#132: The Hidden Power of Ketones: Fueling + Signaling with Dr. Ben Bikman

Ketones aren't just fuel, they act like hormones. For decades, ketones were dismissed as metabolic leftovers, then downgraded to backup energy when glucose runs low. But one ketone, beta hydroxybutyrate, does far more than just make ATP. It actually sends signals. BHB can bind to receptors, reduce inflammation, protect mitochondria, and even change how genes are expressed. They that's extremely rare in biology. Most nutrients provide calories. Most hormones send messages. Ketones do both. When ketones rise during fasting, exercise or a ketogenic diet, cells receive a coordinated reduce inflammation, increase resilience and protect energy production. Ketones aren't just an alternative fuel, they are a metabolic signal. This is lecture 132 of the Metabolic Classroom.

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Welcome to the Metabolic Classroom. I'm Ben Bickman, metabolic scientist and professor of cell biology. In today's mini lecture we are exploring one of the most fascinating developments in metabolic research over the past several decades. The discovery that ketones, specifically beta hydroxybutyrate, or bhb, they're not just fuel molecules but potent signaling agents. For decades, biochemistry textbooks treated ketones as metabolic garbage. Then they were finally upgraded to a backup fuel, a sort of Metabolic Plan B that kicks in if glucose runs low. But we now understand that this view was far too limited. BHB does something genuinely remarkable in the world of biology. It functions simultaneously as both the calorie providing nutrient and a signaling molecule that can alter gene expression, reduce inflammation and protect our mitochondria. This dual identity is actually quite rare in biology. Think about it. Most signaling molecules, hormones, neurotransmitters or cytokines don't provide calories or any energy at all. And most nutrients like glucose, fats, etc. Which can provide energy, are not considered signaling molecules in any classic sense. But BHB blurs these boundaries completely. It's like discovering that gasoline doesn't just power your car's engine, but it also unlocks the doors. So today we're going to unpack this signaling story. We'll talk about specific receptors, we'll discuss how in which tissues respond to these signals, and we'll explore what this means for inflammation and mitochondrial function. First, lets establish a foundation Beta hydroxybutyrate or bhb, is the most abundant of the three ketone bodies, as they're classically called, and BHB makes up roughly 70% of all of the circulating ketones in the body. The other two are acetoacetate and acetone. BHB is primarily synthesized in liver mitochondria when fatty acids are being oxidized at a high rate. Here's an important structural detail that will matter later. BHB is a chiral molecule, meaning it exists in two mirror image forms. The body mostly produces what's called dbhb, but it's also sometimes indicated as R bhb. This is the majority form that we make. The L form, or sometimes known as S form, is also made, and it can be about 10% of what we have circulating in our blood when we are making our own ketones. That lbhb, as you'll see, can both be consumed as energy but for the context of this lecture, also act as a signaling molecule. Now, unfortunately, we're just really starting to learn about L BHB with Though ketones were long considered a metabolic garbage, even once they were considered not to be garbage, LBHB was sometimes still considered garbage. But they that's all being rewritten in almost real time. But the degree to which the L is metabolized and whether it's a signaling molecule as well has been a little vague. So some of what I'm going to share with you. It looks like it applies to both D and L, but suffice it to say, there's less known about L being more of a new kid on the block than there is about D. Under typical feeding conditions, blood BHB concentrations are very low, generally even below the level of detection on most devices, 0.1 millimolar or so. Now, after an overnight fast, depending of course on what you ate before you went to bed, you might see levels of ketones get to around 0.3 or so millimolar. During prolonged fasting or a ketogenic diet, concentrations can get to above 1, up from 1, 2 or 3 or even 4. And in extreme cases like diabetic ketoacidosis, levels can get up into the high teens and even twenties. Unless you're a type 1 diabetic, you're not going to get there. That range of around 1 to 2 millimolar is interesting because, as you'll see, this is the concentration range where many of BHB's signaling effects become physiologically relevant. Now, as a fuel, BHB follows a well characterized pathway. It enters cells through monocarboxylic acid transporters MCT1 and 2, crosses into mitochondria, gets converted back to acetoacetate by the enzyme BDH1, then is activated to acetyl COA using an enzyme, and then acetyl COA is cleaved into acetyl COA molecules into two of them, which will go directly into the citrate cycle to make a lot of ATP. The liver, interestingly, can make ketones, but does not use them. Liver cells don't have the proper catabolic enzymes to break down their own ketones. So the liver produce this fuel exclusively for export to other tissues. And many tissues will use it quite greedily. In fact, every tissue with mitochondria or every cell with mitochondria will use ketones. But this includes things like the brain or the heart or skeletal muscle or fat cells and more. Of course, nowadays, if you don't want to go through the process of making ketones, you can simply take BHB in the form of go bhb. Now, let's shift from the metabolism to the signaling, which is the point of this mini lecture. When it comes to signaling, you have to consider that we have the molecule BHB in this case, and then a specific receptor, or it's something that the BHB can act on when it comes to the cell. The first receptor we need to discuss is GPR109A, also known as hydroxycarboxylic acid receptor 2 or HCAR2. This is a G protein coupled receptor and it was originally identified as the receptor for niacin or nicotinic acid. That's why this receptor was initially called the niacin receptor. Researchers discovered that DBHB is actually an endogenous ligand for this receptor. At concentrations that you can reach during fasting or ketosis, that low millimolar range, BHB can bind to and activate GPR 109A. This is. This was in particular a landmark discovery because it meant that a metabolite produced during fasting could directly communicate with cells through a receptor pathway. Now, let me explain the signaling cascade just to give you a little appreciation for what's going on here. GPR 109A is coupled to inhibitory G proteins. So if you start diving into the G protein coupled receptor biology, you'll find that there are some that activate pathways and some that inhibit. In this case, it's inhibiting. When BHB binds to this receptor, it inhibits adenylyl cyclase activity or adenylate cyclase. This reduces the intracellular levels of cyclic amp. This will often just be abbreviated as little C, then big amp. That in turn will reduce the activity of a very important enzyme called protein kinase A. These receptors are found in many relevant metabolic and immunological tissues. For example, this receptor, GPR109A, is expressed on immune cells including macrophages, neutrophils and microglia. In the brain this immune cell expression is crucial because it mediates many of BHB's anti inflammatory effects in the retina. So we're talking about the eye GPR109A is found on retinal pigment, epithelial cells and microglia where it helps maintain an immuno inhibitory environment. Studies have shown that mice lacking this particular receptor have increased inflammatory cell infiltration in their retinas even under normal conditions. And when researchers induced inflammation, treatment with BHB reduced inflammatory cell recruitment, but only in the animals that had functional GPR109A. In the knockout mice that did not have this receptor, the BHB didn't do anything to protect the animals and similar findings have emerged in the brain. A seminal Nature Communications paper demonstrated that the neuroprotective effects of a ketogenic diet in stroke models depend entirely on GPR109A. When researchers knocked out this receptor, the ketogenic diet no longer reduced infarct size. So talking about strokes, even more striking, they showed the GPR109A expression on infiltrating monocytes and macrophages was required for protection. These immune cells when they encounter BHB through GPR109 a shift toward what the researchers called a neuroprotective phenotype, producing helpful molecules like prostaglandin D2. Now, regarding the stereoselectivity, by that I mean whether the receptor prefers the D form of BHB or L. The evidence suggests it's not strictly stereoselective. Both enantiomers can activate GPR109A, though DBHB appears to have somewhat higher affinity. In other words, it can activate it a little more readily at concentrations around 15 millimolar, which is getting to be a little too high, like more than a little. But both forms at that point appear to work the same to the same degree. So it does suggest that both can work, but D can work at lower, more relevant levels. Alright, let's move on from that one. The second receptor in our story is FFAR3. FFAR3, also called GPR41 or free fatty acid receptor 3. This receptor was initially characterized as a sensor for short chain fatty acids. These are those produced by gut bacteria or consumed when you eat fermented foods like acetate from apple, cider vinegar, propionate or butyrate. Studies examining FR3 function in sympathetic neurons found that BHB acts as an agonist, it activates the receptor. When researchers looked at N type calcium channels in sympathetic neurons, BHB caused voltage dependent inhibition of these channels just like other FR agonists can. The functional outcome seems consistent. Reduced sympathetic outflow FFAR3 is highly expressed in sympathetic ganglia and when activated by propionate, that's one of those short chain fats I mentioned. It increases norepinephrine release release. Either direct inhibition of this receptor by BHB or modulating of downstream signaling appears to dampen sympathetic tone during fasting states. Recent work has also implicated FR3 and BHB's effects on cancer cells. In non small cell lung cancer models, BHB suppressed cell proliferation, migration and invasion through FFAR dependent mechanisms. When researchers removed that receptor, BHB's antitumor effects were abolished. This suggests that the metabolic state, specifically elevated ketones, can influence tumor behavior through receptor mediated signaling, not just by altering fuel availability. Let me state that again. A lot of the metabolic view of cancer is that by adhering to a ketogenic diet you have relatively less glucose and relatively more ketones. Ketones are a fuel to cancer cells not going to metab metabolize and so you end up kind of starving the cancer cell. That's the traditional view. But these findings suggest there's something more direct. It's not just about the indirect use of fuel, but rather something more specific to the signaling itself. Now we come to one of the most clinically relevant signaling functions of BHB, its ability to inhibit the NLRP3 inflammasome. This is particularly interesting because unlike the receptor mediated effects we've discussed, NLRP3 inhibition appears to be a direct receptor independent action of BHB. Let me explain what this particular inflammasome, the NLRP3 inflammasome, is and why it matters. NLRP3 stands for nucleotide binding domain, leucine rich Repeat pyrin domain containing 3. It's a multiprotein complex that serves as an innate immune sensor. When NLRP 3 detects danger signals, things like ATP out in the flowing in the outside of a cell, or uric acid crystals or bacterial toxins, it assembles into an active what's called inflammasome complex. This complex activates caspase 1, which then cleaves the Pro interleukin 1 beta and Pro interleukin 18, which are cytokines, into their active forms. So essentially by activating NLRP3 we activate these other pro inflammatory cytokines and interleukin 1 beta is one of the most potent pro inflammatory cytokines in the body. Its dysregulation contributes to a staggering array of diseases. It has been implicated in things like type 2 diabetes, atherosclerosis, gout, Alzheimer's disease, multiple sclerosis and various other auto inflammatory and autoimmune syndromes. In 2015, a landmark paper in Nature Medicine showed that BHB specifically inhibits the NLRP3 inflammasome. I want to emphasize specifically because BHB did not affect other inflammasomes, it didn't inhibit NLRC4 or AIM2 inflammasomes. These are ones that are activated by things like bacteria, certain bacteria, as well as cytosolic DNA respectively. So just different signals. The mechanism is fascinating. In this case, BHB actually works to prevent potassium efflux from cells, which is a critical early step in NLRP 3 activation and it further reduces the oligo. Oligomerization. Oligomerization. Sorry, for those who are listening live, let me just try that all again. The mechanism is fascinating. BHB prevents potassium efflux from cells, a critical early step in NLRP 3 activation. And it reduces the combining or the oligomerization of asc, the adapter protein that helps assemble the inflammasome complex. This prevents asc, what's called SPEC formation. In other words, all of this is simply to say that there are very specific devices and mechanisms whereby BHB is blocking the NLRP3 inflammasome from being turned on. Now here's what caught my attention in this research that the effect is not dependent on GPR109A. That's that first G protein coupled receptor I mentioned. The group specifically tested this using GRP109A knockout mice and found that BHB still inhibited that activation. They also showed it wasn't dependent on AMPK activation, autophagy, reactive oxygen species reduction or BHB's oxidation itself through the citrate cycle. The effect was a direct action of the BHB molecule itself. Even More interesting, the NLRP3 inhibition is not stereoselective. Both DBHB and LBHB can inhibit the inflammasome. This has practical Implications Implications for the ketone supplement Industry Racemic mixtures containing both enantiomers should retain this anti inflammatory benefit. In other words, if you're getting exogenous ketones that have both D and L, you're able to add or stack the benefits on top of each other. The physiological relevance has been demonstrated in multiple disease models. BHB attenuates inflammation in models of gout where uric acid crystals are the NLRP3 trigger. In fact, my lab published a report on that very thing just a year ago. It also reduces Caspase 1 activation in various preclinical models. And in Alzheimer's disease models, BHB reduces amyloid plaque formation, microgliosis and that speck formation through the NLRP3 inhibition. This may help explain why patients with Alzheimer's disease have been found to have lower BHB levels in their blood and brain tissue compared to age matched controls. Their reduced capacity for this endogenous anti inflammatory signal may contribute to the chronic neuroinflammation that drives disease progression. Our next signaling mechanism takes us into the nucleus in the realm of epigenetics. BHB is an endogenous inhibitor of Class 1 histone deacetylases, specifically HDAC1, HDAC2 and HDAC3. For those who need a quick refresher on epigenetics, histones are proteins around which DNA is wrapped. When lysine residues on histones are acetylated, the chromatin structure loosens and that just basically allows the genes to have more accessibility for transcription. So you can take a gene and then start to turn it into a protein. Histone deacetylases remove these acetyl groups, causing chromatin to condense, and in turn it will generally suppress gene expression. By inhibiting HDACs, BHB promotes histone acetylation and enables the transcription of specific gene programs. This was first demonstrated by Eric Verdin's group at the Gladstone Institutes. They showed that BHB inhibits HDAC activity at very normal physiological concentrations as low as 1 millimolar. That's right. In that physiological range, the functional consequences are remarkable. When BHB inhibits HDACs, it increases acetylation at the promoters of specific genes, including FoxO3A and metallothione 2 or MT2. Both of these genes encode proteins that protect against oxidative stress. The Virdin group demonstrated that mice treated with BHB were protected against oxidative stress induced by various noxious stimuli. This protection was mediated by HDAC inhibition and the resulting upregulation of antioxidant defenses. By upregulating antioxidant gene expression, BHB essentially preconditions cells to handle oxidative stress. The mitochondria don't necessarily produce fewer free radicals, though some evidence suggests ketone metabolism is in fact cleaner than other fuels like glucose in this regard. But even further, the cell becomes much better equipped to neutralize those radicals before they cause damage. There's another layer to this epigenetic story. Beyond inhibiting histone deacetylation, BHB itself can act directly to modify proteins through a process called beta hydroxybutylation. This is a newly discovered post translational modification where the beta hydroxybutyryl group is covalently attached to lysine residues on histones and other proteins. This represents just another one more way that BHB can directly couple metabolic state to gene expression, not just by inhibiting enzymes that erase acetylation marks, but by providing a substrate for an entirely distinct type of histone modification. Let me review what we've covered and focus on the mitochondrial implications, because I think this is where the signaling story of BHB becomes most relevant to metabolic health. First, BHB as a fuel when peripheral tissues oxidize bhb, the conversion back to acetoacetate generates nadh. The subsequent entry of acetyl COA into the citrate cycle generates additional NADH and another reducing equivalent, FADH2. These reducing equivalents feed the electron transport system to produce a lot of ATP. Some researchers have suggested that ketone metabolism may be thermodynamically more efficient than glucose metabolism, that the P O ratio or the ATP that is generated per oxygen consumed may be slightly higher. The evidence for this is debated, but what's clear is that ketones are an extremely efficient fuel that can sustain tissues even when glucose is limited and indeed do so very well. Second, oxidative stress mitigation through HDAC inhibition and the resulting upregulation of FoxO3A and other antioxidant genes. BHB helps cells cope with the reactive oxygen species that are an inevitable byproduct of mitochondrial respiration. This is particularly important in high energy demand tissues like the brain and the heart, where mitochondrial density is high and oxidative damage can be devastating. Third, inflammation and mitochondrial health are intimately connected. Chronic inflammation damages mitochondria pro. Inflammatory cytokines like interleukin 1 beta can impair mitochondrial function, reduce ATP production and increase reactive oxygen species generation in a vicious cycle by inhibiting the NLRP3 inflammasome and reducing interleukin 1 beta production, BHB protects mitochondria from this inflammation induced damage. Fourth, the GPR109A pathway on immune cells appears to shift them toward phenotypes that are less damaging to host tissues. The neuroprotective macrophages we discussed earlier likely represent cells that clean up damage without perpetuating inflammation. Exactly what you want when tissues are under any kind of stress. And fifth, consider that all of these effects happen simultaneously. When you fast, when you follow a ketogenic diet or you are consuming exogenous ketones in the form of GO bhb, your BHB levels rise and you get this coordinated multi pathway response. Reduced inflammation through NLRP3 inhibition, enhanced antioxidant defenses through HDAC inhibition and modulation of immune cell behavior through GPR109A. This is not one drug hitting one target. It's a fundamental metabolic signal that orchestrates cellular resilience. Before I conclude, let me briefly touch on where this science is heading. Understanding BHB as a signaling molecule has opened up new therapeutic possibilities that go beyond simply recommending fasting or ketogenic diets. Exogenous ketone supplements, specifically GO BHB in the form of the ketone salts or the BHB acid, can elevate blood BHB levels without requiring dietary carbohydrate restriction. Clinical trials are now examining whether these supplements can provide anti inflammatory and neuroprotective effects in various conditions. For conditions like Alzheimer's disease, where patients have lower BHB levels and impaired brain glucose metabolism, ketone supplementation offers a way to both provide an alternative fuel and engagement these protective signaling pathways there are similar benefits in the heart. In the heart failure research space, there's growing interest in ketones as a super fuel for the failing heart, which often has impaired glucose and fatty acid metabolism. The heart is one of the most avid ketone consumers in the body and some evidence suggests that elevated ketones during heart failure may be a beneficial adaptation rather than just a metabolic byproduct. The anti inflammatory effects of BHB are also being explored in autoimmune conditions where the NLRP3 inflammasome activation contributes to some of the progression of the disease. Now let's bring this all together. BHB is far more than metabolic backup fuel. First and foremost, it's a viable and competitive fuel in its own right. But it is also a signaling molecule that activates cell surface receptors, inhibits inflammatory complexes and modifies gene expression through epigenetic mechanism. This dual role as both nutrient and signal is unusual in biology and suggests that ketones evolved to communicate something important about our metabolic state to every tissue in the body. When BHB rises, cells receive a coordinated message. Glucose is scarce, but alternative fuel is available. Reduce inflammation, prepare for oxidative stress Shift gene expression toward a more resilient, protected phenotype from the GPR109A receptor on various immune cells and other tissues, to the NLRP3 inflammasome in macrophages and to histone deacetylases in the nucleus. BHB touches virtually every aspect of cellular biology and the downstream effects reduced interleukin 1 beta, increased Fox O3A, enhanced antioxidant capacity are precisely what we'd want to protect against the chronic diseases of our time, like diabetes, neurodegeneration, cardiovascular disease, certain cancers and more. So the next time someone dismisses ketones as just an alternative fuel, you can tell them it's so much more than that. BHB is a signaling metabolite that connects our eating patterns to our inflammatory status, our gene expression, and the very health of our mitochondria. Thanks for listening. Until next time. More knowledge Better Health.

Looking to improve your own metabolic health? Visit insuliniq.com for courses, coaching, consultations and a 10 day free community membership trial to dive deep into the science behind metabolic health. Become an insider@Benbickman.com com where you'll enjoy my exclusive content ad, free podcasts, livestream, Q and A access and more.