Ketone production is your body’s backup fuel system, activated when glucose runs low. The liver breaks down fatty acids into molecules called ketone bodies, chiefly beta-hydroxybutyrate (BHB), which are then shipped through the bloodstream to organs that need energy. This process kicks in during fasting, prolonged exercise, carbohydrate restriction, or any situation where glucose is scarce or cannot be used properly. But ketones turn out to be far more than emergency fuel: they also act as signaling molecules that influence inflammation, gene expression, and even how your brain adapts to nutritional stress.
Where Ketones Are Made
The liver is the primary ketone factory. Inside liver cells, mitochondria convert fatty acids into acetyl-CoA through a process called beta-oxidation. When the liver has more acetyl-CoA than its own energy cycle can handle, it funnels the excess into ketone body production. The result is three related molecules: BHB (the most abundant), acetoacetate, and acetone. The liver itself cannot burn these ketones for fuel; it simply exports them. Organs that can use them include the brain, heart, skeletal muscle, and kidneys.1PubMed Central. Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease
The liver is not the only tissue capable of making ketones, though. The kidneys, the lining of the colon, and the retina can also produce them to a limited extent. This matters because it means certain tissues may generate ketones locally for their own signaling or metabolic needs, rather than depending entirely on what the liver sends out through the bloodstream.
The Hormonal Switch
Two hormones control whether your liver is making ketones or storing energy: insulin and glucagon. When you eat, insulin rises and suppresses the release of fatty acids from fat tissue. Without that stream of fatty acids reaching the liver, there is nothing to convert into ketones. Glucagon does the opposite. When blood sugar drops between meals or during a fast, glucagon rises and promotes fatty acid release, which in turn feeds ketone production in the liver.2PubMed. The role of insulin, glucagon, dexamethasone, and leptin in the regulation of ketogenesis and glycogen storage in primary cultures of porcine hepatocytes prepared from 60 kg pigs
Insulin is the stronger player in this tug-of-war. Classic research on human subjects showed that when glucagon was infused into healthy people, it triggered insulin secretion that then shut down both fat breakdown and ketone production almost entirely. In people with type 1 diabetes who could not produce insulin, the same glucagon infusion caused both fat breakdown and ketone production to rise significantly. The takeaway: mole for mole, insulin has more power to suppress ketones than glucagon has to promote them.3JCI Insight. Effects of Glucagon on Lipolysis and Ketogenesis in Normal and Diabetic Men
Fasting and the Timeline of Ketosis
Ketone levels in your blood follow a predictable trajectory during a fast. In the first several hours after your last meal, your body draws on liver glycogen (stored glucose). As those stores deplete, insulin drops and fatty acids begin flowing to the liver. Detectable ketones appear in the blood within roughly 12 to 16 hours of fasting for most people, though the speed varies with activity level and how much glycogen you started with.
When fasting continues beyond the first day or two, your body shifts deeper into ketone reliance. Research in people with type 1 diabetes showed that after a 32-hour fast, the rate of ketone accumulation during insulin withdrawal was about 40% faster compared to the postprandial state.4The Journal of Clinical Endocrinology & Metabolism. Short-term fasting is a mechanism for the development of euglycemic ketoacidosis during periods of insulin deficiency This accelerated rate is a normal part of fasting physiology in healthy people too, but it explains why individuals with diabetes who miss meals can slide into dangerous ketoacidosis more quickly than expected.
How the Kidneys Conserve Ketones During Prolonged Fasting
If your body is generating all these ketones to replace glucose, losing them in the urine would be wasteful. The kidneys address this problem through an adaptive increase in ketone reabsorption. In a study of obese subjects undergoing total starvation, the rate at which kidneys reclaimed BHB from the urine nearly tripled between day 3 and day 10, rising from about 154 to 419 micromoles per minute. Acetoacetate reabsorption roughly doubled over the same period.5Metabolism. Renal conservation of ketone bodies during starvation
This conservation has several benefits beyond just preserving calories. It spares roughly 225 kilocalories per day that would otherwise be lost in the urine. It also limits the excretion of sodium and potassium (which would be dragged out alongside ketone salts), reduces the need for protein breakdown by cutting kidney ammonia production, and helps buffer the blood against the acidity that ketones introduce.6American Journal of Nephrology. Starvation Ketosis and the Kidney This is why the initial rapid weight loss on a fast or very low-carb diet is largely water and sodium: during the first few days, before renal adaptation kicks in, ketone excretion pulls sodium and water with it.
Exercise and Post-Exercise Ketosis
Hard exercise can trigger a brief spike in ketone production, even if you have eaten recently. The mechanism ties back to glycogen depletion. When intense effort drains liver glycogen, a key intermediate molecule (oxaloacetate) gets redirected from the liver’s main energy cycle toward making new glucose. That diversion frees up acetyl-CoA to be shunted into ketone production instead.7PubMed Central. Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation
Interestingly, well-trained athletes tend to resist this post-exercise ketone spike. Animal studies have shown a strong negative correlation between liver glycogen stores and blood ketone levels after exercise, and trained subjects maintain larger glycogen reserves.8PubMed. Glycogen metabolism and post-exercise ketosis in carbohydrate-restricted trained and untrained rats So the fitter you are, the less likely you are to see a big post-workout ketone surge, simply because your liver still has glycogen to spare.
How the Brain Gets Access to Ketones
The brain sits behind the blood-brain barrier, a selective filter that prevents most molecules from crossing freely. Ketones rely on a transporter protein called MCT1 to get through. Under normal conditions, when you are eating regularly and blood ketone levels are low, there is relatively little MCT1 at the barrier. But when fasting or a ketogenic diet raises blood ketone levels, the body upregulates MCT1 to let more ketones into the brain.9PubMed Central. Fasting upregulates the monocarboxylate transporter MCT1 at the rat blood-brain barrier through PPAR δ activation
The scale of this adaptation is impressive. In rats fed a ketogenic diet, MCT1 levels in brain blood-vessel cells increased roughly eightfold after four weeks. The brain also simultaneously increased levels of its glucose transporter, GLUT1, suggesting it hedges its bets rather than fully committing to one fuel.10PubMed. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain This transporter upregulation is one reason why the cognitive “fog” people report in the first days of a low-carb diet often clears after a week or two: the brain has physically remodeled its access ports.
Ketones as Heart Fuel
The heart is among the most metabolically flexible organs in the body. It can burn fatty acids, glucose, lactate, and ketones, and it shifts between them depending on what is available. There is a direct correlation between circulating BHB levels and how much energy heart muscle cells derive from ketone oxidation.11PubMed Central. Ketone bodies and the heart
In failing hearts, the picture gets more complex. Research using mouse models of heart failure found that raising ketone concentration boosted the share of energy coming from ketone oxidation from about 8% to 18% in failing hearts. Perhaps more surprisingly, the extra ketones also increased glucose oxidation and overall energy production without displacing fatty acid use. But this additional fuel did not translate into better cardiac efficiency, meaning the failing heart worked harder overall without getting proportionally more useful output.12Cardiovascular Research. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency This finding has kept researchers cautious about recommending ketone-based therapies for heart failure, despite the appealing logic that “more fuel equals better performance.”
Beyond Energy: Ketones as Signaling Molecules
One of the most exciting developments in ketone research is the recognition that BHB does more than feed cells. It acts directly on gene expression by inhibiting a class of enzymes called histone deacetylases (HDACs). When these enzymes are blocked, certain stretches of DNA become more accessible, ramping up the production of proteins involved in resisting oxidative stress. In mice, both fasting and calorie restriction increased this effect across multiple tissues, and the protective genes activated included FOXO3A and MT2, both of which help cells cope with damage from reactive oxygen species.13PubMed Central. Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor
BHB also appears to dampen inflammatory pathways. In a study of diabetic retinal damage, systemic BHB treatment significantly reduced markers of a key inflammatory complex called the NLRP3 inflammasome, along with the inflammatory cytokines it produces.14PubMed Central. The activation of retinal HCA2 receptors by systemic beta-hydroxybutyrate inhibits diabetic retinal damage through reduction of endoplasmic reticulum stress and the NLRP3 inflammasome These signaling roles help explain why ketogenic diets show promise in conditions beyond simple metabolic disease, including drug-resistant epilepsy, where the diet reduces neuronal excitability through multiple mechanisms including improved mitochondrial function and changes to the gut microbiome.15World Neurosurgery: X. Drug resistant epilepsy and ketogenic diet: A narrative review of mechanisms of action
When Ketone Production Goes Wrong
The difference between helpful nutritional ketosis and dangerous ketoacidosis is primarily a matter of insulin. In healthy people, rising ketone levels trigger just enough insulin to keep ketone production in check, so blood levels plateau at a moderate concentration. In type 1 diabetes, and sometimes in advanced type 2, the insulin brake is missing or severely weakened. Without it, fatty acids flood the liver unchecked, ketone production spirals, and the blood becomes dangerously acidic. This is diabetic ketoacidosis (DKA), characterized by the combination of insulin deficiency, which unleashes fatty acids from fat tissue, and glucagon excess, which drives the liver to convert those fatty acids into ketone acids at a pace the body cannot buffer.16PubMed. Diabetic ketoacidosis
A newer clinical concern is DKA caused by a class of diabetes drugs called SGLT2 inhibitors (gliflozins). These medications work by forcing the kidneys to excrete glucose in the urine, which lowers blood sugar. But the drop in blood sugar also lowers insulin secretion and raises glucagon, mimicking a fasting state and promoting ketone production. In some patients, this can tip into full ketoacidosis even though blood sugar appears near-normal, a condition called euglycemic DKA. Triggers like carbohydrate restriction, illness, surgery, or trauma can accelerate the process by further stimulating stress hormones that drive fat breakdown.17Diabetes & Metabolism Journal. Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights The near-normal glucose level is what makes euglycemic DKA sneaky: neither the patient nor the clinician may suspect ketoacidosis because the typical red flag of high blood sugar is absent.
Keto-Adaptation and the Dietary Ketogenic State
People who drastically cut carbohydrate intake often describe a rough transition period before their bodies settle into using ketones efficiently. This process, called keto-adaptation, involves sustained ketosis, increased rates of fat oxidation, and a decreased reliance on carbohydrate oxidation in energy-demanding tissues like skeletal muscle.18The American Journal of Clinical Nutrition. The impact of keto-adaptation on exercise performance and the role of metabolic-regulating cytokines The adaptation is not instantaneous; most researchers consider it a process that takes several weeks of consistent carbohydrate restriction.
One controlled study comparing different methods of raising ketones found that a ketogenic diet increased total daily energy expenditure by about 110 kilocalories per day and sleeping energy expenditure by roughly 200 kilocalories per day compared to an isocaloric standard diet. Neither a one-day fast nor exogenous ketone drinks produced the same bump in expenditure.19PubMed. Impact of one-day fasting, ketogenic diet or exogenous ketones on control of energy balance in healthy participants The fact that simply drinking ketones did not replicate the metabolic effect of a ketogenic diet suggests the increase in expenditure is not about the ketones themselves, but about the broader metabolic shift that accompanies producing them endogenously from fat.
Exogenous Ketones and What They Can and Cannot Do
Ketone supplements have become popular with athletes and dieters who want the metabolic benefits of ketosis without cutting carbs. These products come in two main forms: ketone salts (BHB bound to minerals like sodium or calcium) and ketone monoesters (a more concentrated liquid form). A systematic review and meta-analysis found that ketone monoesters raised blood BHB roughly five times higher than ketone salts and lowered blood glucose about three times more.20Advances in Nutrition. Effects of Exogenous Ketone Supplementation on Blood Glucose: A Systematic Review and Meta-analysis
But flooding the blood with BHB from a bottle is metabolically very different from generating it through fasting or carbohydrate restriction. When you produce ketones endogenously, the entire hormonal landscape shifts: insulin drops, glucagon rises, fat tissue releases fatty acids, and the liver upregulates a whole suite of enzymes. Drinking a ketone ester raises BHB without any of those upstream changes. This is likely why exogenous ketones did not increase energy expenditure the way a ketogenic diet did in the study mentioned above. Whether they still deliver the signaling benefits of BHB, like HDAC inhibition and anti-inflammatory effects, is an active research question without a definitive answer yet.
An Evolutionary Perspective on Ketone Metabolism
Humans have unusually large brains for their body size, and those brains are energy-hungry. The ability to produce and use ketones efficiently may have been one of the adaptations that made this brain expansion possible. Throughout human evolution, unpredictable food availability meant long gaps between meals, and ketone bodies provided a way to keep the brain fueled when glucose from food was unavailable.21PubMed Central. Brain Ketone Bodies in Health, Evolution and Disease
This connection between fat, ketones, and the brain starts before birth. Human infants are born with a unique and substantial layer of body fat compared to other primates. This fat layer develops during the third trimester and serves as a reservoir for fatty acids that can be converted into ketones to fuel the infant’s rapidly growing brain well into childhood.22PubMed. Energetic and nutritional constraints on infant brain development: implications for brain expansion during human evolution Newborn humans are, in a sense, running on a partly ketogenic metabolism by design. The brain’s capacity to switch to ketone fuel is not an emergency workaround; it is a deeply embedded feature of human biology that has been under selection pressure for millions of years.
A Recently Discovered Ketone Metabolite
Research published in 2024 revealed that BHB does not just get burned for energy or act on gene expression. An enzyme called CNDP2, previously known for producing a molecule called Lac-Phe after exercise, also conjugates BHB with the amino acid phenylalanine to create a new metabolite called BHB-Phe. In laboratory experiments, cells expressing CNDP2 showed more than 140-fold greater production of BHB-Phe compared to controls. The enzyme was highly specific: it worked with BHB and phenylalanine but showed little or no activity with most other amino acids or with organic acids of different chain lengths.23Cell. A ketone metabolite regulates body weight and energy balance Early evidence suggests BHB-Phe plays a role in regulating body weight and energy balance, adding yet another layer to the expanding portfolio of what ketone bodies do in the body. The discovery underscores how much remains unknown about ketone metabolism despite decades of study.