Jay Feldman
Welcome to the Energy Balance Podcast, a podcast where we explore health and nutrition from the bioenergetics view and teach you how to maximize your cellular energy to maximize your health. Today's episode is going to be a bit of a different episode. I'm going to be doing a follow-up from my debate with Dr. Eric Westman on Ben Greenfield's podcast. And I'll be digging into a number of the disagreements we had and some other comments that Dr. Westman made that I didn't really have a chance to address during the debate.

And this includes things like the mitochondrial effects of low carb diets and whether they're actually worse for energy production, as well as the downstream hormonal effects of low carb diets. I'll also be going through whether insulin resistance is a problem of excess glucose metabolism or excess fat metabolism, whether high carb diets cause overeating and insulin resistance, as well as a handful of other points that Dr. Westman brought up. As always, to check out the show notes where I'll link to the studies, articles, and anything else that I reference,

Throughout today's episode, can head over to jfeldmanwellness.com slash podcast. And with that, let's jump right in. So I do just want to start by saying that I appreciate that Dr. Westman agreed to the debate and yeah, throughout that debate, there were a number of points that we disagreed on and that we didn't have a chance to dig into as much because the conversation jumped around quite a bit. The topics changed pretty quickly and we didn't really have a chance to close many of the open loops and really dig into the extent that I would have liked to. I looking forward to talking in a bit more detail about a lot of the points that were brought up and there's a number of other points that I wanted to bring up. So I'll be doing that more so in this episode. I'm recording this about a week or so after the debate. So I don't remember all of the points that he had mentioned, but I did take some notes. So I'll be commenting at least on those and I might make another video after the debate comes out if there's anything major that I missed. So definitely let me know in the comments if there's anything that you'd like me to discuss beyond what I'll be going through in this video. This will probably be a pretty long video, a long podcast episode. There's quite a bit to go through, a ton of studies to share that I would have loved to have discussed on the debate, but just didn't have a chance to. I'll be diving pretty deep into the research that supports the perspectives that I shared there and that I will be sharing.

Jay
because that's what a lot of the debate was focused on. And so we'll get a little bit in depth. That being said, some of the topics will be a bit more straightforward. It won't be going into as much depth with all of them. So as always, if you aren't as interested in a particular point of contention or topic, then just use the timestamps and jump around to whatever might interest you. And one other thing that I didn't have a chance to discuss as much on the debate or really at all is what I think  the optimal diet is. And I did touch on the fact that even though don't think carbs are the problem, I don't think that all carbohydrates are created equal. You know, so even though I think we do want to include carbs in our diet, that doesn't mean that we should just be including any carbohydrates in our diet. So for any of you who are interested in supporting your metabolic health with the right carbohydrates, I'd recommend that you head over to jtheldmanwellness.com slash guide, where you can download the free energy balanced food guide.

The 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 adjusts the scale for you in the case that you're dealing with various digestive issues. The food guide makes it extremely easy to get started with a bio-energetic approach to optimizing your health. So head over to jfeldmanwellness.com slash guide to download the free energy balance food guide. Let's start with just the overarching picture that I don't even, I didn't really even have a chance to dig into. got a portion of the way through and then got derailed. The conversation took some twists and turns. So I want to just provide that picture from start to finish and then we'll talk about the research supporting it and a couple of the points of contention and things that Dr. Westman brought up that he disagreed with. So we'll talk about the research supporting those. So I mentioned during the debate that I don't think that a standard Western diet is an optimally healthy diet. So I just want to start with that.

Make sure that that's clear. not saying that that's the diet that we should be opting for. I'm not saying it doesn't matter what types of foods we're eating. And I would agree that the carbohydrate choices, the foods that people are eating on standard Western diets that contain carbohydrates are typically not ideal. So I'm not advocating for any of that. And also, and I did mention this at one point during the debate and meant to mention it earlier. I do agree with the general premise that there are a lot of benefits to low carb diets. I've seen these myself. I've seen these in clients.

Jay
But I would also say that there's a long-term cost. And again, I see this play out not only in myself, not only in people, you know, other prominent health influencers who have mentioned these things, but also I see it in members of my programs, people who I work with one-on-one, where while there are benefits, there's an inherent cost to the low-carb diets that I'll be focusing on today. And that then leads to a cost health-wise. And basically we see a situation where there might be a number of short-term benefits.

But over time, the costs tend to accumulate and we tend to see some negative effects. And so we'll be talking about and kind of breaking down how that occurs and what my larger concerns are with the low carb keto diet approach. We'll start by digging into the bio-energetic effects, the mitochondrial effects, basically looking at what happens with fuel usage on a low carb or ketogenic diet compared to a higher carb diet and why we produce less

We produce energy less efficiently on a low carb diet and why this also then signals stress. And that as a result of that, we have certain downstream hormonal effects, including increases in stress hormones as a result of this inefficiency in energy production, which then has other downstream effects on our reproductive hormones, on our thyroid hormones, and therefore also downstream effects on other bodily systems, our immune system, reproductive function, cognitive function, nervous system function, digestive system function.

And so we'll be talking a little bit about that, but that's kind of the broad picture here. And that basically as a result of these underlying effects and the chronic physiological stress of carb restriction, there are downstream consequences. And, you know, I've mentioned that I see these in people who I work with, you know, where initially there was all these benefits of the low carb diet relief from joint pain, autoimmune issues, brain fog, whatever it is. then over time, we start to see an increase in anxiety, we start to see trouble sleeping, we see lower energy, lower libido, increasing blood sugar values, low body temperature. And for people who are losing weight, potentially weight regain as well. And so we'll be discussing the underlying physiology that leads to those things. And, you know, it's worth mentioning as well here that I did do different variations, different iterations of low carb diets for years. I did ketogenic diets, cyclical ketogenic diets. I was doing some intermittent fasting.

Jay
I did just kind of more of a standard low carb approach as well on the kind of paleo low carb approach. And I experienced some of those positives and also some of negatives. so we'll be digging into the physiology here that underpins all of that. And to start in terms of the broad picture of what's going on with these low carb diets and why they affect our physiology in the way that they do, I think it's important to, uh, to key into that biological context. And so when we're looking at our fat reserves or body fat, this is really our backup fuel source and it's reserved for times when carbohydrates aren't available, when food isn't available, like a state of famine or starvation, you know, there's not a lot of food available or if there's just an excessively stressful period of time. And this is a time when our bodies are oriented towards survival. They're just trying to do everything they can to get by and get through this period of basically a suboptimal environment. And we know that when the diet doesn't have carbohydrates, when we're on a low carb diet, It mimics this sort of state of famine or starvation or fasting. It's known as a fasting mimicking state. And the lack of carbs is what determines our fuel usage and basically shifts us to using more fat as our primary fuel. And of course, there's also the production of ketones that we'll talk about as well. But in a broad sense, this shift toward utilizing fat as our primary fuel coincides with mechanisms that are survival mechanisms that are intended to decrease our energy production and our metabolic rate allow us to survive for longer periods of time during extended stress. If we're starving, if there's no food available, we don't want to keep running our engine at a high level. We want to decrease our function so that we can survive for longer without food available until we're able to get food again. And so all of that coincides with the utilization of more fat as a fuel and the production of ketones as well. And we see this on the mitochondrial, biochemical, bioenergetic level, and then it gets reflected in the hormones and in other downstream effects that's kind of the broad picture. One other factor that's worth noting here is that carbohydrates are a nutrient that is essential to our bodies. And so if we're not getting that from our diet, but of course we still need the carbohydrate, we need the glucose. Then we have to induce various processes in order to produce that nutrient. And the same goes if we're eating very, very little fat and obviously fat is also an essential nutrient for our bodies. And so if we're not eating enough from our diet, then we'll produce it, but there's an inherent cost to that. And that goes hand in hand with some of these stress effects.

Jay
Just like, you know, again, it's a parallel if we're not getting enough carbohydrate, there's a stress effect there if we don't get enough fat or protein. There's also stress effects with those as well, because these are essential nutrients to our physiology. So let's start to zoom in on these energetic mitochondrial effects and what's going on when we're using, what's going on in terms of fuel usage on a low carb diet. So when we're on a low carb diet, when we shift away from utilizing carbs as a fuel, we see a much greater reliance on fat as a fuel for the vast majority of our bodies, but there are certain areas that normally require glucose to function, but they can't actually use fat efficiently. And so they will use ketones. We'll start to produce ketones in these instances for those different areas. So in general, our bodies are mostly running on fat for not eating any carbs. And there's certain portions that are utilizing ketones and there are certain portions that are still utilizing glucose that actually can't use fat or ketones. And the biggest concern here is that fat as a fuel is far less efficient than carbohydrate as a fuel and glucose as a fuel. And what we basically see, we'll dig into the details, but what we see on a broad sense is that fat oxidation or fat burning leads to slower, less efficient ATP production, slower, less efficient oxidative phosphorylation or mitochondrial respiration and higher rates of reactive oxygen species production and higher oxidative stress as a result.

And this Less efficient energy production is fine for low energy demands. So if we're talking about the muscles at rest, they don't have high energy needs. It's like a low energy demand state. There's not much activity going on. So in a state like that, fat is fine to be used as a fuel, even though it's less efficient. But when we look at a tissue like the brain or the nervous system, there are extremely high energy demands and the nervous system is very sensitive to damage and oxidative stress.

So this is a system that can't actually use fat as a fuel. And this is a system that has to rely on glucose or a combination of glucose and ketones. And so that detail is going to become important here in terms of why, when we look at the physiology, it becomes clear as to why fats are not used as a fuel in the brain, but ketones or glucose are. And so when we're looking at the difference between glucose burning and fat burning, glucose oxidation, fat oxidation, there is really only one central difference that leads to other downstream effects because there's, can separate the energy production into three processes. So with glucose, have glycolysis and then that produces pyruvate, which gets converted to acetyl-CoA and that enters into the citric acid cycle. And then that also leads to the production of reducing equivalents like NADH and FADH2, which go to the electron transport chain and lead to ATP production there. When it comes to fat metabolism, most of that is the same, except instead of having glycolysis, we're converting it to biruvate, the fatty acid undergoes what's called beta oxidation and gets converted into acetyl-CoA. And then that enters the citric acid cycle just the same. And then we have energy production at the electron transport chain. So a lot of what happens is very similar. There's a lot of overlap between glucose and fat metabolism. And the real difference comes in in the earlier parts, the glycolysis versus the beta oxidation. And so we want to zoom in a little bit on that.

And essentially when we have beta oxidation from fats, we produce in the process, far higher FADH2 relative to NADH compared to glycolysis. And these, the NADH and FADH2 are what then go to the electron transport chain where we're producing energy. They drop off the electrons there and we use that to produce energy. And we'll get into a little bit of, just a little bit of detail there. But so the main difference is the amount of FADH2 that gets produced relative to NADH.

And so when we're undergoing beta oxidation, there's a 2.5 times greater ratio of FADH2 to NADH than when we undergo glycolysis. And this is, not just between those two. It's when we do the full fatty acid oxidation. So we go through beta oxidation and then the citric acid cycle, we end up with a 2.5 times greater FADH2 to NADH ratio relative to glucose oxidation. And as a result, we can see this here at the electron transport chain, we see that the NADH and FADH2 are both dropping off electrons at different complexes of the electron transport chain. have complex one and complex two, and we'll get into some detail here. And then those electrons are passed on to coenzyme Q or ubiquinone, and then they get passed on from there. we use, we basically use the drop off of electrons to pump protons across the membrane and create a gradient. And we use that gradient to produce ATP.  And When we're dropping off more electrons with FADH2, we end up with a lot of electrons being dropped off to coenzyme Q at the same time. And this leads to a buildup of electrons there faster than they can be offloaded. And so the whole chain here gets clogged up. And as a result, there's excess electrons that end up getting passed on and creating reactive oxygen species. We also see that there's a potential for what's called a reverse electron transport, where the Electrons actually go backward, back to complex one and produce reactive oxygen species there. And we also see there's an increase in the NADH to NAD plus ratio, because when there's this buildup of electrons here, NADH can't drop off electrons to complex one as efficiently. So the NADH builds up and you get less NAD plus. So that ratio builds up as well. And that's going to have some downstream effects. So there's three kind of general concerns there. Now we can see some of those play out here. So this is a... diagram from a study titled, the Randall cycle revisited a new head for an old hat. And we see that with beta oxidation, they're showing that there's far more FADH2 being produced relative to NADH, whereas glucose, it much more favors NADH. And so as a result with the beta oxidation, in this case, they're actually showing reverse electron transport that's creating reactive oxygen species from complex one, which is a factor. But we also see some other places where reactive oxygen species are produced. And then as we said, in this case of beta oxidation or fatty acid metabolism, we'll also see an increased NADH to NAD plus ratio. So if we take a look at this diagram, this is from a study titled Electron Transport Dependent and Independent Mechanisms of Mitochondrial Hydrogen Peroxide Emission During Long-Chain Fatty Acid Oxidation. So we can see a bit more detail here. Obviously, this is a bit more complicated of a diagram, but what we actually see is that there are some other places where reactive oxygen species are produced.

And we also see some other details in the electron transport chain. So we actually see that from the beta oxidation of the fats, the FADH2 there actually drops its electrons off at what's called ETF, the electron transfer flavor protein, which then transfers those on to what's called the ETF ubiquinone oxidoreductase or electron transfer flavor protein ubiquinone oxidoreductase, which obviously is a mouthful, but essentially we have ETF and ETF ubiquinone oxidoreductase.

Jay
And those electrons get transferred there. And we actually see that this is a major site of reactive oxygen species production in this case, because of this buildup of electrons, as well as, you know, they show here the possibility of reverse electron transport, increased reactive oxygen species from complex one. And then also, it doesn't look like they actually show it directly here, but there can also be increased. well, they essentially do, but there can also be increased reactive oxygen species production from complex three of the electron transport chain. The important thing here basically being that because of the way that the electrons are brought to the electron transport chain due to this difference between fat and glucose metabolism, we have the buildup of electrons, we have more reactive oxygen species production, and we have less efficient ATP production as a result. in response to this, there's a number of responses that happen inside the cells when there's a lot of ROS being produced. We'll talk about those, but one of them is uncoupling. There's a tendency toward increased uncoupling.

With fat metabolism. And that essentially leads to an even less efficient energy production state where we're producing even less ATP and basically burning off fuel as heat essentially. So for a number of reasons, in this kind of underlying mitochondrial sense, fats are far less efficient of a fuel compared to glucose. It stems from this FADH2 to NADH ratio, which then leads to these issues at the electron transport chain, far more ROS production and less efficient ATP production. And there's another set of downstream effects that occur. So we mentioned that there's an increased NADH to NAD plus ratio when this happens, and that then it goes on to affect the citric acid cycle. And so you can see here in the citric acid cycle, there's a number of enzymes, three in particular, that utilize NAD plus, and that gets converted to NADH in the process. When we have a buildup of NADH to NAD plus, it actually slows down these enzymes. And this is especially important at the level of isocitrate dehydrogenase, which is the rate limiting step. The citric acid cycle. And so this actually gets inhibited by the buildup of NADH to NAD +, which then leads to a buildup of isocitrate and citrate, especially also because the aconitase enzyme gets inhibited by the oxidative stress. And so we see this buildup of citrate, which has a number of effects that we won't touch on in too much detail here, but it also leads to an accumulation of acyl-CoA.

Jay
And so as a result of this buildup of acetyl-CoA, we actually see an inhibition of the enzyme pyruvate dehydrogenase. This is the enzyme that basically ties glucose to the citric acid cycle. And when the glucose ends up getting converted to pyruvate, it then has to get converted to acetyl-CoA by pyruvate dehydrogenase. This enzyme gets inhibited by that buildup of acetyl-CoA as well as the higher NADH to NAD plus ratio. So what we see here is that when we're metabolizing fats, A, it blocks glucose's entry into the citric acid cycle, but also we see a slowdown of the entire citric acid cycle due to the increased NADH to NAD plus ratio and the inhibition of a number of these different enzymes. So those are the main effects here in the citric acid cycle. There is one other thing to mention here, which is that when we're looking at fat metabolism versus glucose metabolism, because fat metabolism doesn't undergo that pyruvate dehydrogenase step, there's less carbon dioxide production actually 50 % less. So it's a pretty considerable difference in terms of carbon dioxide production. And when we have less carbon dioxide, that actually leads to less oxygenation of the cells via an effect called the Bohr effect. And it also leads to less protection against reactive oxygen species and reactive nitrogen species because both of those, well, carbon dioxide essentially protects us against both of those and leads to reduced production of them. So those are our general differences here between fat metabolism and glucose metabolism, we have this difference in FADH2 to NADH ratio leads to more ROS production, less efficient ATP production, an increased NADH to NAD plus ratio, or another way of saying that is a decreased NAD plus to NADH ratio. And we also see less carbon dioxide production and that all of these effects lead to a slower rate of respiration and less efficient respiration. So that's our general underlying kind of biochemical bioenergetic concerns. And we're going to be going through studies that demonstrate all of this, but it's also worth highlighting a little bit of the difference between glucose metabolism and fat metabolism versus ketone metabolism. So ketone oxidation is more efficient than fat oxidation. It's actually more similar to that of glucose oxidation. So with fat metabolism, you had a 2.5 times greater ratio of FADH2 to NADH. With ketone metabolism, you have a 1.5 times greater ratio of FADH2 to NADH relative to glucose.higher.

Jay
 So it's still but not as much higher. You do still have the less carbon dioxide production. so between those things, ketone oxidation is still less efficient than glucose, but it's far closer to glucose than fatty acid metabolism. So it's nowhere near as problematic as fatty acid metabolism, and it's still relatively efficient. Now there are a couple of sources of confusion when it comes to the metabolism of these different fuels. So just want to touch on those really briefly. The first is that there's normally a conflation between glucose oxidation and glycolysis. So with glycolysis, we have the conversion of glucose to pyruvate, and then we can have this conversion from pyruvate to lactate. And so when a cell is only running glycolysis, essentially it's a state where the glucose is getting converted to lactate. And this is something that we do when we're, we see it in the muscles essentially, when we're sprinting or doing like really high intensity movements, we rely on this glycolysis to produce energy because it's very quick.

Doesn't actually utilize oxygen. But when we're utilizing glucose the vast majority of the time, we're actually doing complete glucose oxidation, which produces a lot more energy and is much more efficient. Glycolysis is not particularly efficient. Now we do see an upregulation of glycolysis in different chronic health conditions or negative health situations. So that's not something that we want. We don't want to be in a state where we're stuck in glycolysis, but that's very different from glucose oxidation, a full complete oxidation of glucose where we're actually producing energy far more efficiently. So that's one thing that I want to clarify. We're definitely not advocating for suggesting that glycolysis is an optimal way to produce energy on its own. Now, the second part is that we do see that in these states where glucose oxidation, glucose metabolism is impaired, providing an alternate fuel source is beneficial. So providing ketones in a state like that, let's say this is a state where the brain is dealing with some metabolic issues and it's not efficiently producing energy from glucose, If you provide ketones, you'll see benefits in a case like that. You can even see benefits from utilizing fat as a fuel instead of inefficiently utilizing glucose as a fuel in other areas, not the brain. again, this comes back to a situation where it's, the problem is not that the glucose metabolism itself is, is the issue, but rather that we're not efficiently using that glucose, we're not efficiently metabolizing it. And so in that situation, we would see benefits from using these other fuel sources, but we haven't actually fixed the issue.

Jay
We haven't fixed metabolic problem with glucose. And we'll talk about how this is actually what happens in insulin resistance, fatty liver disease, heart failure. And on from there, these are states where we have inefficient glucose metabolism and we therefore end up relying more so on fat metabolism, but that's actually not an ideal state. That's not a state that we want to be encouraging. And instead we want to actually fix the glucose metabolism issue. So that's our broad picture when it comes to the difference in fuel utilization and how it impacts energy production in the mitochondria. And as a result of that, as a result of this difference in fuel utilization and energy production, we then see certain hormonal effects on a low carb diet where we're using these fuels or fasting or starvation that we see this parallel hormonal effect as a result of these underlying energetic effects, as well as just the lack of this dietary nutrient. And so what we see is that with this impaired energy production, this less efficient energy production, this results in the chronic reliance on stress hormones namely glucagon, epinephrine and cortisol, which increase energy production. They force the cells to continue producing energy despite this inefficiency. They essentially say, we need more energy regardless of the cost. So let's upregulate our energy production. And the byproduct of this is a couple of things. One is they maintain increased levels of fatty acid metabolism, and they also increase the production of glucose via gluconeogenesis.

So this is also, you know, a part of the stress pathway that increases glucose production for the tissues that need it. Now, while these stress hormones increase mitochondrial respiration, in the short term, they slow our metabolic rate in the long term by turning down the other hormones that regulate our long term metabolic rate, basically like our metabolic dials. And this includes the thyroid hormones and the reproductive hormones. So we know, for example, that glucagon decreases the conversion of T4 to T3.

And these are thyroid hormones. T3 is our active thyroid hormone. So when we have less T3, we have a decreased metabolic rate. We also know that there are a number of downstream effects of this. For example, T3 is necessary for steroid hormone production, like for the reproductive sex hormones, sex steroids. And this is via control over a protein called the star protein, the steroidogenic acute regulatory protein.

Jay
Basically T3 increases that so we can stimulate steroidogenesis. We can increase the production of steroid hormones. And so when we don't have enough T3, we'll also see a down regulation of those reproductive hormones. And this is just with glucagon, but we have parallel effects with epinephrine and cortisol and even stronger effects, especially when we get to cortisol where it turns down not just T4 to T3 conversion, but it turns down thyroid hormone production at the thyroid gland. It lowers GnRH and LH and FSH that all stimulate the reproductive hormone production, so as well as a number of other areas where cortisol interferes with these sorts of hormones. So it's a stronger signal, but basically all of these hormones work together in this state to turn down our metabolic rate and basically help us deal with the stress at hand due to starvation, fasting, or just the lack of carbs in the diet. And so as a result of this, we see this basically accumulated stress over time.

And while there might be benefits initially for a number of reasons on a low carb diet, due to removing a lot of problematic foods, due to maybe providing fuels that we can use more efficiently when we can't use glucose effectively, or for, again, a number of other reasons which I've dug into in prior podcast episodes, we might see various benefits, but we also see this accumulating stress over time that leads to reduced thyroid hormone activity, lower reproductive hormones, lower metabolic rate, and a number of other effects that these hormones have. know, thyroid hormones have effect on everything from I mean function to digestion to cognitive function, you know, these are very global hormones. And this is why, again, as I mentioned, you know, I'm often seeing these sorts of negative effects like anxiety, low energy, low libido, rising blood sugar, trouble sleeping, low body temperature, and various other symptoms, you know, over time and people on these low carb diets. So that's kind of the broad overview picture. And it seems like on one hand, Dr. Westman might've actually agreed with.

At least the conclusion that low-carb or ketogenic diets lower the metabolic rate through these mechanisms. Because at the, the end of the debate, he did agree that ketogenic diets would lower the metabolic rate. And he was just saying, this is actually a good thing due to the rate of living theory. We'll come back to this point later because I would say this is definitely not a good thing. And we'll talk about the rate of living theory a little bit and why this doesn't actually mean what people think that it means, but It does seem like maybe he was at least in agreement. You know, we didn't actually get to this point where I was able to kind of lay everything out from start to finish in terms of the broad picture, but it seems like maybe he would have agreed that these low carb diets, I mean, it seems like he did agree that the low carb diets lower the metabolic rate. At least that's what he was suggesting, but he was just saying this is a good thing. We'll come back to that later. And I would argue that it's definitely not a good thing physiologically, but part of reason we didn't really get to that point was because there's this big sticking point from Dr. Westman where he was basically saying, how do we know that these biochemical pathways are actually happening? And also what if there are certain adaptations on a ketogenic diet that prevent it from happening or change the function in some way? So I want to dig into that quite a bit here. We're going to go through a ton of research supporting everything that I was just describing. And I do want to say on one hand, it is always a good question to ask, right? When somebody is pointing to some biochemical pathway, we want to know that this is actually happening in the context that we're talking about. For example, we want to see that in fat metabolism, there actually is an increase in FADH2 to NADH. We want to see these other downstream effects rather than it just being some particular biochemical pathway that we're pointing to that isn't actually relevant or heavily relied on in the case of this context of fat metabolism. So we do want to see that that biochemistry actually plays out. But I was actually kind of surprised about this point of contention in this scenario because you know, with the, the pathways I'm describing here and the impacts on energy production are not, you know, obscure biochemical pathways that aren't really well known. It's pretty well established. It's pretty well known that this is what happens when we metabolize fats versus glucose. And it's been known for a very long time. you know, we'll be digging into this in a little bit, but this includes, you know, work from researchers in the ketogenic diet field, know, pioneers of ketogenic diet research, including Richard Veitch. We'll touch on that in a second. These mechanisms are also well-established parts of the Randall cycle, which is basically mechanisms that are recognized to happen during fat metabolism versus glucose metabolism. And these have been recognized since the 1960s. So this isn't really new or controversial information. And so I not really expecting to get stuck at this point, but just to kind of demonstrate this a little bit, we'll look at a paper from Randall in 1977.

Jay
This is a paper titled diabetes and the control of pyruvate dehydrogenase in rat heart mitochondria by concentration ratios of ATP to ADP of reduced to oxidized NAD and of acetyl CoA to CoA ratios. And what they basically found in the study was that with fat metabolism, there's an increase in NADH to NAD plus and acetyl CoA to CoA, and this reduces pyruvate dehydrogenase activity. So this is one of the aspects I was talking about earlier with fat metabolism versus glucose metabolism, where they state in earlier studies it was suggested that the inhibition of pyruvate oxidation in rat heart by the oxidation of fatty acids or ketone bodies is mediated by an increased ratio of acetyl-CoA to CoA, which can increase up to 60 fold. And then he cites one of his own papers from 1964 and another one from 1970. So this set of mechanisms has been known since that point. And he goes on to say, the present studies have shown that the phosphorylation and inactivation of pyruvate dehydrogenase in rat heart mitochondria
is facilitated by increased ratios of either NADH to NAD plus or acetyl CoA to CoA. So these mechanisms I was touching on that lead to an increased NADH to NAD plus ratio, increased acetyl CoA to CoA have been well described and documented since the 1960s. And we see this as well described by Richard Veach, who again, he's a pioneer in keto and basically keto diet research and a major advocate for the benefits of ketones. But he described this as well.

This is a paper of his titled ketone ester effects on metabolism and transcription. And he's basically explaining here why using exogenous ketones is a good idea and could be therapeutic without a ketogenic diet. And that we might want to do this to avoid the negative effects of a ketogenic diet being driven by fatty acid metabolism, by fat and oxidation. And he states here, ketosis induced by starvation or being a ketogenic diet has widespread and often contradictory effects due to the simultaneous elevation of both ketone bodies and free fatty acids.

The elevation of ketone bodies increases the energy of ATP hydrolysis by reducing the mitochondrial NAD couple and oxidizing the coenzyme Q couple, thus increasing the redox span between site one and site two. In contrast, metabolism of fatty acids leads to a reduction of both mitochondrial NAD and mitochondrial coenzyme Q, causing a decrease in the delta G of ATP hydrolysis. You know, he's touching on some kind of more in-depth biochemistry here, but the short of it being essentially that he was noting that fat metabolism is far less efficient than ketone metabolism. And that's why we can have negative effects on a ketogenic diet because of the increased fats. And he's suggesting this paper, maybe we should just use exogenous ketones instead. And he's basically pointing to that there's a decrease in NAD as we were talking about a decreased NAD plus to NADH ratio and more reduced coenzyme Q and as opposed to the more oxidized coenzyme Q that he described with ketone metabolism. And then as a result of basically this inefficiency, there's a decrease in the Delta G of ATP hydrolysis, which is more complex than is worth explaining here. But the short of it is that this is, you these are some pretty well established pathways and effects of fat metabolism versus glucose metabolism kind of throughout the research field. And, the identification of these biochemical pathways comes from studies where they're, you know, they do a biopsy and they're looking at cells or the mitochondria, typically from rodent models, and they provide them different fuels and they see what the different results are.

And then there are other research that they'll do that they do later where they're looking at this in vivo and we'll talk about that too. But Dr. Westman brought up this idea that we're very different from rats and so the research on rats and other rodents might not apply to us. And I wanted to touch on that briefly here before we dig into more of the research and mention that there is some truth to this. In particular, pathways, enzymes,
areas of physiology, there are important differences between humans and rodents, but in general, there's a huge overlap way more is overlapping than not when it comes to rodent physiology versus human physiology. And that's why we do a lot of rodent research. If it didn't apply to humans, we wouldn't, we wouldn't really do it very much, whether it's when we're looking at different diets or medications or supplements or any intervention. And this is especially the case when it comes to fat and glucose metabolism. It's not like we're looking at an animal model that never uses fat and we're trying to provide them fats and see what happens. Whereas we as humans, we always use fats. You know, it's not something like that. Rodents oxidize fatty acids extremely effectively. Their bodies physiologically are accustomed to utilizing fats and there's no physiological basis to suggest that the effects that we'd be looking at in rodents would be different in humans.

Jay
And we'll actually be looking at some research that shows that these mechanisms are conserved across all species. or a number of species that we'll look at, it's not just looking at rodents and humans, but you see it in birds, you see it in cows, that you see these same mechanisms at play. And so, you know, in general, I don't think there's really any basis to suggest that there would be a difference here. And when we look at rodents versus humans, in terms of these biopsy studies, we don't see any difference. And it's also worth mentioning as well, we're looking at tissues that are very well equipped to metabolize fats. You know, they're looking at, in these studies, skeletal muscle or heart muscle, which you normally are utilizing fats, whether we're a higher carb diet or a lower carb diet, these tissues are always going to be exercising fats. So it's not like, again, we're looking at a very different situation on a keto diet versus a higher carb diet. And we'll talk about this a bit later, but this is a situation where we're seeing what would happen in normal fat metabolism. And there shouldn't be any, there's no basis to suggest that there would be any difference whether we're looking at, mitochondria for someone on a ketogenic diet here or a higher carb diet, because In both cases, skeletal muscle and heart muscle are going to be using a lot of fatty acids. But we'll get into that in a little bit more detail in a bit and break that down a bit more. But I just wanted to at least start by looking at these studies in different animal and human models showing what happens with fat metabolism versus carb metabolism. Now, I know I shared one of these on the debate. I don't remember which it was. So I'll just go through both of these to start. The first one is a paper titled, Palmitate Induced Changes in Energy Demand. Cause reallocation of ATP supply in rat and human skeletal muscle cells, and they state, probing the bioenergetics of rat and human myoblasts in real time, we show here that the saturated fatty acid palmitate lowers the rate and coupling efficiency of oxidative phosphorylation under conditions it causes insulin resistance. So we're seeing here they looked at both rat and human skeletal muscle and found that palmitate was basically reducing the efficiency of ATP production. In this study, this is a study titled Indubation of NADPH oxidase two or NOX2 prevents oxidative stress and mitochondrial abnormalities caused by saturated fat and cardiomyocytes. So we're looking at the heart mitochondria here and they state the saturated fatty acid palmitate causes a decrease in mitochondrial respiration and cardiomyocytes. Palmitate causes an increase in both total cellular reactive oxygen species and mitochondrial reactive oxygen species. And so I should be clear here. We're not just looking at mitochondria. We're looking at the entire cardiomyocyte, the entire cell.

Jay
And seeing an increase in ROS in the mitochondria and outside of the mitochondria from utilizing saturated acid, palmitate as a fuel. they go on to state, cardiomyocytes treated with palmitate have increased total and mitochondrial reactive oxygen species. So again, we're seeing this play out in the mitochondria and in the cells when they're respiring on fat as a fuel. And we see this in some other animals as well. So this first study is looking at pigeons. We won't go into detail here. I'm just going to comment on it real briefly or mentioned the title, which is the mitochondrial generation of hydrogen peroxide, general properties and effect of hyperbaric oxygen. And in this study, they looked at pigeon heart mitochondria and they provided them palmitate in the form of palmitoyl carnitine. So it's palmitate bound with carnitine so that it could be used in the mitochondria. And they found that it increased reactive oxygen species. So this is in pigeons we're seeing that. And in this study, we're looking at cows and this is a study titled Nuclear factor erythroid two related factor two, that's NRF2, protects bovine mammary epithelial cells against free fatty acid induced mitochondrial dysfunction in vitro. And the study states, results indicated that exogenous free fatty acid challenge induced linear and quadratic increases in concentrations of mitochondrial ROS. So essentially as they increased fatty acid availability and increased fat metabolism, there was a linear and quadratic increase in ROS production in these mitochondria.

Again, we're looking at the mitochondria in cows in this case, and they go on to state high concentrations of free fatty acids, similar to circulating free fatty acid concentrations in dairy cows with fatty liver during the transition period, induced mitochondrial dysfunction in bovine hepatocytes and vitro. So they're talking about other studies showing that you saw the same effect in liver cells from the cows, as well as in this study when they were looking at the mammary epithelial cells. So we're seeing this, these same mechanisms

throughout species in different tissues as well that all are used to utilizing fats, that when they utilize fats as a fuel and you increase that fat utilization, you see increased ROS and less efficient ATP production. And then we have a number of studies. I I'm sharing a fraction of all these studies here. I'll be citing more in the show notes, but these are just some of the more notable ones. But in this case, we can look at studies that are looking at exactly how these ROS are produced, how the rate of oxygen species are getting produced in this scenario, how efficient the ATP production is and how exactly that's happening. They're able to break it all down by, you know, blocking certain complexes or zooming in at, know, basically what's happening and what products are being produced. And so we can see this all very clearly. It's all very well documented. And we'll take a look first at the study titled topology of superoxide production from different sites in the mitochondrial electron transport chain. And in this case, they looked at skeletal muscle. They looked at heart. They looked at liver cells um, and the mitochondria there, and they basically provided fatty acids and saw that there was far more reactive oxygen species being produced. And in this case, this is, you know, in a rodent model. And so we'll just look at a couple of quotes here where they describe in detail how this is all happening. We already went through this in terms of the mechanisms, but, uh, you know, touched on it before, but this is the research that's supporting it. That's saying this is actually what's happening in these scenarios. And so they go on to state here.

Mitochondria from skeletal muscle or heart generated significant amounts of superoxide, that's a reactive oxygen species, from complex I when respiring on palmitoyl carnitine. So that's basically fatty acid palmitate bound with carnitine. They go on to state, the greater hydrogen peroxide production with palmitoyl carnitine than with complex I substrates could be because complex I is more reduced with palmitoyl carnitine due to reversed electron transport and competition with the ETF, ubiquinonexidoreductase for oxidized Q.

I'll just pause there, but they're describing exactly what we were seeing earlier. With the fatty acid metabolism, you have far greater drop off of electrons from FADH2 relative to NADH compared to glucose, where you have far more NADH electron drop off relative to FADH2. And in this scenario, they're describing exactly what we were describing earlier, which is that they saw increased reactive oxygen species due to potential reverse electron transport and also the competition due to

Basically the fact that all of the coenzyme Q gets reduced and there's not enough oxidized Q left or ubiquinone left. They go on to state, greater steady state reduction of complex one would lead to greater matrix ROS production with palmitoyl carnitine as a substrate. Additionally, it could be that the ETF ubiquinone oxido reductase and ETF can also produce superoxide on the matrix side of the membrane when palmitoyl carnitine is added. So we saw this in that earlier diagram that there's actually ROS being produced at those enzymes.

Jay
And they go on to state fatty acid beta oxidation does lead to release of reactive oxygen species, primarily from complex one on the matrix side of the inner membrane, which can lead to hydrogen peroxide spilling out into the cytosol. So that's what they found to actually be the case. We'll go on to this next study, which is titled Electron Transport Chain-Dependent and Independent Mechanisms of Mitochondrial Hydrogen Peroxide Emission During Long-Chained Fatty Acid Oxidation. So again, similar study in this case looking at a different rodent model in mice.

Seeing those same effects and identifying where these ROS are coming from, when the cells in mitochondria are utilizing fat as a fuel, they state using skeletal muscle mitochondria, our findings indicate that even a low supply of long chain fatty acids is associated with ROS formation in excess of that generated by NADH linked substrates. So the NADH linked substrates being, you know, glucose and pyruvate, whereas we have more of an FADH2 linked substrate here with the fats. And so... This was associated with greater ROS formation, go on to state. Moreover, ROS production was evident across the physiological range of membrane potential and was relatively insensitive to membrane potential changes. Determinations of topology and membrane potential, as well as use of inhibitors, revealed complex III and the electron transfer of flavoprotein ETF and ETF-AXIDO reductase as likely sites of ROS production. So they were able to identify, you we know there's ROS, where is it coming from? And by blocking, you know, you mentioned using different inhibitors and using different techniques in the research, so they're able to identify this is actually where it's coming from. And that's how we end up with these pathways is we actually see that they're happening in these sorts of studies. And then we identify, okay, we know that when we're oxidizing fats, we're getting ROS from these places. Here's a couple of other studies showing similar effects. So this is a study titled oxidation of fatty acids is the source of increased mitochondrial ROS production in kidney, cortical tubules, and early diabetes.

So in this case, they induced type one diabetes in rats and they were looking at mitochondria in the kidneys. And at first they state owing to kidney cellular complexity, the current study was performed specifically on mitochondria isolated from cortical tubular structures, the highly oxidative nephron segments that depend on the ATP generation from fatty acid oxidation, free of medullary structures, which are highly glycolytic. So they're just identifying they were specifically using mitochondria that normally use fats as a fuel.

Jay
They were making sure not to use the mitochondria that normally are just using glycolysis as a fuel because that wouldn't be a good representation of what goes on with fatty acid metabolism in mitochondria. And what they found looking at those mitochondria was that mitochondrial fatty acid oxidation is the source of the increased net ROS production and the site of electron leakage is located proximal to coenzyme Q at the electron transfer flavor protein that shuttles electrons from acetyl-CoA dehydrogenases to coenzyme Q. Oxidation of fatty acid substrates was reported to be a source of ROS in the normal heart and skeletal muscle mitochondria. Increased oxidation of fatty acids in aortic endothelial cells was reported to increase superoxide production from sites located within the electron transport. So we're just talking about other studies here, looking at this in other cells, other tissues and other sources of ROS production. They go on to state the Eagle decrease of ROS with rotenone indicates that an additional site rather than the reverse electron transport to complex one is responsible for the increased ROS generation by diabetic tubule mitochondria, oxidizing fat substrates. So basically by using certain inhibitors here, they were identifying that it's not just reverse electron transport driving the ROs production, although that can be a factor as shown in other studies, but they were finding that there are other places where we're seeing this ROS generated. They go on to state these data also indicate that a site other than complex three significantly contributes to ROS generation when fatty acids are used as substrates in diabetes. So there is ROS generation at complex three, but they're saying there's another site as well.

And they go on to state the study identifies fatty acids as the source of reducing equivalents responsible for increased ROS production by kidney, tubule, mitochondria, and diabetes, and shows that ETF, the electron transfer flavor protein, is the major site of electron linkage. So in the study, they were showing that that's where most of the ROS are coming from. But again, this is just another study demonstrating that we can see very clearly that when we're exercising fats, this is actually occurring. We are seeing an increase in ROS directly correlational with the increase in fat metabolism and

We know exactly how this is happening in a mitochondria. can see exactly where it's coming from. And this last study is looking at uncoupling, which I had touched on earlier. We'll touch on it a bit more here. And this study is titled induction of endogenous uncoupling protein three suppresses mitochondrial oxidant emission during fatty acid supported respiration. And they state uncoupling protein three expression increases dramatically in skeletal muscle under metabolic states associated with elevated lipid metabolism. Yet the function of UCP three in a physiological context remains controversial.

Jay
Elevated uncoupling activity was evident in the EXR fibers only upon the addition of palmitate, which is a known activator of UCP3, or under substrate conditions eliciting substantial rates of hydrogen peroxide production, such as respiration supported by succinate or palmitoyl alkarnitine malate, but not with pyruvate malate. Indicative of UCP3 activation by endogenous ROS. In this study, they were actually not just looking at vitro and isolated mitochondria. They were looking at rat and mouse muscle fibers.

This is what's called an in situ study. it's more relevant to what happens in vivo as opposed to just looking at mitochondria individually. What they basically found was that with elevated fat metabolism, specifically with using palmitate as a source of, you know, as the fat metabolism source, they found increased ROS production and they found that this increased uncoupling activity, which as I touched on earlier, is something that helps the cells, deal with increased oxidative stress by basically stopping ROS production because it dissipates the gradient in the mitochondria. But as a result, you also get less ATP production. And so we saw this playing out here in this study. So on the whole, we have a huge body of research demonstrating that these pathways I was talking about, the effects of fatty acid metabolism do directly happen. We know that these are actually what happens when we're metabolizing fats. We're not talking about some kind of random obscure pathway.

That's leading to some, you know, an increase in some metabolite that, that could be harmful. We're talking about the basic function, the basic way that cells utilize fats as a fuel, including the cells that are basically designed to utilize fats as a fuel. In those cases, we still see this happening. We see it not only in rodents, not only in humans, not only in pigeons, we see it in cows. mean, this is something that's conserved throughout species and is basically built into the nature of fat metabolism.

Dr. Westman had also suggested that maybe there would be some adaptations on a ketogenic diet that would prevent these effects. Now he didn't mention what those adaptations might be. And there's also no physiological basis for this. As I was saying, this isn't a case where we're going from zero fat metabolism to a lot of fat metabolism. In that case, of course you would expect there to be some, some physiological changes, some adaptation that goes on. But we're talking about a situation where even on a higher carb diet, there's still a lot of fat utilization in the muscle.

Jay
And in the heart, which of course is a muscle. that the amount of fat metabolism will increase when we're on a low carb diet, but these are tissues that are already used to burning fat. So there wouldn't be a reason to see some major adaptation, some difference on a low carb diet. And so there's no reason why, you know, on a higher carb diet, someone would be maladapted to utilizing fats. You know, a lot of their tissues are still utilizing fats and you know, totally fine. There's not an inherent problem with that. So there's no real basis.

for an idea that there should be an adaptation in a case like this. And then on top of that, these effects are also inherent to the differences between fat metabolism and carb metabolism. You know, there's no support for the, this idea, the supposition that there would not be a 2.5 times greater FADH2 to NADH ratio with palmitate metabolism versus glucose metabolism. You know, in order for that to happen, there would have to be some totally different way of utilizing fats for fuel that's never been identified that no one has ever heard of or come up with. so at that point, we're just talking about, we're just kind of making up some, some stories, some, know, we're saying like, maybe fats are used some totally different way from the way that we know that they're used. And there's no reason to think that there's no support for that. And the same process is being undergone whether we're on a low carb diet or a high carb diet. So, and, and he didn't, know, Dr. Westman didn't provide any explanation as to what would be different. didn't say that there was, you know, there's no support that he pointed to.

No research for it, no possible mechanism pointed to is just maybe this is different on a low carb diet, but there's generally just no basis for that. That being said, we will look at some research on animals and on humans on low carb diets and ketogenic diets and see what actually plays out there. Although it is worth noting that unfortunately, and we touch on this a little bit in the debate, there isn't as much data on humans and ketogenic diets as we'd like. It would be great to have more data there.

So that there are fewer question marks. But again, everything that we see right now in the research points us in a certain direction and there's no reason to think otherwise. At this point, nothing that's been pointed to as far as a reason why it would be different. But before we dig into that research on humans and rodent models on low-carb and ketogenic diets, I wanted to comment on something else that Dr. Westman had mentioned around this point in our discussion.

Jay
So I was talking about the effects of fatty acid metabolism on FADH2 to NADH ratio and the impact on the NAD plus to NADH ratio and on ROS production. And he had suggested that a muscle biopsy from humans on a ketogenic diet would be a way to look at this. And I was a little thrown off in the moment by that suggestion because you typically can't actually see something like the FADH2 to NADH ratio or NAD plus to NADH ratio from a biopsy like that because these reactions are occurring extremely quickly. There's inner conversion that would be going on based on procedure itself of a biopsy, looking at changes in blood flow, oxygenation, temperature. It would also depend on whether the tissue is actually utilizing fuel in that moment and at what stage it is, whether it's just been, whether you were fasted, whether you were doing exercise, whether you just ate, all of these things would affect the momentary changes in these ratios. So it's not, it wouldn't actually be an effective technique for looking at this, not to mention another huge factor we have to consider when looking at this in vivo, which is that our bodies are always adapting and responding to our current scenario, our current situation. And so when there's a lot of oxidative stress, we have the activation of various defensive pathways. We talked about one of these in a coupling, right? So we had shown, you know, there's that study was saying when you have increased reactive oxygen species production,

There's an increase in uncoupling as a protective factor. And we see this that happened with fat oxidation. So depending on what you were looking, if there was a point where you had been producing energy from fats and then got accumulated enough oxidative stress to drive uncoupling, and then oxidative stress lowers, the ROS lowers, it would depend on exactly which moment you're seeing these things happening. And you might, in that case, need to look at the uncoupling protein levels as opposed to the actual ROS levels. And the same thing happens due to other pathways here, other defensive adaptive pathways that we have when we have a lot of oxidative stress. For example, there's, and this was touched on in one of the studies and we'll be going into some other studies talking about these antioxidant pathways. But one of the main ones is called the NRF2 pathway. And that gets activated when there's a lot of oxidative stress and increases the production of antioxidants to deal with that stress. So depending on when, you know, what exact moment in time you're looking, you'll see a different state of the tissues.

Jay
Different state of the adaptive response. And this also applies to the NAD to NADH ratio. So when you have a low NAD plus to NADH ratio due to this kind of poor metabolism of the electron transport chain, and as we said, this backs up the whole citric acid cycle, it's something that slows down respiration, that's something that obviously is a problem for ourselves. So one thing that happens is there's a pathway called the NAD salvage pathway that gets activated. There's an enzyme called NAMPT that gets increased in order to restore and basically recover the NAD plus level. So you have a better NAD plus to NADH ratio. And this has been shown to happen in something like fasting and also likely on a ketogenic diet. So initially or in the short term or depending on what point we're looking, yes, we might have inefficient energy production, but then there's a defensive response to try to deal with that. That doesn't mean that this is a good thing. In the long term, I would say that the underlying inefficiency and trying to deal with that inefficiency. Of course, like we're able as humans to deal with suboptimal environments very well. That's how we've survived for so long. That's how we're as robust as we are. But that doesn't mean that that's actually going to be supportive of our health. We don't want to try to constantly be putting ourselves into an inefficient energy production state and see how long we can get by on that by inducing all these adaptive pathways. And this gets into a longer conversation on Hormesis, which we've done a handful of podcast episodes on this and I've written a couple of articles on this in the past. So I'll link to those in the notes. Let's start going back. So Dr. Westhorn had suggested this biopsy as an option to see these things. And it seemed like initially he was suggesting we would be able to see these ratios, the NAD plus to NADH ratio or FADH2 to NADH ratio or ROS levels. that might've been what he was initially suggesting. I'm not sure. But then he was, after that, he was talking about isolated mitochondria from someone who's, know, a human who's been on a keto diet and then provide that mitochondria with the fuel. See if it would be any different. And to my knowledge, I haven't seen any research doing that, you know, doing a muscle biopsy on people on a ketogenic diet to look at those effects. Probably for a number of reasons. mean, one, there's, there isn't research on all of the detailed areas of every different possible state that could exist. But also with that biopsies themselves are really invasive. And so typically the international review boards are pretty resistant to those sorts of studies, unless there's a strong basis for it.

Jay
But this is why we have much clearer data looking at rodents, which is something that I mentioned on the debate. Obviously a lot of the research we're looking at here isn't in rodents, but there is also research on humans. And we looked at a study earlier doing, looking at mitochondria from a biopsy on humans and seeing that fatty acid metabolism led to more arrest production and inefficient respiration. But of course they weren't on a ketogenic diet. But as I was saying, there's no basis to think that that would be that that would matter in terms of fatty acid metabolism, you know, as I already described. So there's just a couple of things to mention there as far as the kind of state of the research. you know, one other thing to mention is there is a newer technique called phosphorus 31 magnetic resonance spectroscopy. And this would potentially be a more effective option than a biopsy for actually seeing things like the NAD plus to NADH ratio levels in vivo without needing to do a biopsy. And it has been done in humans in the brain specifically. I haven't seen it done elsewhere. But it has been done in humans on a ketogenic diet, looking at the brain and looking at NAD plus to NADH levels. But again, that's when they're utilizing ketones in the brain, ketones and glucose as opposed to fats. So it doesn't really tell us much about what we're talking about here in terms of the inefficiencies of fatty acid metabolism. So all that being said, you know, what I'm pointing to is there are some limitations with the research, of course, but we'll look at the research that we do have, and obviously we've already looked at some of it, and whether it corroborates this idea that there would be any difference on a low-carb diet and whether there's not actually the ROS production we would expect on a low-carb diet and whether there's not actually the ATP production inefficiency or the increase in stress hormones that we would expect based on all these effects. But of course, when we look at the research, we see that it actually does support all of those things. Now, one of the suggestions you know, that Dr. Westman was making in terms of maybe an adaptation that happens, you know, he wasn't really clear on what he meant. And I, I'm pretty sure I don't remember the, the, the debate exactly, but it was pretty sure I said, are you talking about an increase in fatty acid oxidation enzymes, you know, an increase in enzymes regarding beta oxidation or something like that. And I think he said, I think he was agreeing that, yeah, like that or something like that. And so we'll look at a study here where there actually are increased levels of fatty acid oxidation enzymes.

Jay
And what the impact is on FADH2 to NADH ratio, ROS production, efficiency of ATP production and all of that. And so this is a study that we actually already had gone through a little bit to study titled oxidation of fatty acids. This is the source of increased mitochondrial ROS production in kidney cortical tubules and early diabetes. And as I mentioned, this was done in rats, but they induced type one diabetes. And they found that in that case, when they did that, there was an increase in fatty acid metabolism and an increase in ROS production. And so they go on to state that here they say, diabetic mitochondria, the increased amounts and activities of selective fatty acid oxidation enzymes is associated with increased oxidative phosphorylation and net ROS production with fatty acid substrates by 40 % and 30 % respectively, whereas pyruvate oxidation is decreased and pyruvate supported ROS production is unchanged. So what they found is that in this scenario, there is an increase of utilization of fat as a fuel, there was an increase in the enzymes for utilizing fat as a fuel, and yet there was increased ROS production with fatty acid substrates despite the increased enzyme availability. So having more fatty acid oxidation enzymes actually wasn't any better. It actually increased ROS production further with fatty acid metabolism. To go on to state that diabetic tubule mitochondria oxidize fatty acid substrates at higher rates than the controls.

So they were better at oxidizing fat and yet they produced more ROS. And then they go on to state proximal kidney tubules, which is over 90 % of the kidney cortex, rely on fatty acids rather than glucose to form ATP during normal metabolic conditions. We found that this feature is enhanced in diabetes. Our data also showed that diabetic tubule mitochondria produce more ROS than the controls under both basal and maximal conditions when oxidizing fatty acid substrates compared with the oxidation of pyruvate.

So they compared the mitochondria that were more equipped to metabolize fat had greater fatty acid oxidation enzymes to the mitochondria that, you know, to the controls that didn't have that, that weren't, that didn't have this increase in fatty acid oxidation enzymes. And they actually found that there was more ROS produced in the mitochondria that were better at metabolizing fats than the ones, than the controls. So this is not, not only does it not support the idea that, you know, increased fatty acid oxidation enzymes,

Jay
would reduce R-S production and make it more efficient. It's actually suggesting the opposite, that it actually increases the inefficiency of ATP production from fat. that's the first thing I wanted to touch on here. And then now we'll take a look at the research on rodents, where, you know, looking at rodent models where they're fed low carb or ketogenic diets. And we'll see, you know, what occurs in terms of these sorts of effects. And then we'll look at the research on humans on low carb and ketogenic diets as well. looking at this in rodents, first thing to mention here is, you know, again, as I was mentioning earlier, there's no solid basis for the idea that this would be different in rodent models versus human models. Not only because fatty acid metabolism is the same, but also in rodent ketosis is the same as well. It's nearly identical to human ketosis. They actually enter ketosis faster than humans do when they're fasting or on lower carb diets. that's mostly because we have larger glycogen stores. We rely more on carbohydrate metabolism. So they're actually quicker to enter ketosis and they actually increase their expression of fatty acid oxidation enzymes very quickly. And I haven't seen this tested in humans, where I haven't seen this shown in humans, in general, rodents are very much equipped to enter ketosis just like we are. mean, it's something that obviously we do under states of starvation or absence of carbs in the diet and rodents do it as well. They produce the ketones, they shift into more fatty acid metabolism. It's all very much equivalent physiologically. And it's also worth mentioning, it doesn't matter in this case, if they're actually in ketosis and utilizing ketones for fuel, because what we're really looking at is the fatty acid metabolism, whether, and whether there's any difference there. But, you know, we'll look at some animals here that are on ketogenic diets is something that are just on low carb, high fat diets, which both really reflect the same situation. again, when we looked at the, you know, muscle cells from humans versus the muscle cells from rats and rodents, was the same thing. You know, we're seeing the exact same mechanisms play out. So we would, you know, this would essentially suggest that we would expect the same thing that we're seeing here in rodents to happen in humans as well. And there's no reason to suggest otherwise. And we will be looking at the research in humans that supports this too.

Jay
But the first study here is a study titled dietary fat, fatty acid, saturation, and mitochondrial bioenergetics. And in this study, they put mice on a high fat diet, which was 20 % carbs, 60 % fat, 20 % protein versus a control diet, which was 53 % carbs, 13 % fat, and 34 % protein. And what they found was that there was a shift into more fatty acid metabolism on the high fat diet, the RQ decrease. That's our indicator of fat metabolism.

So it's telling us that there was an increase in fat metabolism on the high fat diet, as we would expect. And then they looked at the liver and heart mitochondria using different substrates. And here's what they found. state, respiration and ATP production were significantly reduced at all levels of ADP and resultant clamped membrane potential in liver mitochondria from mice fat high fat compared to controls. At a given membrane potential, ROS production per milligram of mitochondrial protein per unit of respiration or per ATP generated were greater for liver mitochondria of high fat fed mice compared to control or MO fed mice, which was another dietary group that's not as relevant here. But so what we're essentially finding is that there was increased ROS production in the mice that were utilizing more fat as a fuel per unit of respiration and per ATP generated. So the increase, we're basically seeing a reduced efficiency of ATP production. They go on to say, moreover, these ROS metrics began to increase at a lower membrane potential threshold. Similar but less marked changes were observed in heart mitochondria of high fat fed mice compared to controls. In summary, high fat feeding of sufficient duration impairs mitochondrial bioenergetics and is associated with a greater ROS cost of ATP production compared to controls. So they said that there was a similar effect in the heart. It wasn't quite as intense as the effect of the liver. What they found here was exactly what we're talking about. The high fat feeding, you know, even with all of the adaptations that supposedly would happen when shifting into a lower carb higher fat diet, reduced the efficiency of ATP production. So we're seeing that pretty clearly here in this study. Next study is titled effects of a high fat diet on energy metabolism and ROS production in rat liver. And this is another very similar study. They looked at a fat high carb diet versus a high fat low carb diet. And what they basically found was that the high fat low carb diet led to a lower...

Jay
NAD plus to NADH ratio, increased ROS, a more reduced ubiquinone pool. So the coenzyme Q is more reduced and also a higher expression of the genes for fatty acid oxidation enzymes. And when they provided the mitochondria from the high fat, carb diet with palmitoyl carnitine, there was more ROS production than, than in the higher carb, low fat group, despite having the increased mRNA expression for the fatty acid oxidation enzymes. And so they state that in this quote here, they state a lower mitochondrial quinone pool appears to be another important consequence of the high fat diet. The Q9 content, the main ubiquinone in rat liver mitochondria is significantly lower and more reduced in high fat than in controls. The lower and more reduced Q9 pool corresponds not only to a lower oxidative phosphorylation rate as discussed above, but also to the observed pattern of hydrogen peroxide production hydrogen peroxide production, is reactive oxygen species, is markedly increased with acyl carnitine in all conditions. Several findings in the literature support the view of compartmentalization and channeling of mitochondrial beta oxidation acetyl-CoA dehydrogenases, providing electrons directly to the quinone pool via a specific protein, the ETF protein we talked about earlier, therefore bypassing complex I, while 3-hydroxy acyl-CoA dehydrogenase
A NAD-dependent enzyme provides electrons directly to complex 1. Moreover, the fact that the mitochondrial complex 1 respiration alteration is low while in complex 2 it is higher also supports the view of compartmentalization in considering different pools on coenzyme Q. The highly reduced state of Q9 could therefore be a major factor of the high hydrogen peroxide production in high fat feeding, finding an agreement with a seven-fold increase in the mitochondrial alpha-tocopherol content. So, I know that was a lot, but... What we're seeing here is all of this play out, right? With the high fat, low carb feeding, was all, you we saw the exact effects of the mechanisms that we would expect to see based on those bioenergetic mitochondrial differences that we talked about earlier. We're seeing all of those things here. We're seeing the increased ROS production, the more reduced ubiquinone moving to ubiquinol. You know, we were also seeing the increased NADH to NAD plus ratio, which they didn't mention in this quote here. And they also mentioned something else that I had touched on, As a result of the increased oxidative stress, we've seen an increase in antioxidant pathway activation. And so that's why they saw this increase in alpha-to-coferol content where you saw this basically increase in an antioxidant to try to deal with this oxidative stress. And so we saw that play out as well here in this study. And then the last study that we'll mention here is looking at specifically ketogenic diets. So this study is titled ketogenic diet aggravates cardiac remodeling in adults pontaneously hypertensive rats. And they state four weeks of ketogenic diet feeding aggravated interstitial fibrosis and cardiac remodeling in spontaneously hypertensive rats. Now again, four weeks for a rat is far longer in terms of, you know, a human equivalent time. So, you know, this is quite a long time for them to be on a ketogenic diet, considering their lifespans and also how quickly they enter into ketosis and adapt to ketosis. They go on to state, our results showed that A ketogenic diet significantly increased mitochondrial ROS production in the heart of the spontaneously hypertensive rats. Furthermore, ketogenic diet feeding reduced the glutathione content, however increased the malondialdehyde content in hearts of the spontaneously hypertensive rats. Also proving that the ketogenic diet promoted oxidative stress injury in the spontaneously hypertensive rats. So again, we're seeing all these mechanisms play out and we're actually seeing that this reduced the glutathione content.

Typically, what we would see is initially there's this increase in the antioxidant response. You might see an increase in glutathione content initially, but then it will get depleted with time because we can't maintain those defensive reactions forever. And so then we start to see the oxidative stress build up. And that's where we see the MDA, which is a lipid peroxide, basically a marker of oxidative stress increase in this situation, in the rodents on a ketogenic diet. So those are just a few studies looking at this actually play out in terms of you know, a low carb ketogenic diet and wrote it models. And we'll look at this, the research showing this in humans in a moment, but I wanted to touch on something else from the debate. So at one point Bennett asked whether it's possible that ketones protect against these, this oxidative stress from the fatty acid metabolism. So sure, maybe there's fatty acid, there's ROS production from the fatty acids. Maybe the ketones are protected. And of course it's a good question. It's one worth asking.

Jay
You know, in my response there, was trying to explain why I didn't think this was particularly relevant for a handful of reasons and why, you know, in general, this wouldn't actually be enough to make up for the stress and oxidative stress induced by a ketogenic diet. And there was a couple of reasons for that. So one is that in general, this was something that was touched on in that VH paper and we'll touch on it in a couple of others. But while there are ketones available mostly for the nervous system, the peripheral system is largely utilizing fat It uses a little bit of ketones, but it's largely utilizing fat. And so the ketones aren't really present in those areas in the amounts necessary to have that sort of an effect. Not to mention that we actually see that the ketones themselves also drive this effect. They actually also increase some amount of oxidative stress and increase antioxidant pathways as a result. So they're also activating some of these same pathways that occur from fatty acid metabolism. Although ketones do also act as free radical scavengers. So they do have an antioxidant effect in and of themselves. And yeah, you could say that if you introduce ketones to a tissue that had a lot of oxidative stress, you can see a reduction in that oxidative stress. And that is something that you could consider in an isolated context. But the main reason why I was trying to get at, don't think I actually had a chance to get there because the topic kind of got derailed. But the main point I was trying to get at in that moment was that the increased oxidative stress from fatty acid metabolism doesn't really last, right? We've already seen this in a couple of different scenarios that this triggers antioxidant pathways, it triggers uncoupling. So in general, this isn't a case where, you know, you're going to see majorly elevated ROS, you're actually just going to see a major increase in these antioxidant pathways to try to deal with it. You know, and you'll see the increase in uncoupling, you'll see the increased NRF2 activity. And then potentially the long-term you might see the long-term oxidative damage, but that's something that I don't think it would be really feasible that the ketones would be able to prevent that. And it's also worth noting, again, this is even the more central point is that the direct oxidative damage isn't necessarily the central point as much as the reduction in efficiency of ATP production. So if you had this scenario where there's a lot of ROs production relative to ATP production, you're constantly inducing uncoupling, you have this increased NADH to NAD plus ratio constantly slowing down, energy production, and then you bring something in to scavenge those free radicals, it might help lower the oxidative stress a bit, but it's not going to fix the efficiency in ATP production. And we're obviously still seeing constant adaptive responses to oxidative stress. And we saw it even in cases of, know, we already went through one study and we'll go through others, but we already started in that one study on rodents on a ketogenic diet that the ketones themselves obviously weren't enough to protect against the oxidative stress since there was an increase in melo and dialdehyde and a reduction in glutathione.

Yeah, the larger concern is actually the efficiency of ATP production. so the idea that, because maybe an offshoot of that question would be if ketones can to some extent lower the oxidative stress, maybe all we need is extra antioxidants with our low carb diet to prevent all these effects. But even though you can try to reduce some of the side effects here, we're still not able to fix the underlying crux of the issue of the efficiency of ATP production and that especially uniquely driving stress. And so that was really what I was trying to get at.

I don't think I said at any point that it wouldn't be possible that the ketones could be protective, but rather what I was trying to get at is that I don't think it's really particularly relevant to the central issues here. And the central issue being that we don't want to constantly be running on inefficient mitochondrial respiration. We don't want to be constantly generating more oxidative stress and then stimulating antioxidant pathways to protect against them. This doesn't actually lead to improved health. This isn't actually our, our journey toward long-term health. That's not how we want. I mean, we're not going to get here that's not going to help improve our health. And again, this comes back a little bit to that hormesis argument. So I will link back to those episodes for anyone who wants to dig into that in a bit more detail. But I do want to look at a couple of other studies talking about, you know, the net effects on ketogenic diets. We already touched on one in rodents, but looking at a couple of these other ones, basically evaluating this question, you know, is it a scenario where the ketones would be protective enough against the fats where it would significantly lower the amount of damage we're seeing or something like that?

And this was actually something we already touched on in that first Veitch paper where he describes this exact scenario. He basically says, yeah, there are positives of ketone production, but it's not enough to offset the negatives of fatty acid oxidation. And it would be better to just supplement with the ketones and avoid the fat metabolism altogether. And so we're going to expand on that a little bit here. So this is back to that paper titled ketone ester effects on metabolism and transcription. And he states, ketosis induced by starvation or feeding a ketogenic diet.

Jay
Has widespread and often contradictory effects due to the simultaneous elevation of both ketone bodies and free fatty acids. The elevation of ketone bodies increases the energy of ATP hydrolysis by reducing the mitochondrial NAD couple and oxidizing the coenzyme Q couple, thus increasing the redox span between site 1 site 2. In contrast, metabolism of fatty acids leads to a reduction of both mitochondrial NAD and mitochondrial coenzyme Q, causing a decrease in the delta G of ATP hydrolysis. We already touched on these mechanisms, I'm not going to go back through them.

But the important point here is he's pointing out this difference, right? The ketones have the positive effect, but there's this negative effect of fatty acid metabolism. And so in this paper, he's talking about this idea that we want to get the ketones without those negatives. And so he goes on to state, accordingly, to obtain the desirable effects of ketosis in treating Alzheimer's or Parkinson's disease, increasing the Delta G of ATP hydrolysis, decreasing and overcoming the insulin resistance present in many acute injuries or combating free radical toxicity an orally absorbable ketone body ester was synthesized, which was compromised of the monoester of D beta hydroxybutyrate and R1-3 butane dial. So what he's saying here is basically because this is such a concern that there's basically the ketones can't offset all those benefits. We're investigating, you know, creating this ketone body that can be used essentially as a supplement so that we can overcome all these negative effects of the low carb diet.

That's something that was again described by Veach, one of the pioneers in terms of ketosis research. And we see some of these things play out when we look at research on humans in, or on ketogenic diets. And this is a study titled ketogenic diet and epileptic children impact on lipoproteins and oxidative stress. And so they state, Nazarowicz at all investigated the short-term ketogenic diet effects in young women and showed increased levels of total antioxidant status, whereas catalase and SOD remained unchanged.

On the other hand, our group has recently investigated lipid peroxidation in 26 children under the classic ketogenic diet, observed high levels of plasma T-bars. It is possible that ketogenic diets act as an antioxidant at the central nervous system, but induces oxidative stress in the peripheral system, thus contributing to a negative clinical prognosis. So he's describing the exact same thing that Veach was describing, which is that, sure, we might see some benefits in the areas where we're looking at the ketones themselves.

Jay
And in the short term, we do see the activation of these antioxidant pathways, but in the long-term, the negative effects in the peripheral system due to relying on fat as a fuel basically induces oxidative stress. And we see this elevated levels of T-bars, which are an indicator of oxidative stress. And so this is something that was played out and this is in children who are on the ketogenic diet long-term. And that's, what they're seeing there. So we're actually seeing, you know, in the studies that we do have looking at longer term ketogenic diets, that's the kind of thing that we're seeing which is not suggesting that the ketones would be enough to outweigh even just the oxidative stress effects here. and then as I was saying, the key, the ketones themselves are actually shown to increase oxidative stress and increase the antioxidant pathways. So this is actually the same thing that the fatty acid metabolism, does it's not to the same extent because they're more efficiently metabolized compared to fats, but they do still have this. They do still have an increase in oxidative stress relative to glucose metabolism.

And so we'll look at a couple of studies here showing that in rodents on ketosis and looking at their, um, looking even in the brain where they're utilizing ketones and seeing some of these effects. So this is a study titled metabolic responses and endothelial cells following exposure to ketone bodies. So this one isn't actually looking at the brain, but this is looking at the effects of ketones in this scenario. they state the exposure of cells to ketone bodies exerted a moderate genotoxic effect measured by a significant increase in DNA oxidative damage. However, cells pre-treated with ketone bodies for 48 hours and subjected to a secondary oxidative insult significantly decreased DNA damage compared to control oxidized cells. This protection occurred via the activation of the nRF2 pathway. In ketone body treated cells, we found increased levels of nRF2 in nuclear extracts and higher gene expression of HO-1, a target gene of nRF2, compared to control cells. These results suggest that ketone bodies, by inducing moderate oxidative stress, activate the transcription factor nRF2
which induces the transcription of target genes involved in the cellular antioxidant defense system. So we talked about this earlier with fat metabolism, but we're actually seeing it with ketone metabolism here as well, where there's moderate oxidative stress involved that is triggered or driven by the ketone bodies that then activates these antioxidant pathways. So again, if we're thinking about a situation where you have fat metabolism causing oxidative stress and causing the activation of the antioxidant pathways, would adding ketone bodies to that scenario really help?

Jay
When A, you already have the oxidative stress and then you're already trying to quench it with the antioxidant system, would it make sense that ketones would actually help this scenario? So this is the kind of thing that again is why I was saying it probably isn't actually the case. That's why I would say in that question, I don't think the ketone bodies are enough to protect against the fat metabolism. Obviously we saw this play out in that study that I mentioned earlier. And we'll look at this in a couple of other studies. This one is looking at mice, the hippocampus of mice not a ketogenic diet. And this study is titled the ketogenic diet increases mitochondrial uncoupling levels and activity. And they state maximum mitochondrial respiration rates were significantly higher in ketogenic diet versus standard diet treated animals, indicating increased uncoupling protein mediated proton conductance that can reduce ROS production. So we're seeing that same effect. We saw this earlier with fatty acid metabolism, that you see an increase in uncoupling normally due to oxidative stress first that then causes the uncoupling. And we're actually seeing this in the brain in mice.

on a ketogenic diet, that there was this increase in a coupling, which again, means less efficient ATP production. And then lastly, we'll look at this study titled nutritional ketosis and mitohermesis potential implications for mitochondrial function and human health. And in this case, what they found was that the ketogenic diet increased RLS production, stimulated antioxidant pathways. And they found that ketones themselves like beta hydroxybutyrate had signaling effects that basically drive this hormetic intervention, this

situation of increased damage and stress, trying to activate defensive pathways. And, you know, we, this is something we touched on quite a bit in those episodes talking about hermesis, but this is, this argument is made for tons of other things that are also inherently damaging to our physiology. We've seen arguments like this made for cigarette smoke, for heavy metals like mercury and cadmium, that they cause oxidative stress.

increases in antioxidant pathways. So it must be a good thing. And then of course we see it also applied to, you know, fasting, caloric restriction, ketogenic diets. But I would argue, we, we again go through all the research supporting this in the, in those articles and the episodes that this actually is not the way that we drive health. This actually leads to reduced health. But let's, let's look at what the study is, is, or this paper is describing in terms of the effects of a ketogenic diet.

Jay (01:24:05.07)
on oxidative stress and antioxidant pathways. And so they state ketogenic and low carb diets greatly increase reliance on fat oxidation, which would logically be expected to increase mitochondrial respiration and mitochondrial ROS production and in turn induce myohermesis. Furthermore, mitochondrial ROS produced through reverse electron transport appears to have particular relevance to hermetic adaptation, including increased lifespan. We talked through the lifespan related research in regard to hermesis in that series.

They on to state nutritional ketosis is likely to increase reverse electron transport by altering the FADH2 to NADH ratio. As the primary source of acetyl-CoA shifts from glycolysis to beta-oxidation and ketolysis, this ratio increases more than doubling for beta-oxidation of longer chain fatty acids. Electrons from FADH2 reduce the CoQ pool through complex II and ETF-Q oxidoreductase, thereby increasing reverse electron transport. Furthermore, succinate is generated

during ketolysis by succinyl CoA3-oxoacid CoA transferase, which also promotes reverse electron transport by reducing the CoQ pool through complex II. So this is just describing a number of the mechanisms that we were talking about earlier, but they're just explaining that this would all happen during ketosis and low carb diets. I was just describing that in this paper. Then they talk about some of this playing out and they state, a study on hippocampal mitochondrial function in rats more directly supports the induction of myohermesis by a ketogenic diet.

After the first day of the diet, hydrogen peroxide production by isolated mitochondria was increased. After the third day, mitochondrial levels of oxidized glutathione and hippocampal levels of 4-HNE were also increased, further indicating an increase in oxidative stress. However, at completion of the first week, upregulation of antioxidant signaling occurred, indicated by increased nuclear content and transcriptional activity of Nrf2, which persisted through the remainder of the study. By the third week, mitochondrial hydrogen peroxide production decreased to below baseline,

In the liver content of reduced acetyl-CoA, which is indicative of mitochondrial redox status, decreased after three days of the ketogenic diet, but increased relative to the control diet after three weeks, indicating an initial increase in oxidative stress followed by a decrease. So they found this actually play out in mice hippocampus or mice hippocampal mitochondria. When they're on a ketogenic diet, they found that initially there was considerable increased oxidative stress. This is what the ketones themselves.

Jay
That then activated the antioxidant pathways. And then we saw the reduction in oxidative stress. So again, this just directly corroborates what I was describing earlier as to why all the research supports that the ketones wouldn't actually be enough to protect against the effects of the fatty acid oxidation. And they actually cause the same effects just to a slightly gentler extent. And they have a nice figure here from this study, basically just pointing to the hormetic effects, the oxidative stress inducing effects of nutritional ketosis. And they talked about how it increases catecholamines, example, increases AMPK. This is our sensor of oxidative stress and of depletion of energy. We see that it increases that NAMPT, that NAD salvage pathway I talked about earlier. We see that it increases, know, NRF2 increases PGC1 alpha, number of these hormetic pathways that, you know, all go hand in hand with stress and damage and then create defensive responses to them. And again, I would highly recommend taking a look at the, corn Mesa series for more information on that, but we're seeing this all, you know, supported by the research as I've been mentioning. So let's talk through the kind of last section here in regards to this, this topic, which is looking at the research on humans on low carb ketogenic diets and what the effects are and whether we see these things play out. And as I was saying earlier, You know, we don't have the biopsy data that we would like to have looking at long-term ketogenic diets and looking at exactly, you know, what might happen in the mitochondria there, but there's no reason to think or support that there would be any difference based on everything we've gone through so far. But we do have data looking at the effects in humans that, you know, is looking at more downstream effects that, you we can look at without doing the biopsies, for example.

And, you know, it does suggest elevated oxidative stress and impaired energy production. And it does corroborate the mechanisms that we've been going through today. And so one study to start with here is one that we already talked through a little bit. And this is the study titled Ketogenic Diet and Epileptic Children Impact on Lipoproteins and Oxidative Stress. And as we noted earlier, I'm not going to reread the whole quote, but there was an increase in lipid peroxidation in the kids on the classic ketogenic diet based on the elevated levels of T-bars.

Jay
And so they talk about how ketogenic diet was inducing oxidative stress. that's one of the studies. There's not very many looking at long-term ketogenic diets and the impact on oxidative stress. And so we are seeing here increased levels of T-bars. this is corroborating this increase in oxidative stress that we are seeing on a low-carb ketogenic diet. Now, it's also worth looking at some studies showing the effect of a low-carb ketogenic diet on insulin resistance.

And basically that it blocks glucose metabolism. The reason why this is important is because it supports the mechanisms that Randall had pointed to. And we talked through some of those earlier. We went through some of them in certain diagrams and figures. We also looked at a little bit of his research and these mechanisms depend on a decrease in the NAD plus to NADH ratio, which inhibits pyruvate dehydrogenase. They also depend on the buildup of acetyl CoA, which also depends on that ratio to inhibit pyruvate dehydrogenase.

And so, these mechanisms that we've been talking through are central to the Randall cycle and the Randall effect. So when we see here that going on a low carb high fat diet interferes with glucose metabolism and therefore causes an increase in its own resistance, is it supporting these mechanisms that we've been looking at? Basically when we're utilizing more fat, we're going to see the increased FADH2 to NADH ratio, the reduced NAD plus to NADH ratio, the less efficient ATP production, the decrease in the rate of the citric acid cycle inhibition of pyruvate dehydrogenase. So we'll go through a few studies here that are supporting this. First one is titled effective short-term starvation versus high fat diet on intramyocellular triglyceride accumulation and insulin resistance and physically fit men. And so in these men, basically looked at fasting versus a low carb diet versus a normal diet. And the low carb diet was 2 % carbs, 83 % fat, 15 % protein. The normal diet was 50 % carbs, 35 % fat and 15 % protein. And again, this was in physically fit men. And what they found was that in conclusion, this investigation demonstrated that in the same lean physically fit men, dietary induced elevation of intra myocelular triglyceride and impairment of glucose tolerance and insulin sensitivity were similar after 67 hours of the low carb high fat diet and the same period of starvation. So they found basically two important things here. One was that there was a reduction in or impairment in glucose tolerance and insulin sensitivity.

Jay
On the low carb diet and on starvation, you know, in the, in the period of starvation. And they also found something we were talking about earlier, which is that low carb diets mimic the fasting or starvation state. So we saw all of that being supported here. And again, this supporting the, the mechanisms we were describing earlier. And I'm just going to go through a couple of these studies rather quickly. And, you know, I'll cite all of them in the show notes for anyone who wants to dig in deeper, because there are quite a few other studies and other concepts I want to get to.

So this study is titled a high fat, high saturated fat diet decreases insulin sensitivity without changing intra-abdominal fat and weight stable overweight and obese adults. had a control diet, which was 47 % carbohydrates and 35 % fat. They did that for 10 days. And then they looked at a four week low fat diet. So this was 62 % carbs, 20 % fat or a high fat diet, which was 27 % carbs, 55 % fat. And they did an insulin clamp to identify insulin sensitivity.

And they showed reduced glucose disposal on the high fat diet. that basically means there's an impairment in insulin sensitivity on the high fat, low carb diet. Again, supporting what we were describing. And that was of course a longer term study looking at four weeks on a low fat versus a high fat diet. And this next study, which is titled dietary fat content alters insulin mediated glucose metabolism in healthy men. And this study, they looked at three kind of extreme diets. They basically did an extremely low fat diet with high carbs, it was like 0 % fat, 85 % carbs. They then did high fat and high carb, 41 % fat, 44 % carb. And then they did high fat, low carb, which was a 83 % fat, 2 % carbs. And they did each of these diets for 11 days. And they did find there was a major increase in fat metabolism and fat oxidation on the high fat, low carb diet as, know, you see with all these studies that there's an increase in fat metabolism when you shift to these diets. And sometimes, you know, people will say, well, you can't evaluate these things in such a short term, but we're seeing it directly here that there is pretty immediate adaptation to increase fat metabolism. Typically see a pretty immediate effect in terms of ketone production as well. Obviously there's continued adaptations, but we do see a lot of these things early on. And so you can see here very clearly as the fat levels increased and the carb levels decreased, there was far higher fat oxidation. And so they looked at insulin sensitivity on these different diets and they did that by doing a hyperinsulinemic euglycemic clamp and seeing the amount of glucose disposal. So basically they provide extra insulin and see how much glucose gets taken up. And what they found was really interesting here. They found that the total amount of glucose taken up by the tissues was actually the same. There was no statistical difference, but there was a massive inhibition of oxidative glucose metabolism to nearly zero. And there was a major increase in non-oxidative glucose metabolism. It was nearly doubled. this is, you know, we're talking about glycolysis, the conversion of glucose to lactate, which is of course Not ideal. This is not an optimal way to produce energy from glucose. And so we can see that here that on the top, we're looking at the total glucose disposal. So between the three different groups, there wasn't actually a consistent difference. But when we look at the oxidative glucose disposal, so this is the usage of the efficient usage of glucose. It was way lower on the high fat, carb diet. And the non-oxidative glucose disposal is way higher on the high fat, low carb diet. So they basically was a shift toward inefficient glucose metabolism and a shift toward increased glycolysis. And they state here, although glucose transport measured as glucose disposal was not affected by high fat intake, glucose oxidation was around 90 % lower after the high fat, low carb diet. So again, this is directly supporting those mitochondrial mechanisms described by Randall that we talked through earlier that basically show an inhibition of glucose metabolism and pyruvate dehydrogenase from fat metabolism, which supports all of those other pathways we described.

And then the last study here is one titled glucose and lipid homeostasis and inflammation in humans following an isochloro ketogenic diet. And in this study, had the participants do four weeks on a normal diet, which had 50 % carbs, 35 % fat, and then four weeks on a keto diet, which was 5 % carbs and 80 % fat. And this was a metabolic ward study on men without diabetes. And what they found was when they went on the keto diet, there was a clear increase in ketone levels.

There's a clear increase in free fatty acids and on glucagon, which we'll be coming back to that in a second, but it basically demonstrates that we're very obviously in ketosis. And they also found reduced insulin sensitivity on, you know, when they were eating the high carb meal, when they were on the high carb diet versus when they're on the ketogenic diet, where basically there's higher glucose levels and higher insulin levels following the carbohydrate containing meal. And we can see that here, this is looking at both groups. The ketogenic diet is the, the hollow squares and the hollow triangles, whereas the baseline diet is the higher carb diet, which is the filled in squares and the filled in triangles. They both got the same carbohydrate containing meal. And when you look at the ones on the ketogenic diet, that far higher glucose levels and far higher insulin levels, which both demonstrate a clear decrease in insulin sensitivity, a clear increase in insulin resistance. Again, supporting all those earlier mechanisms. Now, as I was saying earlier, we have all of these direct bio-energetic mitochondrial effects, leading to impaired efficiency of mitochondrial respiration of ATP production when we're on a low carb high fat diet or ketogenic diet versus one that contains adequate amounts of carbs. Now, as a result of that, we see increased levels of stress hormones, as I was describing. So we're to look at some studies showing that here. We won't go too in depth in these studies, but there are, you know, it is definitely worth looking at because these hormones are directly reflecting what's going on on the underlying energetic level. So we want to see what effects there are on glucagon and cortisol and what the downstream effects are on thyroid, female reproductive hormones, male reproductive hormones. And so we'll do that a little bit here, starting with glucagon. So the first thing that we'll want to note here is that glucagon is a stress hormone and it responds to classic stress states, which is how stress hormones are defined. And that includes energy depletion. And the reason I bring this up is because It's noted that glucagon is chronically elevated on a low carb ketogenic diet. So people say, you you say that glucagon is a stress hormone, it's not a stress, like, is it a stress hormone? Who says that it's a stress hormone? What, you know, what basis is there for that? And so I wanted to at least start by touching on that because it's very clear that glucagon is a stress hormone in the classic sense, just like epinephrine and cortisol. And that's important to clarify here for anybody who is, unsure about that.

So the first study here is titled metabolic effects of glucagon in humans, they state hyperglucogonemia occurs in clinical conditions involving adrenergic stimulation and metabolic stress, such as exercise, infections, acute hypoglycemia, and starvation to assure availability of glucose to peripheral tissues, such as the brain and skeletal muscle. So they're just saying that this is that you see it elevated levels of glucagon with metabolic stress, not just hypoglycemia, but also things like infections and exercise.

Jay
Because glucagon is classically considered a hypoglycemic hormone because it increases gluconeogenesis and shifts us toward fat metabolism, but it's also involved in classic metabolic stress situations. And they state that here as well in a study titled Mini-Review, Glucogon in Stress and Energy Homeostasis. And they state, evidence for glucagon release in a wide variety of stressful situations began to accumulate after improvements in glucagon assays made accurate measurement possible in the early 1970s. In animal models, large elevations in plasma glucagon are observed immediately after acutely stressful stimuli. Hyperglucagonemia is also well recognized in patients under a range of physiological stress states, including trauma, burns, surgery, sepsis, hemorrhage, acute myocardial infarction, cardiac arrest, and hypoxia, including in neonates. Glucagon release has been demonstrated to be elevated in many forms of physiological stress in which hypoglycemia is not a typical feature. Hyperglucagonemia leads to physiological and behavioral responses such as increased substrate availability and improved cardiovascular performance, which are key features of the stress response. So they're basically describing here that glucagon is in fact a classic stress hormone, just like the other ones we've described. And like those other hormones, it has the same downstream effects of turning down the metabolic rate by reducing hormone conversion and other effects. And so we do see clear elevations in glucagon, especially in short-term studies. It's very obvious. There's tons of studies looking, you know, up to six weeks and showing
elevations in glucagon, but like a lot of the other hormones we'll talk about here, there's a lot less research looking at a number of different markers long-term on a low carb ketogenic diet. And hopefully with time we'll have more of that data. But everything that we do have now in terms of short-term and long-term studies do point in this direction. So this is a study that we'll start with titled energy expenditure and body composition changes after an isochloric ketogenic diet and overweight and obese men.

This is a four week trial and they state as expected, the ketogenic diet was associated with significant increases in ketones, free fatty acids and glycerol. Fasting glucose was not significantly different between the diets, whereas glucagon significantly increased and C peptide, insulin and triglycerides significantly decreased during the ketogenic diet. And this was a massive increase in glu- and glucagon was actually a 40 % increase when they were on the keto diet versus their baseline diet.

Jay
And then they go on to state thyroid stimulating hormone and free thyroxine concentrations were significantly increased during the ketogenic diet phase. Whereas both free and total T3 triiodothyronine were significantly decreased. So decrease in T3 and increase in TSH here. We're going to be coming back to decreases in T3, the active thyroid hormone with low carb ketogenic diets. But just to touch on this here, that we clearly see these effects in this study looking for four weeks. And this was a metabolic ward study, so very well controlled trial.

And then we also see this play out in longer-term studies. So this is a study titled the ketogenic diet alters endocrine regulations of energy metabolism in ultra endurance athletes. And this is a study by Volek, who we mentioned briefly in the debate. And in this paper, he states, in elite ultra endurance athletes, a long-term ketogenic diet is associated with higher glucagon levels before, during, and after aerobic exercise. This is in conjunction with the more than twofold higher rate of peak fat oxidation indicating glucagon may have an important role in keto adaptation. Similar, but less persistent patterns of cortisol suggests that these two hormones may contribute to keto adaptation in a coordinated matter. And this was looking at 20 different athletes who were on a low carb diet for at least six months, a very low carb diet. And they saw this increase in glucagon and they also saw similar patterns of increased cortisol. So we're seeing both of these play out. This is of course, longer term studies, obviously on athletes on a ketogenic diet showing these effects. And that brings us to this next study. This is a study titled post-prandial levels of GLP-1, GIP, and glucagon after two years of weight loss with a Paleolithic diet, randomized controlled trial and healthy obese women. So this was a two year trial looking at 70 healthy post-menopausal obese women. They were on either a Paleo diet or a control diet. And let's see what they found here.

So they state in the Paleolithic diet group, increasing fasting glucagon levels during 24 months of intervention or correlated with decreasing carbohydrate intake and increasing fat intake. So basically in these people over two years, when they had lower carb intake and higher fat intake, they saw elevated glucagon levels. Exactly what we would expect. Again, this is two years and it would be great if we had, you know, a direct two year trial on someone or in people on a ketogenic diet, which I haven't seen one that actually then looks at glucagon levels, but this trial is showing it pretty demonstrably. And they go on to state the ketone body beta hydroxybutyrate increased at six months in the Paleolithic diet group. This increase in ketone bodies was associated with increased fasting glucagon and the increased glucagon to insulin ratio within the whole study population. So basically what they found here is that there was a direct association between ketone levels and glucagon levels, and also between decreased carbon intake and increased fat intake and glucagon levels.

So this is directly corroborating what we've been describing here, which is that you see this increase in the stress hormone glucagon with the less efficient respiration that you get on a low carb ketogenic diet. So now we'll take a look here at cortisol levels. And when it comes to cortisol, this is one, which was kind of mentioned briefly in some of these earlier studies that we went through where you especially see it increase in the short term. And then after that, you tend to see it increase not as much at baseline, but you'll tend to see it higher after stress, after something like exercise, which we'll talk about. But basically what's happened is we've already been on these lower carb diets. We're essentially already a step into stress, right? We've already released the glucagon. We're already shifting into our first stage of stress. And so we're more prone to getting into those deeper stages of stress. And we do that more aggressively essentially. And that's why we see increased cortisol, especially after stress, increased stress induced cortisol.

So we'll first look at these short-term studies. So first study is titled effects of dietary composition during weight loss maintenance, a controlled feeding study. And they state 24 hour urinary cortisol excretion, the hormone measure of stress was highest with a very low carb diet. Consistent with this finding Stimson et al. reported increased whole body regeneration of cortisol by 11 beta HSD1 and reduced inactivation of cortisol by five alpha and five beta reductases over four weeks on a very low carb versus a moderate carb diet. CRP also tended to be higher on the very low low carb diet in our study, consistent with the findings of Rankin and Turpin. Other studies also have found reductions in measures of chronic inflammation, including CRP with a low GI diet. So interestingly, they're pointing out that the very low carb diet increased CRP, but a low GI diet, seemingly seems to lower inflammation. in any case, more important part being here that they found that 24-hour urinary cortisol was elevated here with the very low carb diet, and this was four weeks on a very low carb diet. And then they also were touching on other studies, demonstrating that there's also an increase in, in this case, regeneration of cortisol by 11 beta-HSD1, and also reduced inactivation by the 5 alpha and 5 beta reductases. So we're seeing a number of different mechanisms all pointing toward increased cortisol shown very clearly in shorter term protocols, which again, we're not talking short term, like a couple of days. This is four weeks of elevated, highly elevated stress hormones. And then this next study, they state dietary macronutrient content alters cortisol metabolism independently of body weight changes in obese men. And so this was that study where they were looking at the change in 11 beta HSD levels and the five alpha reductase, five beta reductase levels. And so in this study, it was four weeks.

for obese men on a very low carb diet or a moderate carb diet. And they state here in obese men, the high fat, low carb diet increased whole body regeneration of cortisol by 11 beta HSD1 and reduced the rate of inactivation of cortisol by five alpha and five beta reductases. The increased 11 beta HSD1 activity on the high fat, low carb versus moderate fat, moderate carb diet was independent of differences in energy consumption and weight loss.

The same effect was observed under fixed feeding, approximately isochloric conditions and the moderate fat, moderate carb diet induced substantial weight loss without altering the leaven beta HSD activity. So again, just expanding a little bit on this increase in cortisol that we're seeing over four weeks. And then this is a study comparing shorter term versus longer term trials and it's titled low carbohydrate diets and men's cortisol and testosterone systemic review and meta analysis. did look at other things in this review as well, but One of the things they touched on was short-term versus long-term effects on cortisol. you know, short-term was less than three weeks for the long-term trials. They were between four and eight weeks long. And what they basically found was that based on cortisol was normal, but there was increased exercise, post-exercise cortisol, so increased stress induced cortisol. And, you know, it'd be great if we had tons of other trials that went on far longer than four to eight weeks. But this is all that we have to work with for the moment.

Jay
Although of course we did have that Jeff Voldik study that I mentioned earlier, which was on athletes on a very low carb diet for at least six months. So, and that was showing the same trend in terms of cortisol. But anyway, in this study, they state 27 studies were included with a total of 309 participants short term, less than three weeks, low versus high carbohydrate diets, moderately increased resting cortisol, whereas long term greater than three weeks, but the trials were all four to eight weeks in length. Low carbohydrate diets had no consistent effect on resting cortisol. Low versus high carbohydrate diets resulted in much higher post exercise cortisol after long duration exercise. So they found that in the long-term as well, there was much higher post-exercise cortisol. So we are seeing a number of, you know, as far as the research that we do have available, definitely seeing clear increases in glucagon and cortisol, primary stress hormones. And then we see a similar effect in terms of thyroid. So we touched on this a couple of times already. There's a lot of studies showing the short-term where in over four weeks or even less time, you see a clear decrease in T3.

And we'll just touch on a couple of these first. The first one is a study titled energy expenditure and body composition changes after an isochloro ketogenic diet and overweight and obese men. This was that four week metabolic ward trial where they found that TSH and free T4 concentrations were significantly increased during the ketogenic diet phase, whereas both free and total T3 were significantly decreased. So we're seeing not only reduced T4 to T3 conversion, but also an increase in TSH tells us a generally lower thyroid state moving toward hypothyroidism. This next study is titled the human metabolic response to chronic ketosis without caloric restriction preservation of submaximal exercise capability with reduced carbohydrate oxidation. And this was a study looking at five well-trained cyclists that went on a ketogenic diet for four weeks and they found a decrease in T3 by 35%. So a major decrease in T3 levels in this study. Now there are a couple of longer-term studies that we're going to look at here in terms of the thyroid effects.

From a low carb ketogenic diet. The first one is titled changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy. And so here they looked at 120 patients who had epilepsy. were on a ketogenic diet for at least one year. So pretty long-term here. And we found, or what they found was an increased incidence of hypothyroidism from the ketogenic diet. They found increased levels of TSH at certain points along the study, as well as decreased T3. And they state that here.

Jay
The state ketogenic diet, is high in fat and low in carbohydrates, mimics the metabolic state of starvation, as we described earlier, and is used therapeutically in pharmacoresistant epilepsy. It's known that the generation of T3 from T4 decreases during fasting periods. And they found that the ketogenic diet causes thyroid malfunction and L-thyroxine treatment may be required. This is the first report documenting the effect of the ketogenic diet treatment on thyroid function. Thyroid function should be monitored regularly in epileptic patients treated with the ketogenic diet. So we're seeing here long-term ketogenic diets having these negative effects on thyroid status. And then in this study titled, thyroid markers and body composition predict LDL cholesterol change in lean healthy women on a ketogenic diet, experimental support for the lipid energy model. So this is a study that was done by Isabella Cooper among others. And we're going to be talking about another study of hers that Dr. Westman referenced in the debate. But in this study, they looked at lean healthy women on a low carb diet looked at their body composition and thyroid markers and LDL levels and a number of different markers. And this was on women who consumed a ketogenic diet for at least six months, but the average was four years. So we're talking long-term ketogenic diet here. And what they found was that the baseline free T3 levels were at 2.5 picograms per milliliter, which would be in the subclinical low range. It's not actually below the reference range, but pretty much any kind functional integrative practitioner would consider those levels to be low. I certainly would. And what they found was those levels increased dramatically from 2.5 picograms per milliliter to 3.5 picograms per milliliter after just three weeks on a carbohydrate containing diet. So there's an immediate shift from basically low T3 levels to normal or even optimal T3 levels after three weeks on a carb containing diet when they came from their keto diet. When they went back to their keto diet, the T3 levels went right back down.

They also found that the baseline reverse T3 levels were elevated against subclinically elevated. So they found that the reverse T3 levels were 19.5 nanograms per deciliter. You know, again, based on the standard range, this wouldn't be considered elevated, but based on, you know, functional range, this would definitely be elevated. I would consider this to be elevated. And so what we were basically seeing here is that there's a reduction in T4 to T3 conversion when on a ketogenic diet. And that's why we see lower free T3 and increased reverse T3.

Jay
And we'll just share a quick quote stating this from the study where they state, consistent with what has been documented in randomized crossover trials, free T3 was lower in the ketogenic phases when compared with the higher carbohydrate phase. Additionally, we found that free T3 and T4, but not TSH or reverse T3 were predictive of LDL cholesterol change, which is consistent with the role of thyroid hormones in regulating systemic lipid energy trafficking to meet energy demands during carbohydrate restriction. This is referring to the lipid energy model. did a podcast episode discussing this before, so I'll link to that.

But in this study, know, average, this is looking at women who are on the keto diet for an average of four years saw low T3 and elevated reverse T3. So we're seeing all these effects that we would expect to see from the bottom up play out in these low carb diets. Now we're going to look briefly at some effects on the reproductive hormones. And this is a study titled the ketogenic diet adolescents can do it too. And so this is looking at adolescents on a ketogenic diet for an average of 1.2 years and looking at the girls, especially and the effects on the female hormones. So we'll go ahead and share these quotes here where they state the diet's effect on menses was not surprising with 45 % of our girls reporting amenorrhea or irregular cycles. Although significant weight loss was seen by only half of those with menstrual irregularities. By minimizing body fat, the diet may mimic the menstrual side effects seen in starvation and certain female athletes.

So they were saying that at least in a portion of these women who were reporting amenorrhea or irregular cycles or girls reporting these effects, some of it could have been due to the weight effects. But again, this was only the only half of them actually had a change in weight. So we're seeing a massive effect. mean, 45 % is a huge portion for these girls to be dealing with these sorts of reproductive symptoms. And they go on to state some more details here. They say nine girls, which was 45% reported menstrual problems while on the diet, specifically amenorrhea for six of them and delayed puberty for three of them. Only four of the nine girls with menstrual irregularities had weight loss. One adolescent began hormonal therapy, combination of estrogen, progesterone, oral contraceptive to induce menses. Eight experienced a return of normal menses after diet discontinuation. So when they went off the ketogenic diet, the hormonal issues resolved. They, they normalized.

Jay
So we were seeing basically a huge portion, 45 % of the girls in this study doing long-term ketogenic diets, having some major issues, amenorrhea, irregular cycles. And then again, in 15 % of them, there was delayed puberty. we're seeing some pretty significant harmful effects on the female hormones in this study looking at girls on a longer term ketogenic diet. And then we do see some studies pointing in the direction of some negative effects on testosterone. These especially have to do with excessively high protein diets and diets with a high protein to carbohydrate ratio and showing that those things decrease testosterone. And so this first study is titled low carbohydrate diets and men's cortisol and testosterone systematic review and meta analysis. We touched on this one earlier and here they state that moderate protein, less than 35 % low carbohydrate diets had no consistent effect on resting total testosterone. However, high protein diets of greater than 35 % low carbohydrate diets greatly decreased resting and post exercise total testosterone. So in this case, they were saying that especially with the high protein diets, there was a major cost to testosterone. in this study titled testosterone and cortisol in relationship to dietary nutrients and resistance exercise. what they found was that significant correlations were observed between pre-exercise testosterone and the percent energy protein and the protein and carbohydrate ratio. So basically as the protein to carbohydrate ratio increased testosterone decreased. So what we're seeing here is all of these underlying biochemical mitochondrial bioenergetics mechanisms that we've been citing are playing out in terms of the effects on oxidative stress markers, in terms of the effects on insulin sensitivity, in terms of the effects on the hormones. And so, you know, all of this is, you when we're looking at the research on humans, on low-carb diets, this is what we have to look at that does all corroborate these pathways. And, you know, it'll be great to see further research here that gets into more of these details and further cooperates this. But right now, you know, that's I wanted to make sure to share all that research pointing in this direction that I definitely did not have the opportunity to go through on the debate. And hopefully that helps resolve some of the disagreement regarding that, you know, that sticking point that Dr. Westman had. All right. So at this point, this episode has gotten quite a bit longer than I anticipated. So we're going to wrap up here and we'll dig into a lot more in part two. In part two, I'll be going over the paper that Dr. Westman brought up from Isabella Cooper.

Jay
I'll be talking about whether we should be caring about the changes in some of these markers, which Dr. Westman was suggesting that maybe we shouldn't be caring about these markers. We should care about, you know, if we're seeing other effects here. also be talking about the differences between fat and carb utilization in an insulin resistant state and in the heart and heart failure. We'll be talking bit about the rate of living theory and whether a low metabolic rate is a good thing. We'll talk very briefly about babies being born into ketosis, this was something that he mentioned as well as glycation, related to, higher carb diet and whether carbohydrates are addicting and a couple other things like that. So dig into all that in part two, if you did enjoy today's episode, please leave a like or comment wherever you're listening. And as always to check out the show notes, we're all linked to the studies, articles, and anything else that I referenced throughout today's episode, you can head over to jfeldmanwellness.com slash podcast. And with that, I'll see you on the next episode.