Almanac A1C

Stress Hormones as Metabolic Allies: How Cortisol and Catecholamines Drive Ketogenesis and Metabolic Resilience in the Modern World

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dr. Karunia Valeriani Japar

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Introduction

Metabolic health lies at the heart of disease prevention and longevity, yet many underlying physiological mechanisms remain misunderstood or oversimplified in clinical practice. Among these, the interplay between stress hormones and metabolic pathways such as ketogenesis deserves special attention, especially in the context of modern lifestyles characterized by both chronic stress and dietary abundance. Traditionally, stress hormones, primarily cortisol, epinephrine, and norepinephrine are regarded as biochemical agents of harm, associated with disrupted glucose regulation, insulin resistance, adverse health outcomes. However, emerging evidence suggests that these “stress hormones” may play adaptive, even beneficial roles when activated appropriately in the context of metabolic adaptation processes like fasting, exercise, and carbohydrate restriction.

Ketogenesis, the metabolic pathway enabling the production of ketone bodies from fatty acids, is central to the body’s ability to maintain energy and cognitive function in the absence of dietary carbohydrates. This pathway is tightly regulated by hormonal signals, many of which are triggered by acute physiological stressors, thereby reframing the role of stress hormones as potent drivers of metabolic flexibility and resilience. Insights from recent translational research and clinical observations are challenging conventional paradigms, highlighting the context dependent effects where stress physiology can in fact support metabolic health, improve energy substrate utilization, and offer clinical value in the prevention of metabolic disease.

This article critically examines the dual role of stress hormones in regulating ketogenesis, exploring the underlying biochemistry, physiological scenarios, and clinical implications for disease prevention. By integrating the latest scientific findings and expert perspectives, we seek to answer the provocative question: Can stress hormones actually be good for you?

Understanding Stress Physiology

Definition Of Stress In Biological Terms

Stress, in biological terms, represents a state of threatened homeostasis triggered by intrinsic or extrinsic adverse forces known as stressors. Homeostasis refers to the body’s ability to maintain relatively constant internal conditions essential for survival, including core parameters such as pH, body temperature, oxygen saturation, and blood glucose levels. When an organism encounters a stressor, whether physical, psychological, or environmental, the body initiates a complex repertoire of physiological and behavioural responses aimed at maintaining or reestablishing optimal equilibrium, a state referred to as eustasis [1,2,3].

The concept of allostasis has been introduced to complement and clarify the notion of homeostasis. While homeostasis focuses on maintaining stability through preset physiological parameters, allostasis refers to achieving stability through change, the dynamic adjustment of pericellular parameters such as blood pressure, heart rate, and hormone levels in response to environmental demands. These allostatic processes actively maintain homeostasis over time and represent the body’s capacity for adaptation. The adaptive stress response depend upon a highly interconnected neuroendocrine, cellular, and molecular infrastructure collectively termed the stress system, with key components including the hypothalamic-pituitary-adrenal axis and the autonomic nervous system [1,3].

Acute Vs Chronic Stress

The distinction between acute and chronic stress is fundamental to understanding their divergent effects on metabolic health and physiological function. Acute stress refers to a brief, time-limited exposure to a stressor, typically lasting minutes to hours, which elicits rapid physiological responses designed to promote survival and adaptation. During acute stress, the body activates the sympathetic-adreno-medullary system and the HPA axis to mobilize energy resources, enhance alertness, increase cardiovascular output, and redirect blood flow to vital organs and skeletal muscles. These responses are generally adaptive and self-limiting, with negative feedback mechanisms rapidly terminating the stress response once the stressor subsides [4,5,6,7].

In contrast, chronic stress involves repeated or prolonged exposure to stressors over days, weeks, or months, resulting in sustained activation of stress-responsive systems. Chronic stress can lead to maladaptive changes in hormone secretion patterns, metabolic dysregulation, and pathological outcomes. Studies have demonstrated that chronic repeated stress decreases body weight, alters caloric efficiency, and increases brown adipose tissue activity in rodent models, effects that differ markedly from those observed with acute stress exposure. Furthermore, rats exposed to chronic stress exhibit metabolic adaptation over time, becoming less sensitive to the anorexigenic and weight lowering effects of subsequent stressors. Importantly, chronic stress is associated with persistent elevation of cortisol levels,  which can lead to insulin resistance, visceral adiposity, hypertension, immune suppression, and increased risk of metabolic syndrome and cardiovascular disease [1,3,4,8].

Sympathetic Nervous System And Catecholamines

The sympathetic nervous system constitutes one of the two major divisions of the autonomic nervous system and serves as the rapid response arm of the stress system. When a stressor is perceived, the sympathetic nervous system is immediately activated, triggering the release of catecholamines, primarily norepinephrine and epinephrine from sympathetic nerve terminals and the adrenal medulla. Norepinephrine is released predominantly from sympathetic nerve endings that innervate blood vessels and organs such as the heart and kidneys, while epinephrine is secreted mainly by chromaffin cells in the adrenal medulla directly into the circulation, with approximately 80 epinephrine and 20% norepinephrine being released from these cells [6,7].

Catecholamines exert their diverse physiological effects by binding to adrenergic receptors, the alpha and beta adrenoceptors, which are G-protein coupled receptors present throughout the body. Activation of these receptors initiates intracellular signalling cascades involving cyclic adenosine monophosphate, resulting in increased heart rate and cardiac output, elevated blood pressure through vasoconstriction, bronchodilation to enhance oxygen intake, stimulation of hepatic glycogenolysis and glucogenesis to increase blood glucose availability, lipolysis to mobilize fatty acids, enhanced skeletal muscle blood flow, and increased thermogenesis. Additionally, catecholaminergic activation promotes behavioural changes including heightened arousal, alertness, vigilance, focused attention, and analgesia. These coordinated responses collectively constitute “fight or flight” response, preparing the organism to confront or escape from perceived threats [6,9].

Plasma levels of norepinephrine and epinephrine are commonly assessed to elucidate the role of sympathetic nervous system activation in biological stress pathways. While catecholamines do not cross the blood-brain barrier, peripheral norepinephrine and epinephrine have been shown to produce centrally mediated effects on learning, memory, and emotional processing. It is important to note that high plasma norepinephrine levels do not always correlate linearly with sympathetic nerve traffic, and interpretation of catecholamine measurements must consider the context, timing of sampling, and individual characteristics [10].

Hypothalamic-Pituitary-Adrenal (HPA) Axis And Cortisol

The HPA axis represents the primary neuroendocrine system responsible for coordinating the body’s slower, more sustained response to stress. The HPA axis operates through a cascade of hormonal signals initiated in the brain and culminating in the release of glucocorticoids, primarily cortisol in humans. When stress is perceived, the paraventricular nucleus of the hypothalamus synthesizes and secretes corticotropin releasing hormone and arginine vasopressin into the hypophyseal portal circulation. These neuropeptides travel to the anterior pituitary gland, where they bind to receptors on corticotrope cells, stimulating the synthesis and secretion of adrenocorticotropic hormone into the systemic circulation [1,5,9,12].

Adrenocorticotropic hormone subsequently reaches the adrenal cortex, where it engages melanocortin type 2 receptors in the zona fasciculata, triggering the rapid biosynthesis and secretion of cortisol from cholesterol. Cortisol is a pleiotropic hormone with receptors in virtually all cell types, exerting widespread effects on metabolism, immunity, cardiovascular function, and behaviour. In the context of acute stress, cortisol mobilizes energy resources by stimulating hepatic gluconeogenesis and glycogenolysis, increasing blood glucose availability to fuel vital organs and tissues. Cortisol also enhances the responsiveness of blood vessels to catecholamines, supporting cardiovascular adaptations to stress. Furthermore, cortisol modulates immune function by suppressing proinflammatory cytokine production and adaptive immune responses, thereby preventing excessive inflammation that could be detrimental during stress [9,11,12,13].

The HPA axis is tightly regulated by negative feedback mechanisms, where cortisol acts on glucocorticoid receptors in the hypothalamus, pituitary and higher brain centres to inhibit further corticotropin releasing hormone and adrenocorticotropic hormone secretion. This feedback loop is essential for limiting the duration of cortisol exposure and preventing the catabolic and metabolic consequences of chronic hypercortisolaemia. Cortisol secretion also follows a circadian rhythm, with peak levels occurring in the early morning before waking and nadir levels in the evening, supporting the sleep wake cycle and facilitating stress recovery. Dysregulation of the HPA axis, whether sleep wake cycle and facilitating stress recovery. Dysregulation of the HPA axis, whether through hyper or hypoactivation is implicated in numerous, stress related pathologies, including metabolic syndrome, major depression, anxiety disorders, and neurocognitive decline [9,11,12,13]..

Metabolic Adaptation: Reframing Stress Hormones

Why “Stress Hormones” Are Better Called “Metabolic Adaptation Hormones”

The traditional classification of hormones like cortisol, epinephrine, and norepinephrine as “stress hormones” originates from their central role in the body’s acute response to threats, often summarized as the “fight or flight” reaction. However, expanding research into endocrinology and metabolic physiology suggests that these hormones play much broader roles in orchestrating adaptive responses to environmental and internal stimuli, beyond mere psychological or physical stress. In metabolic contexts, such as fasting, exercise, or carbohydrate restriction, these hormones facilitate the mobilization of energy substrates, promote gluconeogenesis, lipolysis and ketogenesis, and optimize cellular function for survival and resilience. Thus, it is more accurate to reframe them as “ metabolic adaptation hormones,” emphasizing their function in enabling the body to cope with and thrive under changing metabolic demands. This paradigm shift recognizes their core role in supporting physiological adaptation and metabolic homeostasis, rather than simply serving as marker of distress or pathology [1,6,14].

Hormonal Responses To Acute Versus Chronic Stress

The endocrine response to stress varies significantly depending on the duration and intensity of the stressor, acute versus chronic. Acute stress triggers rapid activation of the sympathetic adrenal medullary system and HPA axis, resulting in transient of elevations of catecholamines (epinephrine, norepinephrine) and cortisol. These hormones facilitate immediate physiological adaptations: increased blood glucose through hepatic glycogenolysis, heightened lipolysis, accelerated heart rate, and increased blood flow to muscles, all enhancing alertness and physical readiness for “ fight, or flight”. During acute stress, these hormonal surges are generally adaptive and reversible, supporting homeostatic recovery once the stimulus resolves [15].

By contrast, chronic stress involves prolonged activation of these same hormonal pathways, leading to persistent secretion of stress hormones. Chronic elevation of cortisol and catecholamines disrupts feedback regulation, contributes to insulin resistance, visceral adiposity, immunosuppression, and may result in maladaptive neurochemical changes. Over time, chronic stress undermines metabolic health increasing risk for cardiometabolic and neuropsychiatric conditions. Thus, while acute hormonal responses act as beneficial mediators of adaptation, chronic overexposure shifts their actions toward pathology [1,6,16].

Stress Signals During Fasting, Exercise, And Low Carb Eating

Metabolic adaptation hormones are prominently involved in physiological stress states such as fasting, exercise, and carbohydrate restriction. During fasting, falling blood glucose and insulin levels signal energy deprivation, activating sympathetic nervous system output and the HPA axis. Cortisol and catecholamines rise, promoting lipolysis, increasing circulating non-esterified fatty acids, and glycerol (energy substrate for gluconeogenesis and ketone production), and maintaining blood glucose for critical tissues. These same pathways operate during exercise, where muscular work creates energetic demand, driving release of epinephrine, norepinephrine, and cortisol to measure availability of glucose, fatty acids, and ketones through enhanced substrate mobilization and utilization. Adaptation to regular exercise, as well as repeated fasting cycles, increases tissue sensitivity to these hormones, improving metabolic flexibility and resilience [17].

In low carbohydrate, high fat diets and ketosis, insulin levels decrease and metabolic adaptation hormones predominate, further enhancing fat mobilization and ketone production. This shifts favours of lipid-derived fuels, especially by muscle and brain, and facilitates improved metabolic outcomes in the context of weight management, glycemic control, and disease prevention. Importantly, the context of these stress signals, in controlled, intermittent exposures such as fasting, exercise, or nutritional ketosis, supports beneficial remodelling of metabolism, whereas chronic, uncontrolled stress exposure may be detrimental [18,19,20].

Biochemistry Of Ketogenesis

Fat Mobilization And Lipolysis

Ketogenesis begins with the mobilization of fatty acids from adipose tissue through the process of lipolysis, the sequential hydrolysis of triacylglycerols stored in lipid droplets within adipocytes. Lipolysis is tightly regulated by hormonal and neuronal signals and involves three primary neutral lipases: adipose triglyceride lipase, hormone-sensitive lipase, and monoglyceride lipase. Adipose triglyceride lipase initiates the first and rate-limiting step, catalysing the hydrolysis of triglycerides to diglycerides and releasing one molecule of free fatty acid. Hormone-sensitive lipase then hydrolyses diglycerides to monoglycerides, releasing a second free fatty acid, and monoglyceride lipase completes the process by hydrolysing monoglycerides to glycerol and a third free fatty acid [21,22,23].

The mobilization of these free fatty acids, also termed non-esterified fatty acids, is robustly stimulated by catecholamines, particularly epinephrine and norepinephrine, which bind to beta-adrenergic receptors on adipocytes and activate protein kinase A signalling cascades. Conversely, insulin potently inhibits lipolysis, and its suppression during fasting or carbohydrate restriction removes this brake, enabling fat mobilization. Once released into circulation, free fatty acids are transported to peripheral tissues, including the liver, where they undergo beta-oxidation to generate acetyl-CoA [21,22,23,24].

Role Of Liver Mitochondria

The liver plays a central and indispensable role in ketogenesis, as it is the primary site where ketone bodies are synthesized within mitochondria. Free fatty acids are transported into hepatocytes and subsequently into the mitochondrial matrix via the carnitine shuttle system, which involves carnitine palmitoyltransferase-1 at the outer mitochondrial membrane. Once inside the mitochondria, fatty acids undergo beta-oxidation, a cyclical process in which two-carbon units are sequentially cleaved from the fatty acyl-CoA chain, generating acetyl-CoA, NADH, and FADH₂. The high rate of beta-oxidation during fasting or low-carbohydrate states produces an abundance of acetyl-CoA in hepatic mitochondria [24,25].

Under conditions where the tricarboxylic acid cycle is operating at reduced capacity due to depletion of oxaloacetate for gluconeogenesis or a highly reduced mitochondrial redox state, acetyl-CoA accumulates and is diverted toward ketone body synthesis. Importantly, the liver lacks the enzyme succinyl-CoA:3-ketoacid CoA-transferase, which is required for ketone body utilization; thus, hepatic mitochondria produce but do not oxidize ketone bodies, ensuring their export to extrahepatic tissues [25,26].

Key Molecules: Triglycerides, Free Fatty Acids, Acetyl-Coa, Oxaloacetate

Triglycerides are the storage form of lipids in adipose tissue and represent the ultimate source of carbon for ketogenesis. Upon lipolysis, triglycerides yield three free fatty acids and one glycerol molecule. Free fatty acids are transported via albumin in the bloodstream to the liver, where they are activated to fatty acyl-CoA molecules and subsequently oxidized [21,22,24].

Acetyl-CoA is the central metabolic intermediate derived from beta-oxidation of fatty acids and serves as the direct substrate for ketone body synthesis. Under normal postprandial conditions, acetyl-CoA enters the tricarboxylic acid cycle by condensing with oxaloacetate to form citrate, which is then oxidized to generate ATP, NADH, and FADH₂. However, during fasting or carbohydrate restriction, oxaloacetate is preferentially diverted from the tricarboxylic acid cycle toward gluconeogenesis to maintain blood glucose levels. This withdrawal of oxaloacetate limits citrate synthase flux, preventing acetyl-CoA from entering the cycle and instead promoting its conversion to ketone bodies [21,22,23,24].

Pathways: Gluconeogenesis Vs Ketone Synthesis

The competition between gluconeogenesis and ketone synthesis for oxaloacetate is a critical regulatory node in hepatic metabolism during fasting. Gluconeogenesis is the biosynthetic pathway that produces glucose from non-carbohydrate precursors such as lactate, glycerol, and amino acids, and it requires oxaloacetate as a key intermediate. During prolonged fasting or carbohydrate restriction, hepatic gluconeogenesis is upregulated to maintain normoglycemia, resulting in significant consumption of oxaloacetate [26,27,28].

When oxaloacetate availability is limited due to its diversion into gluconeogenesis, the condensation of acetyl-CoA with oxaloacetate via citrate synthase is reduced, and acetyl-CoA accumulates within mitochondria. This accumulation drives acetyl-CoA toward the ketogenic pathway. The first committed step of ketogenesis is the condensation of two acetyl-CoA molecules by thiolase to form acetoacetyl-CoA. Acetoacetyl-CoA is then condensed with another acetyl-CoA molecule by HMG-CoA synthase 2, the rate-limiting enzyme of ketogenesis, to generate 3-hydroxy-3-methylglutaryl-CoA. HMG-CoA lyase subsequently cleaves HMG-CoA to produce acetoacetate, the first ketone body. Acetoacetate can be reduced to beta-hydroxybutyrate by beta-hydroxybutyrate dehydrogenase using NADH, or it can spontaneously decarboxylate to form acetone, which is exhaled or excreted [24,25,29,30,31].

Thus, the metabolic fate of acetyl-CoA, whether it enters the tricarboxylic acid cycle or the ketogenic pathway depends critically on the availability of oxaloacetate and the relative activity of gluconeogenesis versus ketone synthesis [26] .

How Ketones Fuel The Brain And Muscles

Ketone bodies, primarily beta-hydroxybutyrate and acetoacetate are water-soluble, lipid-derived fuels that can be efficiently transported through the bloodstream and readily cross the blood-brain barrier via monocarboxylate transporters. This characteristic makes them uniquely valuable as an alternative energy source for the brain during periods of glucose scarcity, such as prolonged fasting, starvation, or adherence to a ketogenic diet [32,33] .

Once ketone bodies reach extrahepatic tissues, including the brain and skeletal muscle, they are taken up by cells and transported into mitochondria. Beta-hydroxybutyrate is first oxidized back to acetoacetate by beta-hydroxybutyrate dehydrogenase, regenerating NADH. Acetoacetate is then converted to acetoacetyl-CoA by succinyl-CoA:3-ketoacid CoA-transferase, the rate-limiting enzyme for ketone body utilization. Acetoacetyl-CoA is subsequently cleaved by thiolase to yield two molecules of acetyl-CoA, which enter the tricarboxylic acid cycle for oxidation, generating ATP, NADH, and FADH₂ [24,25,32,34]          .

The brain can derive up to 60% of its energy requirements from ketone bodies during prolonged ketosis. In skeletal muscle, ketone body oxidation is significantly upregulated during fasted exercise, with utilization rates increasing nearly fivefold compared to resting conditions. Ketone bodies also exert metabolic preference over glucose; when both substrates are available, ketone bodies are preferentially oxidized, reducing glycolytic flux and promoting fat-based metabolism. This metabolic flexibility supports energy homeostasis, spares glucose for critical tissues, and enhances endurance and cognitive performance during periods of reduced carbohydrate availability [33,35].

Hormonal Regulation Of Ketogenesis

Epinephrine And Norepinephrine

Epinephrine and norepinephrine, collectively known as catecholamines, are potent stimulators of lipolysis and play critical roles in initiating the metabolic cascade that culminates in ketogenesis. These hormones are released from the adrenal medulla and sympathetic nerve terminals, respectively, particularly during stress, fasting, and exercise. Catecholamines exert their effects by binding to beta-adrenergic receptors on the surface of adipocytes, activating adenylyl cyclase and increasing intracellular cyclic adenosine monophosphate concentrations, which subsequently activates protein kinase A. Activated protein kinase A phosphorylates hormone-sensitive lipase and perilipin, promoting the translocation of lipases to lipid droplets and facilitating the sequential hydrolysis of triglycerides into free fatty acids and glycerol [21,24,36,37].

Studies in conscious dogs demonstrated that infusion of norepinephrine at physiological stress levels caused sustained 50% increases in glycerol and nonesterified fatty acid concentrations, with corresponding elevations in ketone body production. Epinephrine infusion produced an even more pronounced 82% rise in glycerol levels within 30 minutes, although this response was not sustained over time. Importantly, while catecholamines robustly stimulate lipolysis, they do not directly influence hepatic ketogenesis at circulating levels typical of physiological stress. Rather, their ketogenic effect is mediated indirectly through the increased availability of free fatty acids, which serve as the primary substrate for beta-oxidation and subsequent ketone body synthesis in hepatic mitochondria. Unlike other hormones, catecholamines are uniquely capable of inducing lipolysis even in the presence of insulin, making them especially important during acute stress when rapid substrate mobilization is required [21,36,38]

Cortisol

Glucagon has historically been considered a primary ketogenic hormone due to its well-established role in promoting hepatic glucose production and lipid oxidation. Glucagon is secreted by pancreatic alpha cells in response to low blood glucose levels and acts on hepatocytes to increase glycogenolysis, gluconeogenesis, and fatty acid oxidation. In isolated hepatocytes, glucagon potently increases cyclic adenosine monophosphate signalling, which has been tied to both lipid and glucose metabolism, and stimulates ketone body production [24,39,40].

However, recent evidence challenges the dogma that glucagon is necessary or sufficient for ketogenesis under physiological conditions. Studies using glucagon receptor knockout mice demonstrated that loss of glucagon signalling does not prevent the increase in ketone production during fasting or in response to sodium-glucose cotransporter 2 inhibitors. These findings revealed that glucagon’s ketogenic effects are largely dependent on its insulinotropic actions on pancreatic beta cells, which can mask or limit any direct hepatic ketogenic activity. Importantly, glucagon is only capable of modestly stimulating ketone production when insulin signalling is completely abolished, such as in severe diabetic ketoacidosis. Under normal physiological conditions, the insulin secreted in response to glucagon exerts potent antilipolytic effects that prevent substrate mobilization from adipose tissue, thereby limiting ketogenesis. Thus, while glucagon contributes to the metabolic milieu favouring ketogenesis by enhancing hepatic fatty acid oxidation, it is neither necessary nor sufficient for physiological or pharmacologically induced ketosis [39,40].

Glucagon

Glucagon has historically been considered a primary ketogenic hormone due to its well-established role in promoting hepatic glucose production and lipid oxidation. Glucagon is secreted by pancreatic alpha cells in response to low blood glucose levels and acts on hepatocytes to increase glycogenolysis, gluconeogenesis, and fatty acid oxidation. In isolated hepatocytes, glucagon potently increases cyclic adenosine monophosphate signalling, which has been tied to both lipid and glucose metabolism, and stimulates ketone body production [39].

However, recent evidence challenges the dogma that glucagon is necessary or sufficient for ketogenesis under physiological conditions. Studies using glucagon receptor knockout mice demonstrated that loss of glucagon signalling does not prevent the increase in ketone production during fasting or in response to sodium-glucose cotransporter 2 inhibitors. These findings revealed that glucagon’s ketogenic effects are largely dependent on its insulinotropic actions on pancreatic beta cells, which can mask or limit any direct hepatic ketogenic activity. Importantly, glucagon is only capable of modestly stimulating ketone production when insulin signalling is completely abolished, such as in severe diabetic ketoacidosis. Under normal physiological conditions, the insulin secreted in response to glucagon exerts potent antilipolytic effects that prevent substrate mobilization from adipose tissue, thereby limiting ketogenesis. Thus, while glucagon contributes to the metabolic milieu favouring ketogenesis by enhancing hepatic fatty acid oxidation, it is neither necessary nor sufficient for physiological or pharmacologically induced ketosis [21,24,30].

Growth Hormone And Others

Growth hormone is a potent regulator of lipid metabolism with significant lipolytic and ketogenic actions. The most immediate effect of growth hormone administration is a substantial increase in circulating free fatty acids within 1 to 2 hours, reflecting robust stimulation of adipose tissue lipolysis. Growth hormone stimulates lipolysis by activating hormone-sensitive lipase and increasing its translocation to lipid droplets, leading to enhanced breakdown of triglycerides and release of free fatty acids and ketone bodies into circulation. Importantly, fasting-induced elevation of growth hormone secretion is a major physiological mechanism underlying the starvation-induced increase in lipolysis and ketogenesis. Growth hormone also exerts metabolic effects that spare glucose and protein, and these actions depend critically on its ability to stimulate lipolysis [41,42].

Other hormones that contribute to ketogenesis include thyroid hormones and adrenocorticotropic hormone, both of which enhance lipolysis and increase the availability of free fatty acids for ketone body synthesis. Thyroid hormones increase basal metabolic rate and stimulate the breakdown of fat stores, while adrenocorticotropic hormone acts on the adrenal cortex to stimulate cortisol secretion, indirectly promoting ketogenesis through the mechanisms previously described [21,24].

Direct Neural Signalling And Organ Innervation

The regulation of ketogenesis and lipolysis extends beyond circulating hormones to include direct neural signalling through sympathetic and parasympathetic innervation of metabolic organs, including adipose tissue and the liver. The sympathetic nervous system maintains metabolic homeostasis by orchestrating the activity of adipose tissue, liver, pancreas, and other organs through direct neural input. Sympathetic nerve fibres establish neuro-adipose junctions at adipocytes, allowing for precise local regulation of lipolysis through norepinephrine release. Activation of sympathetic outflow increases adipose tissue lipolysis, enhances hepatic glucose production, and modulates energy expenditure [44,45,46].

Recent studies have identified that short-chain fatty acids and ketone bodies directly regulate sympathetic nervous system activity via GPR41, a G-protein-coupled receptor highly expressed in sympathetic ganglia. Propionate, a major short-chain fatty acid, promotes sympathetic outflow via GPR41, while beta-hydroxybutyrate, a major ketone body, antagonizes GPR41 signalling and thereby suppresses sympathetic nervous system activity during fasting and ketogenic states. This feedback mechanism provides a direct metabolic link whereby ketone bodies themselves modulate neural control of energy expenditure and lipolysis.

The liver is predominantly innervated by sympathetic nerves, with minimal parasympathetic input. Electrical stimulation of hepatic sympathetic nerves has been shown to inhibit ketogenesis directly in perfused rat liver, independent of hormonal changes, suggesting that neural regulation of hepatic metabolism operates through distinct intracellular signalling pathways. Additionally, the liver-brain-adipose neural axis plays a critical role in metabolic homeostasis; when hepatic fat accumulation occurs, afferent vagal nerve signals are transmitted to the brain, which then activates sympathetic outflow to adipose tissue to enhance lipolysis. During starvation, activation of this neural axis accelerates fat utilization and ketone body production [47,48,49].

Leptin, an adipokine secreted proportionally to fat mass, acts on the central nervous system to increase sympathetic nerve activity directed toward adipose tissue, thereby stimulating lipolysis and ketogenesis. The lipolytic effects of leptin are mediated entirely by neuronal pathways, as selective denervation of adipose tissue prevents leptin-induced lipolysis. Leptin also modulates the plasticity of sympathetic innervation in adipose tissue and regulates hepatic lipid metabolism via the brain-vagus-liver axis. These findings underscore the essential role of neural innervation in coordinating hormonal and metabolic signals to fine-tune ketogenesis in response to changing physiological demands [44,47,50].

Acute Vs Chronic Stress: Metabolic Outcomes

Adaptive Benefits Of Acute Stress (Fasting, Exercise)

Acute stress responses, exemplified by short-term physiological events such as fasting and exercise, trigger rapid metabolic adaptations that are fundamentally protective and beneficial for human health. In these scenarios, activation of the sympathetic nervous system and the hypothalamic-pituitary-adrenal (HPA) axis leads to the prompt release of catecholamines (epinephrine, norepinephrine) and glucocorticoids (primarily cortisol), driving metabolic events including glycogenolysis, gluconeogenesis, and lipolysis. Fasting induces a marked shift from carbohydrate to fat utilization, increasing mobilization of fatty acids from adipose tissue and accelerating hepatic ketogenesis; this metabolic change provides energy substrates (notably ketone bodies) to vital organs like the brain and heart during glucose scarcity. Exercise similarly evokes a surge in catecholamines, fostering substrate mobilization to fuel muscle work and supporting metabolic flexibility. Studies show acute stress via exercise or fasting lowers body weight, blood pressure, and improves metabolic markers, consistent with adaptive survival mechanisms that promote resilience and health [4,6,51,52].

Risk And Pathophysiology Of Chronic Stress (Insulin Resistance, Metabolic Dysfunction)

Conversely, chronic stress defined as repeated or sustained physiological, psychological, or environmental stressor exposure profoundly disrupts metabolic homeostasis and is a significant risk factor for cardiometabolic pathology. Chronic activation of the HPA axis and persistent elevation of stress hormones, particularly cortisol, foster the development of insulin resistance, hyperglycemia, central adiposity, and ultimately metabolic syndrome. Pathophysiological mechanisms include cortisol-induced beta-cell dysfunction, impaired insulin sensitivity, and enhanced sympathetic outflow all promoting dysregulated glucose and lipid metabolism. Chronic stress triggers sustained production of pro-inflammatory cytokines, establishing a feedback loop between inflammation and insulin resistance that underpins type 2 diabetes and cardiovascular disease. Moreover, chronic stress is associated with increased feed intake and weight gain, as well as altered neuroendocrine and behavioural patterns, further compounding metabolic dysfunction. While acute stress-induced metabolic changes are often transient and self-limiting, chronic stress persistently alters metabolic set-points, driving maladaptive outcomes and promoting disease risk [4,53,54].

Contextual Effects: Why Stress Hormone Actions Depend On Biological And Lifestyle Context

The effects of stress hormones on metabolic outcomes are context-dependent are mediated by the nature, timing, and duration of stress exposure, as well as underlying biological and environmental variables. Short-term activation of the stress response mobilizes energy substrates for rapid adaptation and recovery (e.g., fasting or intermittent exercise), yielding metabolic improvements and health benefits. In contrast, chronic, unremitting stress results in sustained hypersecretion of cortisol and catecholamines, overwhelming feedback systems and shifting hormone actions from adaptive to maladaptive. Individual differences including genetics, age, nutrition, comorbidities, microbiome composition, and lifestyle factors like sleep, physical activity, and social support further modulate the balance between beneficial and detrimental stress hormone effects. Favourable modifications in stressors, behavioural interventions, and appropriate cycles of stress exposure can promote resilience and minimize disease risk, whereas persistent allostatic overload undermines homeostasis and drives metabolic dysfunction [6,52,54,55,56].

Clinical And Practical Implications

Application For Metabolic Disease Prevention

The utilization of carbohydrate-restricted diets and therapeutic fasting protocols has emerged as a practical strategy for metabolic disease prevention and intervention. Evidence increasingly supports the effectiveness of ketogenic diets (KD) in improving clinical markers among individuals with insulin resistance, metabolic syndrome, and type 2 diabetes, such as reducing fasting glucose, insulin requirements, and inflammatory markers, while enhancing ketone body metabolism and cardiometabolic resilience. The metabolic shift toward fat and ketone utilization reduces adiposity and improves glycemic control, with added anti-inflammatory effects that further modulate obesity-related comorbidities. Both clinical trials and real-world studies highlight that application of intermittent fasting or KD can achieve sustained benefits for weight management, glycemic control, cardiovascular risk, and potentially for other pro-inflammatory or metabolic conditions [32,57,58,59].

Relevance To Carb Restriction And Fasting Protocols

Restriction of dietary carbohydrates initiates a distinct metabolic response that underpins the benefits of fasting and KD. Studies demonstrate that it is the absence of carbohydrates, rather than general caloric deprivation per se—that triggers lipolysis, hepatic fatty acid oxidation, and ketogenesis, crucial for adaptation to short-term fasting. Periodically lowering carbohydrate intake, even without extreme calorie restriction, improves metabolic markers, shifts substrate preference from glucose to fat, and may make fasting protocols more tolerable and sustainable for diverse populations. This flexibility expands clinical utility for managing obesity, diabetes, and metabolic syndrome and may enhance adherence to dietary interventions [60,61].

Electrolyte Management In Ketosis

The induction of ketosis, whether through KD, fasting, or exogenous ketones, necessitates diligent electrolyte management in clinical practice. Ketosis and especially diabetic ketoacidosis (DKA) can alter fluid balance and lead to disturbances in blood sodium, potassium, magnesium, and phosphate, all of which require careful monitoring. Current management protocols emphasize hydration with isotonic saline, potassium supplementation prior to insulin therapy, and ongoing metabolic surveillance throughout the transition into and out of ketosis. Effective correction of electrolyte imbalances is critical for safety, symptom management, and optimal clinical outcomes, from ambulatory nutritional ketosis to emergency care for DKA [62].

Use Of Exogenous Ketones

Exogenous ketone supplementation, primarily in the form of ketone salts and esters offers a promising adjunct for manipulating metabolism in both research and therapeutic settings. Human and animal studies suggest that oral exogenous ketones can acutely elevate blood β-hydroxybutyrate and lower glucose, with reported benefits in cognitive performance, cardiovascular metabolism, and as an anti-inflammatory agent. Use cases include diabetes, neurological diseases, and heart failure, as well as performance supplementation and mitigating symptoms during the initial adaptation to KD (“keto flu”). However, long-term safety, metabolic interactions, and cardiovascular effects require further study. Continuous ketone monitoring, palatable formulations, and tailoring to individual metabolic states represent future directions [63,64,65].

Conclusion

The dynamic interplay between stress hormones and ketogenesis reframes our understanding of both physiological adaptation and the pathophysiology of modern metabolic disease. Traditionally considered detrimental, hormones such as cortisol, epinephrine, and norepinephrine play essential roles in metabolic adaptation, especially under conditions of acute stressors like fasting, exercise, and carbohydrate restriction. These “metabolic adaptation hormones” orchestrate substrate mobilization, enable ketone body production, and support metabolic flexibility functions that are foundational for survival and optimal health in environments of nutritional flux.

When activated in controlled, intermittent patterns, the stress response supports resilience: promoting fat utilization, maintaining brain and muscle energy supply, and improving glycemic control. Clinically, leveraging this knowledge through carbohydrate restriction, fasting protocols, and even exogenous ketone supplementation holds significant promise in preventing and managing metabolic disorders, including insulin resistance and type 2 diabetes.

However, the biological and clinical consequences of stress hormone action are highly context-dependent. Chronic, unremitting stress distinct from acute adaptive episodes drives sustained hypersecretion of these hormones, resulting in insulin resistance, visceral adiposity, inflammation, and metabolic dysfunction. Thus, the same physiological systems that underpin evolutionary fitness can, under conditions of persistent modern stress, contribute to the epidemic of metabolic disease.

Ultimately, the integration of mechanistic insights, translational research, and individualized interventions underscores a paradigm shift: stress hormones, when properly harnessed, serve as potent allies in metabolic health rather than inevitable harbingers of disease. Future research and preventive strategies should focus on context, timing, and the cyclical nature of metabolic adaptation to truly unlock the therapeutic power of ketogenesis and stress physiology for modern medicine.

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