Jay 0:00
Welcome to Episode 66 of the energy balance podcast, where we teach you how to live without constant hunger and cravings, fatigue, brain fog, poor sleep and all sorts of other low energy symptoms by maximizing your cellular energy. I'm Jay Feldman. I'm a health coach and independent health researcher, and joining me again today is my good friend Mike Fave. Mike and I have been studying health and nutrition together for a long time now, and Mike also draws on his experiences from working within the healthcare industry. Today's episode is part four of our series discussing non alcoholic fatty liver disease. And in today's episode, we'll be focusing on the role of cortisol and the harmful effects of fasting and fatty liver and throughout this series, we've been explaining the general mechanisms and physiology that underlie non alcoholic fatty liver disease. And we've been spending a lot of time on this, because this is a situation and underlying physiology that directly applies to virtually every other chronic health issue. So because it's so applicable, we've been wanting to spend some extra time discussing it, and we have been trying to simplify some of the physiology by using some graphics. So if you do want to see those, then you want to watch these episodes on YouTube, but we'll also make sure to explain them verbally as well. And this is a slightly different style of podcast where we are focusing a little bit more in depth on the physiology. So for one, if you do enjoy this, or if you don't enjoy this, let me know in the comments. You know what your preferences are. And also, if you're more interested in understanding just a more basic view of the bioenergetic approach to health, then I'd highly recommend you go back and listen through episodes one through seven of the podcast, or take a listen to virtually any other episode throughout the energy balance podcast. And then toward the end of this series, we will take some time to discuss what all this means in terms of diet and lifestyle and supplements for reversing this state. And in today's episode in particular, we'll be discussing where the liver fat comes from in non alcoholic fatty liver disease, which is probably not what you would expect. We'll be talking about how stress hormones drive non alcoholic fatty liver disease, how fasting can contribute to non alcoholic fatty liver disease, and how fatty liver is a logical adaptive response to stress. To check out the show notes for today's episode, you can head over to Jay Feldman wellness.com/podcast, where you can take a look at the studies and articles and anything else that we reference throughout today's episode, and if you are dealing with any of the symptoms or conditions we've been discussing throughout the series, maybe that's fatty liver specifically, or insulin resistance or other related conditions like diabetes or heart disease. Maybe it's other chronic health issues like autoimmune conditions, or maybe it's various chronic low energy symptoms like chronic cravings and hunger, low energy or fatigue, joint pain, weight gain, digestive symptoms like bloating or constipation or other sorts of intestinal inflammation. Maybe it's brain fog or poor sleep or hormonal imbalances. But regardless of what those symptoms are or what the condition is, all of these symptoms and conditions are really caused by a lack of energy. And so if you want to resolve these symptoms and conditions, you'll really want to focus on maximizing your cellular energy. To learn how to do exactly that, head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by a lack of energy, and I'll also explain the main things that you can do from a diet and lifestyle perspective to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman wellness.com/energy, and with that, let's get started. We've been talking about how this is all that energy deficit you and you were just been talking about that as well. And we've been talking about how so easy to just focus on all those other things. But we have to start there and then use that to elucidate the rest and and a huge piece of that, another huge piece of evidence here, is that you see these excess stress hormones in this condition and all of the effects of it. So and again, this is just more evidence. Another like, just more, yeah, more evidence. Or further suggestion that this is what's actually going on in the state. Yeah, the stress hormone stuff? Yeah. So just to clarify first, and we've talked about this previously, it's important to note that stress hormones are produced in direct response to an energy deficit. You tend to see it with low blood sugar, because low blood sugar is a lack of fuel, and that will cause an energy deficit. But you'll also see it in high blood sugar and something like diet. BTS, you'll still see those elevated stress hormones, because they aren't producing the energy very well. So the stress hormones, and this includes glucagon, adrenaline, cortisol, in particular, those ones, growth hormone is another one that can be thrown in there, depending on the context. Those are going to be released in direct response to a lack of energy, and they do so to mobilize a backup energy system to release backup fuel, like fat from the fat tissues and glucose from the liver, to restore the ability to produce energy, which is normally caused in a non pathologic case, just by lack of fuel. For example, if you're exercising, you're running, and your body's starting to run low on fuel and that it had immediately available, it starts to activate these stress hormones, so that way, it has enough fuel to keep running. And so you see a derangement of the situation in in non alcoholic, fatty liver disease, yeah.

And basically what you see in these patients, and it's just high amounts of glucocorticoids, particularly cortisol, and it the amounts and how they are affected depend on the stage of the disease. So in the initial stages of disease, non alcoholic, fatty liver disease, where you're just developing fat in the liver, you have high, you have it's like a, so it's like a chronically high, or sub chronically. It's chronically but sub level high cortisol, compared to a normal person. So it's not like super high, ridiculously out of range, but it is. It is generally higher than the normal person.

Jay Feldman 6:30
Yeah. Sub, sub clinically, subclinical, said, sub chronically, yeah, yeah.

Mike 6:34
And then you also have an elevated ACTH, but then the liver will also, the liver is going to upregulate the conversion or the deactivation of that cortisol and the cortisone and other metabolites to basically export out of the body. But you have this state where you have this higher amounts of stress hormones, and it makes sense, because you also have the higher amounts of free fatty acids and whatnot, and the higher amounts of gluconeogenesis, the litter producing glucose, and that those all happen under the action of cortisol. It mobilizes these functions. So you have this, you have your it's indicative that there's a stress state going on in this pathology, and it's subclinical, and it goes on for an extended period of time. And what's also you can see is with glucocorticoid drugs, you literally can induce fatty liver pretty directly and pretty easily. Fatty Liver, obesity, diabetes, like it causes all these states so, and it's just interesting to see that, like, you give somebody cortisol, and they literally develop metabolic syndrome. And then in most of the metabolic syndrome states you have, you have, like, high levels of subclin or you have subclinical hypercortisolism or hyper hyper adrenal function. So it's driving those states, that's literally what's going on. Um, maybe there may be something else triggering the the stress hormones underneath, like the cellular energy deficit. In some state, it could be endotoxin, right? You could have high amount of endotoxin coming from the gut that could be impairing the liver energetic production, and that could also be raising cortisol. So kind of all will come together and, like chronically become a pathology, and that's the chronic disease state. And the thing is that comes down to lifestyle adjustments. What causes the chronic endotoxemia from the gut is largely lifestyle factors. It's, it's poor diet, excess stress, poor sleep, the certain situations. It's not being breastfed, and then developing like pathological microbiome over the course of life with poor diet, like all of this stuff is, is can come down to these factors, or it could be like an emotional trauma, of very potent emotional trauma in childhood, or something like that, can stimulate the adrenal glands chronically through the course of of life. And you can see things like that, and especially if they're things like that, if they're not addressed. So you have this high amount of cortisol in non alcoholic fatty liver disease. And then the livers like is basically in that state, you see an upregulation of the deactivation and the trying to get rid of that cortisol, as the liver starts to progress into non alcoholic steel hepatitis, where it's actually inflamed, then you basically see an upregulation of cortisol inside the liver cells themselves, where they're they're actually taking the inactive cortisol and they're converting it, I think it's through 11 beta hydroxy steroid whatever, one, Hs hsbd, one is it a decarboxylase? I don't I think so, um, and it basically is, will convert Cortis cortisone into active cortisol. And go ahead,

Jay Feldman 9:40
It's hydroxy steroid dehydrogenase, dehydrogenase.

Mike 9:42
Okay, yeah, um, so, yeah. So basically, that's what you see in these states. And it's just, and it there's the other study I talked about it like, goes very startling. It goes perfectly with with the study is basically showing that. And I can even read a little quote here. Mm. Yeah, so non alcoholic fatty liver disease. Patients were obese with fasting hyper triglyceridemia and the hyperinsulinemia. So basically, they had higher amounts of fat in the blood and high amounts of insulin. Of the triglycerides accounted for in the liver. About 60% of those arose from non esterified fatty acids, which means that they're coming from the fat tissue. 26% came from de novo lipogenesis, which means that the liver was producing them, and only, only about 15% of them came from the diet, which is interesting, right? A lot of people think, oh, it's it's coming from the diet, and the diet can actually make it worse. But in these states, with when you see a high cortisol, and you see high fatty acids in the blood, and then you see high blood sugar as well. Those are the, those are the functions of the cortisol you're seeing that effect play out. And this is in this is in human patients. It's not in rats. So, yeah, you're literally seeing, you're literally seeing the stress hormones in your face, right there, directly there, and then as the same process that I talked about before the liver is like having energetic deficit and then getting flooded with energetic substrate.

Jay Feldman 11:09
Yeah, and so to clarify a little further, just in case people weren't aware, so it was the 60% from non esterified fatty acids, those are coming from body fat, 25% from de novo lipogenesis, that's coming from carbohydrate from the diet, and then 15% was from fat in the diet. So as you were saying, the vast majority is coming from your own body fat stores. And we were talking about how the stress hormones are the mediators there. Those are the ones that are causing the release of body fat. So that's, I mean, that's huge. And another piece here that I want to mention. So you mentioned how everyone thinks that you're just whether it's fructose, you're eating too much fructose or eating too much fat. That's those are where the the fat's coming from in your liver, but it's not. It's coming from your own fat stores, and then the same thing is mirrored in the lipoproteins. So people are saying that this diet is going to increase LDL because of high fructose, or it's going to increase LDL because of high saturated fat. Most of the fat in your lipoproteins is from your stored body fat. So in reality, what you want to be focusing on is the things that cause the release of stored body fat, which are stress hormones, which are released in response to an energy deficit. So again, as they're shifting that focus away from this idea that fructose is causing it or that saturated fat is causing it, and instead toward the problem at hand, which is the energy deficit. And another thing that they point out here is that in the fasted state, the people in these conditions weren't responding properly. They weren't decreasing these processes. And instead, de novo lipogenesis was relatively elevated when they were fasting due to the insulin resistance.

Mike 12:40
And the de novo lipogenesis doesn't necessarily have to be coming from the sugars in their diet, although that's what the assumption was in the graphic that they posted in the article, as we talked about in the other non alcoholic fatty liver disease studies, the de novo lipogenesis can literally be coming from the energetic dysfunction of the cells and them trying to just take the the metabolic intermediators and push them out into glucose. Yeah, yeah. So it doesn't like most of the fat and liver may not actually be coming from the diet, and in these states, even from the de novo lipogenesis perspective, it could actually be coming like it, because they're not actually oxidizing the sugar through and then converting it back to glucose, because you're seeing it in the fasting state as well as in the Fed state, which would lead me to believe that it's actually from the pathology. And like taking in sugars in the diet, is just moving in with the pathology. It's not inducing the pathology.

Jay Feldman 13:35
I see where. So what you're saying is that the de novo lipogenesis could be be the de novo lipogenesis could be from the gluconeogenesis, basically that you're in the stress state. Not only you're producing a lot of free fatty acids, you're also releasing a lot of gluco of glucose through gluconeogenesis, which is through that stress pathway, and that's getting recirculated back to the liver and then being converted to fat, which is so I thank you for mentioning that, because, yeah, you would. It's, I guess it's assumed, that the 25% from de novo lipogenesis is from carbs from the diet, but and then, in a roundabout way, it could be, but it's more that those things are being converted to glucose through stress released and then re esterified, or reconverted, I should say, to to fat and being stored in the liver. And that's how it can happen in that fasted state, because you're, you're, you know, and you see this in diabetes, where you have extremely high fasting glucose, fasting glucose, and that's because of these high stress hormones, even when you haven't had any carbohydrates at all.

Mike 14:35
Yeah, you see that in the morning cortisol. I think it's the dawn phenomenon, where people wake up and they're like, What did I eat last night? My my blood sugar was 300 it's like, that's not your food, that's your cortisol. And the thing is, is what? The other thing is, well, your food can influence it. Well, your yes, your food can influence it directly, especially if it raises your blood sugar fast and crashes it. And you have poor blood sugar control, you can then you're gonna raise. To solve, and then you're going to see, you can see high numbers. And even high numbers would be, like, even 150 in the morning, like, that's very high so, or it's very high for a normal person the but even if, even if the carbs were being converted into de novo lipogenesis from the diet, I would say, like, as we discussed, like on for normal humans and over lipogenesis isn't that large of a portion for for fat. So it's still a process, a product of the the actual derangement going on in the liver here. And like you can even, you can even see what we're talking about when they talk about that the patients had hyper triglyceridemia and hyperinsulinemia. So they had high fats and high insulin in the blood simultaneously.

Jay Feldman 15:43
And probably high blood sugar too. Yeah, and and so. And I had mentioned earlier that there was this other study talking about the fasting state, or talking about fasting also causing this. And so they're talking about the stress hormones. And so they say glucocorticoids have been implicated in the pathogenesis of non alcoholic fatty liver disease across all stages, they have a diverse array of metabolic functions that have the potential to drive non alcoholic fatty liver disease acting on both liver and adipose tissue. In the fasting state, they're able to mobilize lipid increasing fatty acid delivery, and in the Fed state, can promote lipid accumulation. So again, just that, this elevated stress hormones is one layer above the root, which is the energy deficit, but is that mediator that's causing the release of free fatty acids in the fasting state, which is causing the storage of fat and accumulation of fat. Then they also talk about in the Fed state how it can promote lipid accumulation. And I don't like the way that they're putting that because in as they talked about that other study, the body isn't properly responding to the nutritional state. It's not really, it's not really changing whether you're fed or fasted. In both cases, you're releasing fat and you're storing fat at the same time. And that's because, and this is another thing I wanted to mention, is that when we're talking about these high stress hormones, the high chronic stress hormones, have direct effects on impairing energy production. They're one of the things that can directly inhibit energy production, and you alluded to that when you were saying that things like trauma and emotional stress can can cause these issues and all sorts of other physiological or non emotional things can cause it as well, like excess exercise, for example, yep, will increase these stress hormones. So so they are in the same way that fatty acid oxidation, or lipid oxidation, is a part of that vicious cycle that continues to drive the process, the stress hormones continue to drive the process as well, both by releasing substrate to be used and by then impairing the ability to use the substrate, essentially at the same time.

Mike 17:44
And one thing I want to point out here is, this is literally Hans Selye work, but all, like, all the factors that cause stress move to the same pathway, and then you have the same effect on the outside. And there's, like, a great graphic, I think, I think Danny posted it at one point, but it's literally like you have all these feeding in factors, same pathways and then, and they could be like multitude of different factors, whatever it is, diet, traumatic, accident, whatever, like it still works through the same stress pathways, and the outcomes are the same, and it depends on the degree of the activation that stress pathway. And that's why an emotional trauma can be just as damaging metabolically, as certain physical traumas, as poor lifestyle, as chronic stress, whatever it is, because you're up regulating these pathways. And then, even with the the intermittent fasting stuff, even with with the fasting stuff, you literally see decreases in thyroid hormone and testosterone. But they literally were able to rescue testosterone production in men went on a extended fasting period by giving them consistent glucose boluses through that period, and the consistent glucose basically just kept the stress hormones to a degree lower, and then the hypothalamus still allowed for testosterone production. And there's other intermittent fasting studies, where, basically, they show decreased thyroid function and decreased decreased androgens with upregulation of cortisol. And so there's some people talking about, like, the intermittent fasting actually causing weight gain in the long term for them, particularly around the midsection. And that's because, like, while initially, when you do intermittent fasting, like, if it's basically you're coming from, depending on where you're coming from, like, it can fix some pathology, right? If you do have a fatty liver, like, and not adding substrate into the system over an extended period of time. Like, I'm not going to deny that that can be helpful for some people. Would I say that that's the ideal way to go about it? No, it's not correcting the energetic deficit, but you're you're not putting the excess substrate on the system, which can also be helpful if you're not going to, if you're not going to correct the energetic deficit, then you in those situations, like you're decreasing the substrate, like it can still be beneficial, like you don't have an in the the site, the system, the conveyor belts broken in the factory, but and you're not making chairs. Very well, but you don't have all the firewood piling up. That's essentially what's happening in those situations. But once it once it does, once it helps with that. Over the long term, without the adequate supply coming in to to the factory, you're still not producing energy. So you're then you start having, then you're going to have to rely on on the backup stress pathways. You're going to have to start breaking down the factory to get the studs from the wall so that you can produce your chairs, which is what cortisol does.

Jay Feldman 20:28
I think you can make the argument that that's even worse, right? Like, it might be better to produce a small amount of chairs and have a ton of these byproducts that are causing damage than to really be producing no chairs and having no wood coming in at all, you know, it might, it's definitely going to present differently. But I think the biggest factor is more that when you're doing something like fasting or caloric restriction, you're restricting the harmful things. You're removing the a lot of the things that drive that you know, that break the conveyor belt in the first place, or break that you know, prevent you from making chairs in the first place, or prevent energy production in the first place. So I really think that if that wasn't happening, it really might not be any better at all. It might be worse. But that's you can't really separate those things. So, yeah, yeah. So I think that's worth mentioning. The other thing I was thinking as far as the how glucose helps to prevent the harmful effects of fasting. You know, the next biohack is just going to be fasting with an IV drip of glucose. And then if you can't afford the IV drip, you could just have, you know, a little bit of fruit throughout the throughout your fast. And it's like, well, at that point, you're just not fasting at all. You're doing the exact opposite of fasting. And they know this is already acknowledged, that the lack of carbohydrates is what mediates those stress effects of fasting that they're saying are potentially good and all that, and glucose, as a carbohydrate, is the main carbohydrate, is going to directly oppose that. So it's another way of just fasting, just saying, if you fast and but actually don't fast, then you don't have the harmful effects of fasting. Yeah. It just Yeah.

Mike 21:56
I think, I mean, I think Ray even talked about that in a in a podcast where he said, like, if you, like, somebody was asking about fasting. He's like, Well, if you have, like, juice and fruit throughout the fast you can mitigate the harmful effects of the stress. And, like, not basically dissolve your lean tissues, but you'll still be able to lose some of the fatty tissue and, and I think that's this is where, like, the idea of, and again, I'm not neces, not necessarily advocating that. I'm just talking about like, that was the point. But the the that's where you see, like, the protein, the protein sparing fast now, right where it's like to eliminate some of the amino acids is, but Do you also like you have, you're gonna have your carbs and your fats, you keep, I don't think that's there necessarily their point behind it. But if you're going to do any type of fast, and you want to, it would be like, You need to fast from crap food and then replace it with good food. That's kind of exactly, that's kind of like how it would go. And then as as far as the anti aging stuff for the protein modified, or protein sparing fast, like, whatever. I mean, I can't even imagine, like, even in the low carb sphere, like, oh yeah, Saturdays are going to be my and I remember we talked about this, Saturdays are when we were doing our low carb intermit fasting, whatever. It's like, Saturdays is going to be our protein modified fast. But it's kind of like, it's kind of like, there's no, like, you can't do it on low carb, because if you're low carb and you don't have protein, I mean, you all have is fat. So what are you going to eat butter all day long?

Jay Feldman 23:20
Yeah, I know that was Dave asprey's. Yeah, exactly.

Mike 23:23
I remember coming from Dave Asprey, the protein modified fast. The only thing I want to add before you, before you go, is that the true solution to all of this is that we need to do cold thermogenesis during our intermittent fast while we're exercising. I think that is like the pinnacle of solving metabolic issues. And I only bring that up because I've seen people discuss that, and this is absolutely absurd.

Jay Feldman 23:47
Yeah, it is, but, but in reality, maybe here's what we can do instead. We've got the glucose drip while we're fasting, the IV glucose drip to prevent any of those stress effects, and we don't want any protein wasting, but we also don't want the harmful effects of the, you know, anti metabolic amino acids that impair lifespan, you know, methionine, cysteine, tryptophan. So instead, we can only have the anti inflammatory ones, you know, the glycine and proline and everything. And then, you know, you actually find that when you have those in balance with methionine and cysteine, it's just as good. So I guess you could have just an equal amount of those, you know, a good balanced ratio of those, and just take them in capsules or something. And the saturated fats, we all know those are fine. That's what you're running on anyway, if you're in a normal fast. So you could just add some saturated fats to it, and now you've prevented all of the harmful effects of the intermittent fasting. And so you could do it that way with all of like, the technology. Or you could just eat, you know, fruit could quality saturated fats, meat that have, you know, meat that has the collagen and gelatin built into it, and that can be your fast all day, every day, and you're good to go, you know?

Mike 24:46
So wait, you could just eat a normal diet.

Jay Feldman 24:50
I mean, a normal bioenergetic diet, exactly. Yeah.

Mike 24:52
I mean, that is the purpose of all of a lot of our recommendations for as far as the amino acid sparing, stuff like. Like, I for me, like, I don't think it's worthwhile strategy to pursue long term just because it's like, I just want, I'm just going to eat real food. I'm not going to, like, try and micromanage amino acid ratios, you know, in the sense of, like, you know, like, I'm going to try and keep my tryptophan and methionine really, really low and and only eat, like, all this gelatin, and then, like, have my glycine and taurine and yada yada, really high. It's like, I'm just gonna eat steaks and seafood and the food that I tolerate, and then have some some collagen or something with it, or eat, like, certain cuts of meat that have collagen and just kind of leave it at that.

Jay Feldman 25:35
Which I think is perfect. I mean, again, you don't need to. They've found that you don't need to fully restrict methionine and CYN, as long as it's balanced out by the anti inflammatory amino acids. Yeah, exactly. So there's no need to fully avoid them, in my view. Yeah. So it's important to recognize the like, how these stress hormones, how the glucocorticoids, overlie the underlying energy problem, and it's in the same way that when we're looking at the metabolic mechanisms that go on when you have inhibited mitochondrial respiration, when it's impaired by all these different factors, all of the it's really valuable to see how all these different enzymes work together, and you have all these signals that cascade to signal to the cell what's going on, and then to the tissue what's going on, in order to help to shift towards something like fat storage and fatty liver. And we'll talk about why we actually want that, but we know that it's kind of this backup mechanism. And so the stress hormones do the same thing. They have all these different cascading features and affect all these different enzymes, and also then have feedback loops on respiration itself as well. And these are all things to that are really helpful to contextualize too. So let's talk about that a little bit, just the the influence and the different pathways that are affected by the elevated stress hormones.

Mike 27:00
Okay, so the primary elevated stress hormone that we're going to discuss, and I think that's really important, and we just touched on it with intermittent fasting, is cortisol. And cortisol. So just to give a slight overview, you have cortisol. You have a adrenal corticotropin hormone, which is released from the pituitary gland, and that signals the adrenal gland to release glucocorticoids like cortisol. There's one set before that. It's CRH, which is from the hypothalamus of the pituitary, but we're not going to talk about that. The main point here is to just look at cortisol coming from the adrenal gland. Then there's other regulations at the cell with cortisol and and, or glucocorticoids in general, where they can activate or deactivate the glucocorticoid. So in those enzymes are, and we briefly mentioned it 11 beta 11, beta hydroxy steroid dehydrogenase, one which converts the inactive glucocorticoid cortisone into the active cortisol, and then 11 beta hydroxy steroid dehydrogenase, two which converts the active cortisol into the inactive cortisone. So the cell can the cell can regulate these and then there's one other specific enzyme that is the five alpha reductase enzyme, which is the same enzyme that converts testosterone into dihydrotestosterone. So testosterone being the main androgen being converted into the most potent androgen, which is dihydrotestosterone. But five alpha reductase can also inactivate cortisol. So and some interesting things that they find in these states is, while you have you can have the subclinical elevated cortisol levels in obesity, diabetes, non alcoholic, fatty liver disease. You can also have up regulations of the enzyme H HB, or 11 beta hydroxysteroids, dehydrogenase, one which which at the cellular level, at the liver level, where or even at tissue level, at the fat level, where you see these cells are expressing this enzyme and take whatever cortisol they're getting, they're they're turning it or cortisone or glucocorticoid, they're making sure that it's active, and then down regulations in some of the deactivating enzymes. And then, specifically to fatty liver, you it's the same thing. The same process is happening at the liver cell, and then throughout the progression of disease, at first the cell has has, like a deactivating effect on on the cortisol. So it has 11 beta HSD two, is a little more upregulated, so it's trying to deactivate the cortisol. Then eventually, as as the progresses, 11 beta HSD, one, the activating enzyme is increasing, and then eventually the activating enzyme, and this is when you go into Nash, deactivating enzyme is increasing and the deactivating enzyme is decreasing. So you just have constant, elevated glucocorticoid signaling. And in Nash, which is non alcoholics, fetal hepatitis, when eventually cirrhosis, those are. Like the severe forms of this disease and most non alcoholic fatty liver disease doesn't even move into that direction. It doesn't most non alcoholic fatty liver disease just stays as non alcoholic fatty liver disease. It doesn't progress. So you see, like the changes in amounts of act not only released glucocorticoid, but actually the glucocorticoid function at the cell being increased as the pathology increases more. So you see this trend with more glucocorticoid more pathology, and you also see that with the with the mitochondrial dysfunction, more mitochondrial dysfunction, more pathology, more oxidative damage to the mitochondrial structures from the dysregulated metabolism, more pathology so they they all track together. And this is going to be important a little bit later on, when we try and, like, bring everything full circle. Did you want to touch on anything that with those with the enzymes are in.

Jay Feldman 30:59
I think you did a good job of summarizing right the as far as the 11 beta HSD one and two, they're upregulated and down regulated with these different energetic states. And as things get worse, we basically have an amplification of the stress signals, like as energy production is getting worse and worse, as you're having more of these inflammatory states and having this pathology, you amplify that more and more, and initially you're trying to, we kind of talked about this before, as far as kind of an acute and then a chronic issue, where it's the same thing just expanded on a longer term. So when you have an acute issue, you're trying to just get right back to baseline. As it starts to get chronic, the goal is still to get back to baseline, but it's, it's a situation where the problem is being recognized as a more severe problem, and so there's a greater, like, a greater effort to try to recover at that point, to try to mobilize resources and deal with that problem, because it's becoming a much more major problem to the health of the tissue and the health of health of the body. And that's what cortisol and these stress hormones are, is they're mobilizing of our backup systems, our backup fuels. And that's why you see the release of free fatty acids, for example. So we're seeing that as the problem continues not to be solved by the initial stress hormones and the initial backup pathways, they get deeper and deeper in their layers, and, you know, digs that hole further, and then is creating more and more of this, what we call pathology. But the pathology is just trying to recover from this, this damage, and trying to prevent and and reverse the damage, and it's just not able to, because there's this continued insult, or multiple continued insults, which we'll talk about. What exactly are these insults that are causing all these issues? But distress hormones are just a good characterization of what's going on.

Mike 32:50
Yeah, and it's it's also interesting because the cell is a switch, or has the ability to decide what it wants to do with the stress hormone. So the body as an overlying system, the endocrine system, and also the immune system and nervous system are deeply, intimately related in all of these states. But essentially, the body is getting the signal that you're having a cellular energy deficit or having an inflammatory problem. It all essentially comes down to what's going on at the cell and the effects there and then it releases mobilizing hormones to help the cell, and the cell can choose how it responds to those hormones, depending on the cell state. So when you have further disruption in the cell's energetic state and energy production, it can it will change how it actually deals with the glucocorticoids. So the healthy cell can actually just convert the glucocorticoid into an inactive form, whereas an unhealthy or a stress cell will move it into the active form and in and something that's that's interesting to realize here is that the purpose of the court of cortisol, or glucocorticoids, as we discussed, is to mobilize energy resources, and oftentimes this is fat stores. And then that's not only for the for the cells of the liver, but for the rest of the body. So it induces this cyclical, cyclical, or a circular pathology, where it increases lipolysis, or the breakdown of fat from fat tissue, but then it also stimulates the the increased production of fat at the liver and and glucose at the liver, and also triglyceride synthesis at the liver. So you, when you upregulate glucocorticoids very strongly, you start creating a situation where you're taxing the fatty acid metabolism of the liver. So the liver has to produce fat, create fat, and then process fat, all simultaneously from multiple areas. And that's where, I think, when we talked about the study, where we're showing that the majority of the fat coming to the liver, and non alcoholic fatty liver disease was actually non esterified fatty acids from the fat tissue. It's very interesting. And I think that parallels directly with with the glucocorticoids, and basically the glucocorticoids having an effect of upreg. Relating certain genes that increase fat fat production or triglyceride production. So it increases genes that turn acetyl CoA into malonyl CoA, which you talked about earlier as being the main pathway to creating fat so and then also increasing genes like fatty acid synthase, which is literally what it sounds like increasing the synthesis of fatty acids. So the glucocorticoids are trying to mobilize energy for these stressed cells. But the liver is already having, like the liver has that issue already, where it's dealing with too much fat. It's essentially being clogged up with fat metabolism and then, like having too much wood inside, the inside the factory, and not knowing what to do with it, and then having this signal from the rest of the body to increase bringing wood to the factory, because there's an there's a deficit in the amount of chairs, or the amount of energy being produced, so it's like, it's kind of gets a little bit dysregulated and disorganized. And then the increased oxidation of the fat, as we discussed, increasing Ros, and then, you know, amplifying the effects as well. And then the increase Ros, stimulating inflammation at the cell and in the cell, having sending out signals with the inflammation for more glucocorticoids. And it starts to like the initial solution, with the initial adaptive hormones are trying to solve this energetic deficit. But as the pathology increases more and more, and the cells get dug deeper into this energetic deficit, they signal for more glucocorticoids, but it actually can make the situation worse. So and I want to point out here that in many different like avenues of research, knocking out glucocorticoids in some of these states, actually reverses the pathology. And I think that's because you you start to like help with the backlog going at, going on at the cell with the fatty acids and and all these energy substrates that are trying to increase the actual energy production of the cell, and even knocking out the specific enzymes like 11 beta HSD one, which is deactivating enzyme when they knock that out the dysfunction from the pathology, the dysfunction in the pathology actually gets eliminated, because the cell is doesn't respond with active glucocorticoid, corticoid anymore in the fat tissue, not the liver. So it's you The this lens into, like the idea of breaking that cycle. So we already talked about, you know, addressing that the issue with the fat metabolism and the energetic state of the cell, I will, I guess we'll get a little bit more into the oxidation, so fixing the excess oxidative stress of the cell, and then also fixing the glucocorticoid signaling at the cell. So we're going to talk about all these things, I guess, in like a solutions, once we bring everything together, the only, I guess, the other thing that I want to point out is just that we have to, while glucocorticoid signaling is prominent in this pathology, we want to know, and it can be triggered by what's going on at the cell. I think that there's one step beforehand that's triggering that glucocorticoid pathology, and we're gonna, we'll talk about that a little bit later, but there's something that may be up regulating the glucocorticoids very specifically in the fatty liver, liver pathology.

Jay Feldman 38:15
Yeah, yeah. I mean, yeah. And I think there are a few things there that can that can be, you know, implicated, and we will get to that. But so I did want to highlight a couple of things. So one, as far as the mobilization of resources and backup fuels, which you had mentioned, that, you know, there's the shift towards fat metabolism. And that's true, and it's interesting, because you see, you see even a shift like, I think looking at the fuel usage is makes it clear as well. At first you see this reliance more on glucose. Then as that dries up, glycogen stores are low and you have excess stress hormones because the problem's not being solved, you shift more toward fat. And then after that, you shift more toward ketone production, as well as the backup to the glucose half of things like first you slow, you know, you continually minimize and minimize the amount of glucose used, and and increase and increase the amount of fat used. And then when you when that glucose, the amount of glucose available, drops below a certain threshold, then you see the ketone production. And we saw this earlier, looking at those pathological states from mitochondrial respiration inhibition, and the all of those processes that occur in ketogenesis is one of those when the pathology gets gets far enough. And so I think that's a good representation, as well as looking at some of those enzymes that we were talking about, the 11 beta hydroxy steroid decarboxylase, dehydrogenase and and the five AR, five alpha reductase. Did you talk about the five AR? The kind of opposing pattern to the 11 beta hydroxy steroid dehydrogenase.

Mike 39:57
In the sense that a five AR will deactivate cortisol.

Jay Feldman 40:00
yeah, and that you see, okay, and then you see increases in that originally, and then decreases later on.

Mike 40:06
Yeah, exactly. It's the same thing with the eight, the 11 beta hydroxy steroid dehydrogenase two, the enzyme that inactivates cortisol, right? The five AR and that eight, uh, that 11 BHS d2 will be, will be deactivating cortisol. So at first, right there, they can be upregulated NAFLD, and then as the pathology progresses to Nash, which is inflammation, and then cirrhosis, which is the five the replacing of the damaged cells with fibrotic tissue, those enzymes actually get down regulated, and you just have the glucoricoid signaling, right? So, yeah, that's the it. There's it. The reason I think we're that we're bringing that up is just to show that the cell has switches depending on what's going on, and it can actually regulate what's being produced, on a mass scale by the rest of the body. And being in the case of glucocorticoids. And this happens for this happens for all hormones. This happens for thyroid hormone. It happens for androgens. There's different enzymes involved, involved in those but you have the mechanism of control at the brain, then you have the actual glands that's producing the the hormone, and then the cells can respond to that hormone however they're going to respond to it, and and so that's like, that's where you see the integration of the nervous system with the endocrine system, and then exactly what's going on at the cell and the immune system plays into it. And we haven't touched that yet, because we're going to cover that and like in this next section coming up, where all that plays in.

Jay Feldman 41:36
Yeah, absolutely. And so I think you kind of mentioned this a little bit too, and I just wanted to highlight it as well. I as well. One of those more specific enzymes that you see being affected by the high stress hormones, the excess glucocorticoids, excess cortisol is the acetyl CoA carboxylase, which is part of that fat production pathway. I know you mentioned that. Just wanted to highlight that. And we see that in every step of the way. Again, this this kind of state of chronic glucocorticoids, is it tends to shift everything from the initial response, which is, you know, let's get right. Like this. Will just fix everything, because initially the the stress hormones do that. They just up regulate energy production to deal with whatever's there. And then, when it starts to happen over time, and you're realizing your body's realizing, like, we're not getting out of this so easy, then it starts to depress everything and shift everything towards story. More basically, the whole body shifts toward hibernation. You were talking about how this happens on, you know, in our brains. It happens in our livers. It happens in our and reproductive hormones and glands. So your organs, so you see. And then you mentioned thyroid as well. You see this in every layer that there's this shift toward, you know, away from high metabolism, away from optimal function, away from a non fatty liver, and toward that opposite state of of storage and hibernation and slowing things down. And yeah, and it's just one of the main mediators of those things, is cortisol and the glucocorticoids. It's like that main, again, mediator, the messenger that goes between what's going on, on, underlying that lack of energy, and then what we call pathology, but is really just protective, adaptive mechanisms that protect us from what is, what is anticipated to be as future stress. Basically, the body is saying, If this keeps happening, we can't keep we can't keep this up. And so we have to, we have to prep for that. And fatty liver is one of the ways that it does that. And we'll be talking about that later on as well, in that how it, how this is a protective response that actually protects the cells from cell death from excessive oxidative stress. It protects the liver itself from excessive damage and and oxidative stress from things like endotoxin and PUFA. And so we'll get into all that. But it's, yeah, it's, it's just that deeper layer of of response.

Mike 43:55
And it's interesting because every, every piece of the every piece of the system, functions and like kind of, like opposition or the excess glucocorticoid signaling will then lower that the thyroid, the thyroid function, and will lower the androgenic function, or the progestergenic function. And so, like, the one system starts to increase and the other system starts to decrease, and they work directly on each other. So any, like, any periods of excess amounts of glucocorticoids or cortisol, or anything like that, has direct effects on the other hormonal systems as well. So the whole body's regulation systems have a shift as well as, or have a switch as well as the switch at the cell. And it's not just the switch, you know, it doesn't just happen like that. It's kind of a spectrum or gradation of pathology, whereas one side increases, the other side is decreasing, maybe not exactly linearly. They could be in different curves, but that's kind of the general idea. So like everything is is managed at a large part of what's going on at the cell and and then the hormone systems and endocrine system, the endocrine system, the immune system and nervous system and. Mobilize and adjust everything around that, and then, yeah, so it's just a big, beautiful, beautiful system of regulation and feedback loops and adaptive processes to help the cell manage its state and the pathologies are basically just extended periods of chronic stress. And it's about fixing, fixing those, the fixing those extended periods of chronic stress, reversing the damages at every step of the way, and that those are comprehensive approaches. There's not going to be that quick fix, so just block glucocorticoids. Bam, you're done.

Jay Feldman 45:30
Right? Yeah, I think the key takeaway here is that fatty liver is beauty, yes. And obviously I'm joking when I'm saying that, but in reality, it is, I think, really helpful to just keep that in mind that this is not something that we need to be fighting against our bodies with. I know that's that is the common narrative in virtually every disease, every condition, whether it's just obesity or just being overweight, or it's fatty liver or it's heart disease, whatever it is, it's that our bodies are destructive, and if left to their own devices, they will destroy us. They will destroy our health. They will make you eat donuts and french fries, and there's only downhill. And so you need to fight against that. And so, yeah, I just think it's it is helpful to recognize these things as protective and adaptive, and that if we actually remove the things that are that are creating this quote, unquote toxic load, this, this direct damage to our bodily systems, then it relieves these pathologies, which because there's no need for them, right? And the same thing, we've talked about this extensively with weight loss too, and I'll link to those episodes, but basically talking about that as a protective hibernation state in response to a lack of energy, and we're seeing this in the in a more when we're looking at fatty liver, it's just looking at that directly in terms of the liver, but it's basically the same situation. Yeah, yeah, I agree. All right, we're going to wrap up that episode there and pick back up in Part Five, where we'll be discussing how endotoxin and PUFA, the polyunsaturated fats, inhibit our ability to produce energy, and how this can cause fatty liver if you did enjoy today's episode, please leave a like or comment. If you're watching on YouTube and if you're listening elsewhere, please leave a five star rating on iTunes or a review. 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, you can head over to Jay Feldman wellness.com/podcast we're all linked to the studies and articles and anything else that we referenced throughout today's episode. And if you are dealing with any of the symptoms or conditions that we've been discussing throughout the series, maybe that is fatty liver, maybe it's insulin resistance or diabetes or heart disease or other metabolic conditions. Or maybe it's other chronic health conditions, like autoimmune conditions, for example. Or perhaps you're dealing with various low energy symptoms. Maybe that's chronic cravings and hunger, low energy or fatigue, joint pain, weight gain or digestive symptoms, or brain fog or poor sleep, hormonal imbalances, or really, any other low energy symptom or chronic health condition. Then head over to Jay Feldman wellness.com/energy where you can sign up for a free energy balance mini course, where I'll explain how these different symptoms and conditions are really caused by a lack of energy. And I'll also walk you through the main things that you can do from a diet and lifestyle perspective, to maximize your cellular energy and resolve these symptoms and conditions. So to sign up for that free energy balance mini course, head over to Jay Feldman wellness.com/energy, and with that, I'll see you in the next episode.