physiology here. We need to understand how something is increasing energy expenditure, or causing anti-inflammatory effects, because if we don't, we'll say, look, this thing is anti-inflammatory, whether it's seed oils or cortisol [01:16:00] or FGF 21.

Say this thing is anti-inflammatory, it increases insulin sensitivity. This is a good thing. And the problem is just that there's resistance to it in these states when we're not actually recognizing that it's not being anti-inflammatory or improving insulin sensitivity through beneficial mechanisms.

It's doing it through stress and that has an inherent cost to it. We don't want to be fixing, that's not fixing our metabolism. It's not actually improving our metabolic state. It's basically no different than taking ephedrine or taking large amounts of caffeine or T three without actually fixing whatever's impairing the energy production in the first place without actually creating a diet, a lifestyle and environment that supports our health so that we can not have to drive these stress mechanisms to increase energy, expenditure and lose weight, but rather we can lose weight because we are naturally converting the food to energy effectively.

'cause we've fixed the things that we're blocking it. So I think it's a really good summation here of the concerns with focusing on something like FGF 21 and [01:17:00] just. Wanting to increase it without regard to how it's having the effects that it's having. And I should mention as well that this idea of FGF 21 resistance, there's some conflict there because there are FGF 21 analogs that are being studied that do still have effects in these states of obesity.

But again, even if there is some level of resistance, which it seems like there is, it's still not off the hook. Just like I mentioned with those other parts of the stress adaptive pathway, like you see chronically high glucagon in a state of diabetes, hyper glucagon emia is a major driver of diabetes.

And you could say it's highly elevated because it, there's like resistance to it. And there's some truth to that. To an extent, the resistance is due to the underlying state, the problems with energy production and a number of other things. But it doesn't and also you could say glucagon increases energy production.

We talked about this in a couple of episodes, looking at a study on the effects of stress hormones on mitochondria and things like that. So you could say, Hey, glucagon, it increases. Lipolysis, it increases fatty acid oxidation, it increases the metabolic rate. [01:18:00] It is a good thing. It's not actually a problem.

In the case of diabetes, it's only elevated 'cause there's resistance, but that's totally missing what's actually going on, which is that you're creating a poor state, poor energy production, high stress. That's what's driving the glucagon. And initially the glucagon is able to have its effect and deal with that poor environment.

But over time other signals now compete because we can't sustain that stress long term. It's not sustainable. It's going to drain us of nutrients and put ourselves in a state where our body's expecting constant chronic stress, which is going to upregulate other signals that regulate our metabolism so that it can survive.

And again, we see this in other cases too. Just a brief example and I'll point back to the episodes where we talked about this. It's mostly those hormesis episodes, but just like you see hypoglucemia in. Diabetes, increased P par alpha. One of the main things here that drives increased F two F 21, increased PGC one alpha.

Increased uncoupling, increased mitochondrial biogenesis, all in diabetes, one of the most degenerated states. And yet we look at these things and say, these are the [01:19:00] things we want to be increasing 'cause they increase our energy expenditure and will cause weight loss and have all these benefits.

But these are actually the things that are a part of the adaptive response to the states that are causing the problem and increasing them is actually only driving those states further. Alright, so there's one other thing I wanna touch on here, which is the relationship between FGF 21 and lifespan extension and some other effects that we see when we have this lifespan extension.

And the reason why that's important is because it points to some of the other concerns with long-term FGF one activation, but we'll also talk about something else that you can do to get the same benefit without the negative. So we're gonna take a look at this study here where they do see lifespan extension, quite a bit of lifespan extension in mice.

Using FGF 21. And so in this study titled the Starvation Hormone Fibroblast Growth Factor 21 extends lifespan and mice, they basically saw an extension of over 30% of lifespan, I think it was around 36% without calorie restriction, just by over expressing, creating increased chronic exposure to FGF 21. And they basically found that it has a very similar effect to amino acid restriction, where if [01:20:00] you just restrict amino acid, specifically methionine, you're going to see lifespan extension even without calorie restriction.

And part of the reason is probably because it increases FGF 21, it's part of that same pathway. We talked about this in the hormesis series, so again, I recommend taking a of those. But they say here in this study the following quote, they state, in summary, we show that chronic exposure to FGF 21 and naturally occurring hormone and a potent insulin sensitizer markedly extends lifespan and mice through a mechanism that may involve suppression of the growth hormone IGF one, signaling access axis and the liver.

So we're seeing a very similar effect to amino acid restriction where it extends lifespan. And just like other things we've talked about, people will point to this and say this must be a good hormone. It's not just a starvation hormone, it extends lifespan, which oftentimes those two things go hand in hand.

Again, check out the hormesis series for more details on that, but it's worth pointing out the negative effects that they saw in this study. In order to get that lifespan extension, they saw that the mice with [01:21:00] the chronic exposure to FGF 21, had stunted growth. So they're extremely small in size, just like you see with amino acid restriction.

They saw bone loss as well, and of course less lean mass as well. And they also saw infertility specifically in the female mice. So it's not like this was without consequences, which the amino acid restriction isn't either. You basically see the same effects. This is, you could say leading the lifespan extension, but at a very significant negative cost of reproduction, majorly stunted growth and bone loss.

And that's no surprise when we look at. The fact that any protein restriction is going to lead to those kinds of issues long term, we can, if we can only produce so much amino acids and just the signal of getting too little protein tells us to conserve those amino acids and reduce protein synthesis.

So there's going to be an inherent cost to that. And we see that here in this study titled Fibroblasts Growth Factor 21 Controls autophagy and muscle mass, and they state FGF 21 is required for fasting induced muscle atrophy and weakness. I'm gonna say that again. [01:22:00] FGF 21 is required for fasting induced muscle atrophy and weakness.

So if you don't have FGF 21, you're not going to have muscle degradation and weakness during fasting. It is the main mediator that is driving the breakdown of muscle and weakness of muscle from fasting. They go on the state, the mass of isolated muscle cells from control fast and mice was reduced by 15 to 25% compared with fed controlled mice.

So the mice that were fasting, there was a reduction in muscle mass of 15 to 25%. FGF 21 null muscles, however, so this is muscles that don't have any FGF 21. However, we're significantly protected from muscle loss and weakness during fasting. But if you don't have the FGF 21, even if you're doing something to degrade muscle, it actually doesn't happen.

If there's no FGF 21 there, they go on to say such important protection is due to the maintenance of protein synthesis rate and knockout muscles during fasting compared with a 70% reduction in control fasted muscles. So basically you have a group that's fasted. There was a 70% reduction in muscle protein [01:23:00] synthesis.

If you took out the FGF 21, there was no reduction. So the FGF 21 is mediating this reduction in protein synthesis, you wanna say, together with a significant reduction of the mitophagy flux via the regulation of the MI mitochondrial protein B NIP three. This is another one to point out because people talk all the time about the benefits of mitophagy and autophagy and things like that.

We discuss these in detail in the hormesis series, but in this case, the MITOPHAGY is involved with breaking down muscle. So if you have fasting plus FGF 21, you have MIT autophagy, you have the breakdown of muscle and mitochondrial, which is specifically what Mitophagy is, and that is one of the things that's driving the breakdown of muscle.

So you don't actually wanna be dramatically increasing mitophagy or forcing things that increase autophagy like FGF 21. They go on to state the contribution of FGF 21 to the atrophy program with supported by NVivo FGF 21 overexpression of muscles, which was sufficient to induce autophagy and muscle loss by 15%.

So [01:24:00] again, saying this again, we don't just wanna be increasing autophagy, we don't just wanna look at that as this health parameter. It actually can come at a major cost and is not something we want to just induce without consideration of how we're inducing it and what the larger effects are. And we talked about this in that hormesis series, but what we're seeing here is that FGF 21 is basically integral to muscle breakdown and atrophy and loss of muscle mass, which I would say is a major concern here long term on these sorts of diets.

There are certain scenarios where low protein diet doesn't lead to muscle mass reduction. We'll be talking about that in part two and the details here, but this is just a bit of a taste as far as some of the concerns here when it comes to FGF 21 and if you were even trying to get that lifespan extension, it's going to be coming at a cost to things like reproduction and muscle mass as well as bone mass because FGF 21 is integral actually I should say X has FGF 21 activity is going to break down bone.

It's integral to the breakdown of bone and will cause a loss of bone mass. So [01:25:00] another reason to be careful here, and then again, even if we were seeing enough FGF 21 activation to increase lifespan, there would be all of these costs. And the other flip side here to mention is there's a better alternative.

So just like the amino acid restriction research, when you have methionine restriction, especially, benefits to lifespan, but you see these major costs as well. Now the costs are greater when you see this for the entire lifespan. So when they start the rodents off from the beginning with amino acid restriction, you see the most increase in lifespan.

That's where you get those 30% increases. But then you have these major side effects of stunted growth and things like that. When you do methionine restriction later in life, after they've already developed, there are still negative effects, but they're not as severe. There's also less impact on life extension.

You only get, a six or 7% increase in life extension when you start it later. But fewer of the side effects 'cause growth has already, largely taken place, but certainly will be some side effects there. [01:26:00] But. The important thing to note here is that you don't have to restrict the methionine to get that benefit.

You can just provide glycine on top of a normal amino acid containing diet and get that same lifespan extension without the cost. And so that would be my recommendation, is basically that you don't want to be doing something to increase FGF 21 to the point where it's increasing lifespan that's going to be coming at a major cost to lean mass and fertility and other things like we've talked about.

But instead, if you're trying to get the lifespan extension, just make sure you get a large amount of glycine from collagen, gelatin, bone broth or glycine supplement, and that'll have that benefit from for lifespan extension without those costs. So if that's something that is a focus of yours, I would go that route.

To generally summarize here, what we're basically seeing is FGF 21 as a central stress hormone stress factor that's produced under stress from different circumstances, largely from protein restriction, but also from other general forms of stress that cause reductive stress in the liver, and also excess carbohydrate consumption to the point where it produces [01:27:00] fat.

And while you might get some benefits in terms of energy expenditure, just like you would with other excessively stimulating things like as I said, ephedrine, large amounts of T three caffeine, and other substances, there's a cost there to just increasing sympathetic activity, just increasing stress to potentially lose weight, and that cost involves decreased.

All the things that go along with the decreased metabolic rate, all the things that drive us toward a starvation state, reduced reproduction, going to see lower thyroid activity over time, worse thyroid hormone conversion and various other concerns. So on the whole, I would say the induction of FGF 21 is not something we would want to be encouraging, and I, it does very likely happen on these sugar diets, a honey diet and all of that, but I don't think it's actually a good thing.

I also don't think that's everything with these diets. I think there are actually positives of these diets as well and, that actually do lead to [01:28:00] lasting benefits. And I want to talk about those, we'll talk about those in part two since this is already a, an extremely long episode. But we wanna be able to get those positives without these sorts of negatives, and so we'll focus on that in the next episode.

We'll talk about the other factors with these diets and how they work. Aside from FGF 21. We'll talk about how you can lose weight while still eating sugar and without sacrificing your health, without driving FGF 21. We'll talk about other side effects of these diets, the sugar diet, honey diet and how to modify them to prevent those side effects.

We'll talk about the effects of these diets on testosterone, on digestion, on bone health. We'll talk about whether you should be concerned about losing muscle on these sorts of low protein diets. Obviously, I alluded to the fact that from FGF 21 activation, we should be concerned and we'll talk about the context in which a low protein diet seems to actually provide benefit for insulin sensitivity.

Reversing insulin resistance versus when it actually doesn't and when I think it might be worth considering and what kinda level, what amount of protein is important. And then we'll also talk about [01:29:00] whether you shouldn't be eating carbs and fat together due to the cycle. So we'll be going through all of that in part two.

If you didn't enjoy this episode, please leave a liker comment. If you're watching on YouTube, and if you're listening elsewhere, please leave a review or five star rating. All of those things really do a lot to help support the podcast and are very much appreciated. To check out the show notes for today's episode where I'll link to the studies and articles that I mentioned, episodes that I mentioned throughout today's episode, as well as many other studies that I didn't go through here.

Head over to j feldman wellness.com/podcast. And I do wanna mention as well, I'm assuming that if you're trying any of these diets, you're probably looking to optimally support your metabolism and lose weight. You might also be looking for help with improving your digestion, getting amazing sleep, rebalancing your hormones, boosting your energy, or resolving various other health issues.

If you'd like to accomplish all of that, using clear action steps and strategies alongside personalized guidance from me, that head over to j feldman wellness.com/solution where you can find all of the information for the Energy Balance Solution Program. This program includes [01:30:00] customized health coaching, it includes a video library with videos on how to properly regulate blood sugar, how to lose weight without destroying your metabolism, how to restore gut health, boost your metabolism, get amazing restorative sleep, rebalance your hormones and tons more.

It also includes resources like sample meal plans, recipes, a calorie and macronutrient calculator, and a supplement guide as well as a private community. So head over to jfeldmanwellness.com/solution to check out all the details. And with that, I'll see you on the next episode.