122: How Stress Triggers Ketone Production (Surprising Science!) with Dr. Ben Bikman

Can stress actually help your metabolism? Surprisingly, yes. When you're fasting, carb restricted or even just under pressure, your body starts shifting fuel sources. Stress hormones like epinephrine and cortisol rise not just to help you survive, but to burn fat and make ketones. That's right, stress kicks off ketogenesis. Fat is broken down, insulin drops, and the liver starts pumping out ketones to fuel your brain and muscles. Clean, efficient energy, even in hard times. So maybe we shouldn't fear these so called stress hormones. Maybe we should start seeing them as metabolic hormones, essential tools for energy adaptation and resilience. This is lecture 122 of the Metabolic Classroom. Looking to improve your own metabolic health?

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Welcome to the Metabolic Classroom. I'm Professor Benjamin Bickman, a biomedical scientist and professor of cell biology. Today we're exploring a topic that connects two powerful forces in the body, stress and ketones. Or to say all that another way, we're simply talking about metabolism because we often think of stress as something that harms us. It's some insult, and certainly in many ways chronic stress can do that. But stress also initiates some incredible adaptations in the body, particularly when it comes to how we produce and use energy. So in this mini lecture, we're going to explore how stress can actually activate ketogenesis, the process of making ketones. Specifically, we'll look at how canonical stress hormones like epinephrine and cortisol, along with the sympathetic nervous system, influence this shift in fuel use. And ultimately, we'll answer the question, to what degree does stress play a role in driving ketone production? To start, we'll actually look at the physiology of stress, and then we'll walk through some of the biochemistry and how that weaves into ketogenesis. And finally we'll connect connect the two to just understand how thoroughly stress sets the powerful metabolic pathway in motion. All right, as I mentioned, let's start with an over a brief primer, an overview of the physiology of stress in biological terms. Stress is the body's coordinated response to a perceived threat, whether it's physical or emotional, or even metabolic, such as a lack of food. But as I'll come to in a bit, it's just not that simple. But nevertheless, the classic view is that stress Is designed to help us survive by, in the context of this lecture, mobilizing energy and focusing the body's resources where they're most needed. The response, no surprise, is orchestrated through two main systems. And this is just reflective of redundancies in systems that are very important. And in most instances in the body, where I guess it's feasible, something may be important enough that you have some redundancies here. I think this is one of those instances. First of all, we have the sympathetic nervous system, which in a way acts like the rapid response team. This is the most immediate response. So within seconds of a stress or, say a physical injury or an emotional aggravate, like an argument or even intense exercise, the brain will send a signal to the adrenal medulla. So the adrenal glands are the small little hormone producing glands right on top of the kidneys, and the medulla is the inner part of it. The adrenal glands are kind of like an orange, where there's a peel portion to it, albeit a thick one, and then there's the fleshy center. They are very distinct parts of the adrenal gland, which is why I'm pointing it out. The adrenal medulla, or the center part, is releasing, in response to this signal, epinephrine into the bloodstream and nor and a little bit of norepinephrine. Collectively, these are known as the catecholamines. So epinephrine and norepinephrine, also known as adrenaline and noradrenaline. These hormones prepare the body for action within seconds. They raise heart rate, they increase blood pressure, they dilate the pupils. And most relevant for today, they mobilize energy. They signal to fat cells to start breaking down stored fat to make it available to be burned for fuel. Now, I noticed, I noted earlier that we have two things, two signals here. The first was the sympathetic nervous system. But then second, we have the hypothalamic pituitary adrenal axis, or the HPA axis, which takes slightly longer, or it's a slightly slower but longer lasting approach. This, this pathway begins in the brain where the hypothalamus releases a hormone called crh. Corticotropin releasing hormone. CRH signals the pituitary gland to release acth, which then travels through the bloodstream to the adrenal cortex. Now, this is the other part of the adrenal gland. A moment ago, I mentioned the adrenal medulla producing the catecholamines. That's from the center fleshy part of the orange. If you will of the adrenal gland. But the adrenal cortex is the outer part, the peel. And in response to acth, the adrenal cortex or the orange peel, now releases cortisol. Cortisol is really, in a way, the stress hormone. It's like the poster child of all stress hormones, but it's more accurately termed an adaptation hormone. It prepares the body for sustained stress by increasing blood sugar, promoting fat breakdown selectively and reducing inflammation. Cortisol also makes the body less sensitive to insulin, which further favors the release of stored energy, especially fat. Alongside cortisol and catecholamines, stress also triggers increases in other hormones which may not typically be considered stress hormones, but are released in response to stressful stimuli, including glucagon, which of course powerfully raises blood glucose, as well as growth hormone, which also promotes fat breakdown and even further reduces insulin's efficacy or signaling in certain cells. Even prolactin and antidiuretic hormone ADH will rise in response to stress. Now, admittedly, they have a perhaps more modest role in metabolism, so we could consider them more secondary. Indeed, to the point that we won't, they're not relevant in this mini lecture. But suffice it to say, there are many hormones that are released in response to a stressful stimuli, very few of which we would actually consider stress hormones. And that's a point I'll come back to at the end, that perhaps calling these guys stress hormones, while not wrong, perhaps gives rise to some incorrect thinking. The level and type of hormonal response depends on whether the stress is acute, it's short lived or intense, or whether it's chronic, persistent and more subtle. In summary, for this first section of the mini lecture, stress shifts metabolism generally into a catabolic state, a breakdown mode, liberating stored fat and from fat cells and glycogen from the liver to provide energy that the body may need in order to face whatever the threat could be. And again, it doesn't have to be something as dramatic as running away from the canonical bear. And here's where it gets fascinating. All of these hormones that help us respond to danger, overt stressful stimuli like epinephrine, cortisol, glucagon and others are also ones that rise during fasting or even just a low carbohydrate diet. Why? Why might that be? Because the body may perceive these states as a bit of a metabolic stress. Now, that does not mean it's harmful, but it does mean that the body needs to adapt. And perhaps that's one of the best ways to look at even the term stress, what that means physiologically, it's, it's, it's a stimulus that requires the body to change its approach. It needs to adapt, so it's responding to the absence or the relative reduction in glucose by shifting to an alternative fuel source. So perhaps it's time we reconsider how we label these hormones. Rather than thinking of them strictly as stress hormones, we might more accurately think of them as metabolic adaptation hormones, signals that help the body adapt, switch fuel sources and just maintain balance in the face of changing energy availability. It is, after all, all about homeostasis or balance. And this, in the end, sets the stage for ketogenesis. Let's discuss that. Ketogenesis is the body's elegant solution to a shortage of carbohydrates. When glucose is scarce, whether from fasting or carbohydrate restriction or even some intense stress, the body turns to fat as its primary fuel. But the brain can't burn fat directly for fuel. It needs a water soluble fuel that can cross the blood brain barrier very easily with transporters, specifically these. In fact, interestingly, these are monocarboxylate transporters, abbreviated as mcts. And this is where ketones come in. The process begins in adipose tissue or fat tissue, where fat cells break down triglycerides into free fatty acids and glycerol. These free fatty acids will enter the bloodstream and travel to the liver where they undergo beta oxidation inside the mitochondria. So they break down, they're getting burned, but not all the way. What happens here is that through beta oxidation we end up generating a lot of a molecule called acetyl coa. And acetyl COA sits at a great nex or center point when it comes to nutrient metabolism within a cell. Normally at this point, the acetyl COA would enter. It would go on, if you will, to enter the citrate cycle or sometimes called citric acid cycle, sometimes called Krebs cycle. I like just calling it the citrate cycle. But acetyl COA has limited options in this specific scenario. There's another molecule that becomes relevant here called oxaloacetate. Oxaloacetate is a key molecule that's requ for the citrate cycle to work. So acetyl COA comes into the citrate cycle, but it has to interact with oxaloacetate. However, in this low carb state, oxaloacetate is actually getting diverted out of the citrate cycle, if you will, and into gluconeogenesis in the liver. This is now involved in creating glucose from the citrate cycle. So we're, we're, that is gluconeogenesis. So we're kind of moving the whole pathway, what was once just glycolysis, taking a glucose molecule, burning it down to acetyl Coa, then going into the mitochondria. Now we're taking that stuff and building it up into glucose. So back to the fatty acid oxidation, because that's where I'd gotten to in this story of biochemistry. We have a lot of acetyl CoA, but the citrate cycle isn't open to it, that that pathway is closed because again, the oxaloacetate is being used for something else. Thus we start to have a lot of acetyl COA accumulate. Now when it does, sometimes acetyl Coa, when it accumulates in a liver cell, it can be used to create new fat. But that can only happen if insulin is elevated. In this case, insulin is down because there's not a lot of carbs coming in. And now there's only one last route. And the liver shifts gears and it begins turning acetyl COA into ketones. And these are then released into the bloodstream where they travel to the brain muscles and any other cell that has mitochondria to be used for energy. Unlike glucose, ketones don't require a gatekeeping hormone like insulin to enter certain cells or any cells. So every cell with mitochondria will gladly take in ketones without the need of insulin to regulate it. And then the ketones just get burned as a fuel. So this makes ketogenesis not a fallback, but just an adaptive response. A very efficient, adaptive, even preferred fuel when the body is perceiving, is sensing a lack of carbohydrate coming in. So blood glucose is having a downward pressure. Ketogenesis is now stepping up. And again, this is why stress hormones rise in response to fasting or low carb diets. They're helping the body transition into a fat burning, ketone producing mode. What we often interpret as a stress response is simply in reality, the body executing a pretty brilliant metabolic pivot. Now that we've covered stress, physiology and ketone production, let's bring it all together. How exactly does stress drive ketogenesis? Well, we could say it all begins probably with epinephrine. That's that fact. Acting fast acting catecholamine released during acute stress, Epinephrine will bind to receptors on fat cells, activating an enzyme called hormone sensitive lipase, which in turn unleashes a wave of free fatty acids into the blood. Now, the free fatty acids go to the liver, which is going to be burned through the process I mentioned earlier, lots of acetyl CoA. Then acetyl CoA gets diverted into ketogenes. In fact, some studies show that acute epinephrine exposure can increase fatty acid mobilization by well over 50%, which in turn can roughly double the amount of ketones being produced very quickly. But epinephrine does more than just unlock fat stores. It also promotes the release of glucagon and it inhibits insulin. So it's going to help keep insulin levels low, which is further enhancing the liver's ketogenic machinery, if you will. Norepinephrine, the close cousin to epinephrine, is also released from nerve endings. So that's the sympathetic nervous system. When we think of the sympathetic nervous system, it has these little, at my fingertips, if you will, as the end of a little nerve, and norepinephrine starts coming from that, including going directly to fat cells. So you have little nerve endings that are going to fat cells, releasing norepinephrine, which further activates lipolysis. So it's the very local effect where the nerves are directly coming to the fat tissue. But then we also have cortisol. Unlike epinephrine, cortisol doesn't appear to initiate ketogenesis, but it does help keep it going. Firstly, it ensures that gluconeogenesis continues so that the liver is making the glucose that some cells of the body needs, like the red blood cells. And that's be ensuring that oxaloacetate is pretty depleted. Remember, oxaloacetate is the molecule that acetyl coa needs in order to access into the citrate cycle. But in this case, the liver is using that oxaloacetate to make new glucose. So it shuns thus the acetyl coa into ketogenesis, but it also leads to selective lipolysis. And this is cortisol that I'm talking about. Now, I say selective lipolysis because there are some fat tissues that, when cortisol is elevated, that are selectively burned like fat out in the limbs of the body, maybe fat on the arms or fat on the legs or buttocks. And in this case, like epinephrine, those free fatty acids are going to be used as building blocks by the liver for ketogenesis. Now, I'd mentioned growth hormone, growth hormone increases in both fasting and stress and low carb diets, and that will also activate lipolysis. So growth hormone also stimulates the breakdown of stored fat. And it further helps that happen by impairing insulin. So it will make fat cells a little insulin resistant, so they're even less responsive to insulin, breaking down more fat, providing more substrate in the form of free fatty acids for the liver to turn it into ketones. But finally, glucagon, which rises in response to stress and fasting, also acts as a ketogenic accelerator. It increases some of the enzymes needed for ketone synthesis. I could also even include content about antidiuretic hormone. Antidiuretic hormone also plays a role at stimulating lipolysis. So many of these so called stress hormones are maybe are mislabeled and we ought to call them metabolic adaptation hormones. But altogether these hormones push the liver into ketone production mode, sometimes increasing ketogenesis by multiples over baseline levels. Of course, depending on the intensity and the duration of whatever the stressor may be, whatever the signal may be, something even as benign as fasting. Now, I've mentioned the nervous system, the sympathetic nervous system, and as much as I touched on it initially, I want to revisit it because this does go beyond hormones per se, and, and have that other level of regulation. The sympathetic nervous system doesn't just trigger hormone release, but it will also directly innervate the liver and the fat tissue. So this is nerves from the spinal cord that directly release norepinephrine into fat tissue and at the liver, into the liver, further stimulating both fat breakdown and enhancing ketogenesis. And this is something that can happen before the blood levels of these hormones even change. So the body doesn't wait passively until hormones change. You know, the several minutes of epinephrine changing, then the even longer, the hour or so of cortisol changing, we can get within almost seconds changing in this response through the sympathetic nervous system because of the rapid neural signaling, which of course is happening alongside hormones complementing hormones. But this is coordinating a very rapid, efficient, swift switch to ketone production whenever the energy needs rise or glucose becomes scarce. So what can we take away from all this? The body's stress response is not just about survival, it's about fuel selection and energy availability. Stress hormones like epinephrine, norepinephrine, cortisol, glucagon, even growth hormone, even antidiuretic hormone all shift the body toward fat mobilization and ketogenesis. Of course, preceding and complementing all of this, the sympathetic nervous system works alongside to help push along these changes with almost real time nerve signaling. These hormones often get painted in a negative light. But the truth is they are critical metabolic tools, especially in the context of fasting and carbohydrate restriction, even exercise. They help the body adapt to energy scarcity, preserve brain function and burn fat in an orderly way. Of course, balance matters when stress becomes chronic, like when cortisol and catecholamine stay elevated without a break for hours or even days. These same pathways can promote now long term insulin resistance, catabolism in muscle tissue, and of course, metabolic dysfunction negative metabolic consequences. But that does not make the hormones themselves harmful. It simply means that context matters. The same hormones that protect us during fasting can harm us when triggered, perhaps by poor sleep or chronic anxiety or even processed foods. So perhaps we should stop thinking of these as mere stress hormones and instead recognize them as adaptive metabolic signals. Signals that, when activated intentionally and periodically, help us become metabolically resilient and certainly better equipped to handle whatever metabolic changes or nature may throw at us. 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@Ben Bickman.com where you'll enjoy my exclusive content ad, free podcasts, livestream, Q and A access and more.