Search Results (461)

A 65-year-old man with type 2 diabetes presented with abdominal pain. Although he had no typical reflux symptoms such as heartburn or acid regurgitation, esophagogastroduodenoscopy (EGD) showed findings suggestive of reflux esophagitis, and proton pump inhibitor therapy was initiated. Two months later, he was admitted with intractable vomiting. EGD demonstrated diffuse circumferential mucosal injury without black discoloration, predominantly in the distal esophagus. These findings were interpreted as severe reflux esophagitis (Los Angeles grade D; RE-D). Symptoms improved with supportive care, glycemic control, and continued PPI therapy; follow-up EGD showed marked improvement. Six months later, he re-presented with identical symptoms and endoscopic findings. Laboratory testing confirmed diabetic ketoacidosis (DKA), with ketonuria, elevated total ketone bodies (2469 µmol/L), and high-anion gap metabolic acidosis (anion gap 17.2 mEq/L). The diagnosis was revised to DKA-associated acute esophageal mucosal lesion (AEML). He improved with fluid resuscitation and insulin therapy, and medication adherence was reinforced. Follow-up EGD showed complete healing without recurrence. AEML has been proposed as a spectrum that includes acute esophageal necrosis (AEN; “black esophagus”) and esophagitis without black-appearing mucosa. This case highlights a diagnostic pitfall in which DKA-associated AEML without black discoloration may be misattributed to severe reflux esophagitis. When the clinical presentation or endoscopic appearance is severe or atypical, clinicians should consider AEML and evaluate for underlying systemic precipitants. Full article

Background/Objectives: Weight loss and hypermetabolism are negative prognostic factors in amyotrophic lateral sclerosis (ALS). Ketone bodies (β-hydroxybutyrate, βHB) as high-energy substrates may compensate for this energy deficit, since a ketogenic diet (KD) has been shown to increase survival and stabilize body weight in the SOD1 mouse model. In this case series, we tested exogenous ketone salts (KS), ketone esters (KE), and a KD, in patients with ALS and in healthy subjects to identify novel therapeutic interventions for subsequent clinical studies. Methods: KS (KetoForce^® (KetoSports, Frisco, TX, USA)) were tested in healthy subjects (11.7 g and 15.6 g βHB) and patients (15.6 g βHB 3×/day over 3 days). KE (KE4^® (KetoneAid, Falls Church, VA, USA)) containing 10.0 g βHB were applied in healthy subjects (once) and in patients (3×/day over 2 days). For the KD, KetoCal^® 2.5:1 LQ MCT MF Vanilla (Nutricia, Frankfurt, Germany) was applied via percutaneous endoscopic gastrostomy over four weeks. Regular capillary βHB measurements were conducted, and adverse events were recorded. Results: Between January 2021 and March 2025, we treated nine patients with ALS and two healthy subjects at the Department of Neurology of Ulm University, Germany. KE and KS increased βHB temporarily. However, the elevation was more pronounced following KE (maximum 2.2–2.7 mmol/L vs. 0.8–1.2 mmol/L). The KD increased βHB levels continuously with nighttime fluctuations. No adverse events occurred under KE. KS caused diarrhea in 3/5 patients and 1/2 healthy subjects. The KD was well tolerated, with mild gastrointestinal symptoms occurring in all patients. Conclusions: All ketogenic approaches increased βHB blood levels. While the KD and KE provided good tolerability, KS caused significant gastrointestinal side effects. KD seems to be an interesting candidate for future clinical studies, as it prompted a long-term increase in βHB while providing satisfying tolerability. Since maintaining a KD long-term is difficult for oral-feeding patients, KE may constitute a feasible alternative. Full article

Background/Objectives: Intermittent fasting (IF) has been widely investigated for its metabolic effects, including improvements in insulin sensitivity, lipid metabolism, and inflammatory markers. However, its psychological and experiential dimensions remain comparatively underexplored. The present narrative review examines IF within a psychobiological framework, integrating evidence from metabolic science, neuroendocrinology, and affective neuroscience to explore its potential impact on emotional regulation and interoceptive processes. Methods: A structured narrative literature search was conducted across PubMed, Scopus, and Google Scholar, focusing on studies published between 2010 and 2025. Eligible studies included human and relevant animal research addressing metabolic, hormonal, interoceptive, and psychological responses to IF. Evidence was synthesized thematically to identify convergent mechanisms linking metabolic adaptations to emotional and regulatory outcomes. Results: Available literature suggests that IF is associated with a metabolic shift toward lipid utilization, characterized by increased ketone body production, particularly β-hydroxybutyrate. These adaptations appear to be accompanied by modulation of neuroendocrine pathways and may influence central nervous system functioning through mechanisms potentially related to neuroinflammation, mitochondrial efficiency, and synaptic plasticity. Emerging evidence further suggests that IF may modulate BDNF signaling and gut–brain axis activity, although direct causal pathways in humans remain to be established. At the psychological level, IF is associated with heterogeneous emotional outcomes: structured fasting protocols have been linked to modest improvements in perceived stress and mood in metabolically healthy individuals, whereas irritability, anxiety, or behavioral rigidity may emerge in those with pre-existing psychological vulnerabilities. Individual differences in interoceptive sensitivity, emotion regulation strategies, and moderating biological factors—including sex, circadian timing, and habitual physical activity—appear to influence these responses. Conclusions: Overall, IF may be conceptualized as a context-dependent psychobiological stressor whose effects extend beyond metabolic regulation to include interoceptive and emotional processes. These effects appear bidirectional, potentially promoting psychological resilience in some individuals while increasing the risk of affective destabilization or maladaptive behaviors in others. Current evidence remains limited by a lack of integrative and longitudinal studies combining metabolic and psychological measures. Future research adopting multidisciplinary approaches is needed to clarify the mechanisms underlying individual variability and to better define the potential benefits and risks of IF in both clinical and non-clinical populations. Full article

The brain has a higher energy demand per unit weight than any other organ in the body; however, links between metabolism, diet and neurological function have historically been underexplored. This partly stems from early assumptions that brain metabolism is primarily dependent on glucose and ketone bodies, whereas more recent evidence indicates broader metabolic flexibility and complex cell-type specialisation. In the past few decades, brain metabolism has become increasingly recognised as relevant to neurological and mental health, and many neurodegenerative disorders are accompanied by changes in brain energy utilisation. In parallel, epidemiological studies associate hypercaloric dietary patterns and metabolic disorders—particularly type-2 diabetes mellitus—with increased risk of later cognitive decline and sporadic Alzheimer’s disease, although causal pathways remain difficult to establish in humans. In this narrative review, we summarise selected findings linking “unhealthy” diets to synaptic function, focusing on synaptic plasticity, neuroinflammation and adult hippocampal neurogenesis, and we distinguish between evidence from human observational studies and mechanistic insights from animal and cellular models. We also discuss candidate mechanisms—including insulin resistance-linked signalling changes, lipid-driven inflammatory amplification, oxidative stress, and altered lipid handling—that may contribute to synaptic vulnerability. Finally, we outline translational considerations and key knowledge gaps (including physiological exposure levels and heterogeneity of experimental paradigms) that currently limit inference from preclinical models to clinical intervention. Full article

The growing demand for sustainable alternative proteins has intensified interest in fungal mycelia as a nutrient-dense biomass for food applications. This study compared Pleurotus ostreatus fruiting bodies with mycelia grown in liquid state on amaranth seed- and Bambara groundnut-based media, evaluating aroma-active volatiles and amino acid composition. Across 52 identified volatiles, C8 oxylipin-derived compounds dominated all matrices, with exceptionally high odour activity values (OAVs) for 1-octen-3-one (~4.1 × 10³), 3-octanone (~1.5 × 10³), 1-octen-3-ol (~8.3 × 10²) and 3-octanol (~5.3 × 10²). Amaranth-grown mycelia showed intensified mushroom/green/fatty notes due to elevated C8 ketones and unsaturated aldehydes, whereas Bambara-grown mycelia exhibited reduced C8 prominence and stronger malty, nutty and fermented nuances driven by Ehrlich-pathway aldehydes (e.g., 3-methylbutanal ~2.0 × 10³), with floral contributions from linalool (~3.8 × 10²). Mycelial protein contents ranged from 35.8 to 36.1 g/100 g (amaranth) and up to 38.2 g/100 g (Bambara), compared with 39.5 g/100 g in the fruiting body. Amino acid scores (AAS) identified cystine + methionine as limiting; mycelia exhibited higher AAS, with more indispensable amino acids exceeding reference requirements. Elevated glutamic and aspartic acids underscore the umami potential of the mycelial biomass. Overall, these plant-based substrates can strategically modulate both flavour chemistry and amino acid balance in P. ostreatus mycelia, supporting their use as nutritionally relevant, flavour-active ingredients in alternative protein and hybrid food systems. Full article

Using alternative energy sources for animal feed, such as hybrid corn varieties rather than genetically modified ones, is important. Therefore, the objective of this work was to assess the effects of supplementation at the end of gestation with Mexican Puma hybrid corn grain on productive and behavioral parameters in sheep. Twenty Columbia multiparous ewes were used; along with their diet, they were provided 600 g/animal/day of cracked corn during the last 20 days of pregnancy and the first week of lactation. The animals were divided into two groups: one fed commercial cracked corn (n = 11) and the other Mexican Tlaoli Puma hybrid cracked corn (n = 9). The productive parameters evaluated in the mother were: body weight, body condition score (BCS), feed intake, weight change, glucose, and ketone body levels, as well as the estimated quality of milk using Brix refractometer values on days 15 and 30 of lactation. In lambs, their rectal and external temperature was measured 2 h after birth, while their weight was measured 2 h after birth and every week until week 6 postpartum. Behavioral parameters were measured in the first two hours postpartum, including the maternal latency of cleaning the offspring, duration of the first cleaning episode, the lamb’s latencies of standing and nursing, and vocalizations in mother and lamb. Weight, BCS and weight change were not affected by the group but were affected by time; these parameters increased at the end of gestation and decreased significantly after delivery (p < 0.05). Ketone body levels were not affected by group or time (p > 0.05) and remained at low values. Glucose levels were not affected by the group but were affected by time; they increased significantly after birth (p < 0.05). Feed intake was similar in both groups (p > 0.05) and decreased as parturition approached (p < 0.05). The estimated milk quality was not affected by the group, nor by the time (p > 0.05). Mothers in both groups began cleaning their offspring within the first three minutes after giving birth and emitted a similar frequency of vocalizations (p > 0.05). However, mothers in the commercial maize group had a longer cleaning episode than those in the hybrid maize group (p < 0.05). The lambs in both groups stood up within the first half hour of birth, suckled before one hour after birth and emitted a similar number of vocalizations (p > 0.05). Temperatures and lamb weight were similar in both groups (p > 0.05); however, lamb weight increased as they aged (p < 0.05). It is concluded that supplementing sheep at the end of gestation with Puma hybrid Mexican corn grain can yield similar productive and behavioral benefits as supplementing with commercial grain. Full article

A high-fat (HF) diet disrupts metabolic homeostasis and impairs peripheral circadian rhythms in key metabolic tissues. β-Hydroxybutyrate (BHB), a major circulating ketone body, functions not only as an energy substrate but also as a signaling metabolite regulating nutrient-sensing and inflammatory pathways. However, its role in modulating metabolic–circadian interactions under conditions of nutrient excess remains unclear. In this study, we investigated whether BHB supplementation influences metabolic signaling and circadian clock oscillations in liver, skeletal muscle and adipose tissue under chow and HF conditions. Male C57BL/6 mice were fed chow or HF with or without BHB supplementation (500 mg/kg body weight in the diet) for 7 weeks. Metabolic parameters were assessed by indirect calorimetry, and tissues were collected every 4 h across the circadian cycle. HF feeding increased body weight and adiposity (p < 0.01), reduced AMPK activation, enhanced AKT/mTOR signaling, elevated NF-κB levels and dampened clock gene rhythmicity. BHB supplementation significantly decreased food intake in HF-fed mice (p < 0.01) and partially reversed several molecular alterations in a tissue-specific manner. In skeletal muscle and adipose tissue, BHB increased AMPK activation and reduced mTOR and NF-κB signaling (p < 0.05), whereas hepatic effects were more modest. Notably, BHB modulated circadian gene expression, restoring aspects of rhythmic amplitude and/or phase, particularly in adipose tissue. These findings may indicate that BHB supplementation modulates nutrient-sensing pathways and partially restores peripheral circadian rhythms under HF conditions. While some effects may be influenced by reduced energy intake, BHB may serve as a metabolic signal linking nutrient status to circadian regulation. Full article

Background/Objectives: The ketogenic diet (KD) has been shown to exert beneficial effects on human immunity by enhancing cytotoxic T lymphocyte function through metabolic reprogramming. However, strict dietary restrictions limit adherence and complicate its use in clinical practice. Exogenous ketone supplements have therefore been promoted as a more feasible alternative to elevate ketone body levels without the need for dietary changes. The objective of this study was to assess whether ketone salt or ketone ester supplementation can reproduce KD-mediated immunometabolic effects on CD8⁺ T cells in healthy individuals. Methods: In a prospective interventional study, healthy volunteers received either ketone salts (KS) or ketone esters (KE) for three weeks. Plasma β-hydroxybutyrate (BHB) concentrations were determined, and CD8⁺ T-cell cytokine secretion, functional responses, and mitochondrial energy metabolism were analyzed. In a subgroup, KS supplementation was combined with a carbohydrate-restricted, non-ketogenic diet. Results: While KS supplementation resulted in a short-lived increase in plasma BHB concentrations followed by increased BHB uptake in immune cells, KE supplementation led to more sustained plasma BHB levels, however, without detectable intracellular BHB accumulation. Neither intervention affected CD8⁺ T-cell cytokine production, functional capacity, or mitochondrial energy metabolism, and KS intake combined with a carbohydrate-restricted, non-ketogenic diet likewise did not alter CD8⁺ T-cell immunometabolic parameters. Conclusions: Transient elevation of circulating ketone body levels through supplementation seems insufficient to reproduce the immunometabolic effects of a KD, which likely require broader metabolic adaptations. Thus, the impact of exogenous ketones on adaptive immunity in healthy individuals appears limited. Full article

Sarcopenia, characterized by the progressive loss of skeletal muscle mass, strength, and function, represents a growing public health challenge in aging populations. Emerging mechanistic evidence suggests that ketogenic diets (KDs) and elevated circulating β-hydroxybutyrate (βOHB) levels may offer selective and context-dependent nutritional strategies to support muscle health during aging. This review summarizes current evidence on the effects of ketogenic diets and ketone body metabolism on muscle mass and function, with a focus on underlying molecular mechanisms and clinical relevance in older adults. βOHB acts not only as an alternative energy substrate but also as a signaling molecule, notably through histone deacetylase inhibition and modulation of inflammatory pathways. Nutritional ketosis in humans typically results in circulating βOHB concentrations of approximately 0.5–3.0 mM, which may be sufficient to engage some of these signaling pathways, although the extent of these effects in human tissues remains incompletely defined. Preclinical studies indicate that long-term ketogenic diets preserve muscle mass, strength, and mitochondrial function in aging models. Limited clinical evidence, largely derived from populations with sarcopenic obesity or metabolic comorbidities, suggests that protein-adequate ketogenic diets, when implemented as an adjunct to physical exercise, may help preserve fat-free mass and improve functional outcomes, while exogenous ketones show potential to augment post-exercise anabolic signaling. Overall, the integration of mechanistic and preliminary clinical data provides a supplementary and exploratory framework suggesting that ketogenic diets may represent a promising adjunctive strategy for sarcopenia prevention, although well-designed long-term randomized controlled trials are required to define their efficacy, safety, and optimal clinical application. Full article

Multiple sclerosis (MS) is characterized by progressive mitochondrial dysfunction affecting complexes I, III, and IV of the electron transport chain, contributing to axonal energy failure and neurodegeneration. This review examines the potential of combining β-hydroxybutyrate (βHB), epigallocatechin-3-gallate (EGCG), and ellagic acid (EA) as a multi-target therapeutic strategy to restore mitochondrial function in patients with MS. Experimental and clinical studies demonstrate that each compound exerts complementary mechanisms. Ketone bodies provide an alternative energy substrate and restore complex I activity via sirtuin-dependent pathways. EGCG acts predominantly at the peripheral level by reducing systemic inflammation and oxidative stress. EA-derived urolithins effectively cross the blood–brain barrier to directly enhance mitochondrial biogenesis and respiratory chain function in the central nervous system. Clinical trials have reported improvements in fatigue, cognition, mood, and muscle function following supplementation with these compounds. The convergence of their actions on energy restoration, reactive oxygen species reduction, and epigenetic modulation of protective pathways suggests their synergistic potential. Optimized delivery strategies, including exogenous ketone salts, liposomal EGCG, and microencapsulated EA, may overcome bioavailability limitations and interindividual variability in the gut microbiota metabolism. Full article

Ketone bodies (KBs) are the only energy substrates oxidized by the brain, whose concentration in the circulation can greatly increase when a physiological situation requires it. For example, when an adult human fasts for two days, circulating KBs rise twenty-fold from ~0.1 to ~2 mM. As a fuel, KBs provide the brain with acetyl-CoA that produces ATP or glutamate, notably in certain brain regions. Remarkably, KBs activate the expression of their own cerebral transporters and KB-utilizing enzymes so that circulating levels determine cerebral utilization of KBs. Throughout evolution, the energetic role of KBs has been crucial for the metabolic homeostasis of humans endowed with a large brain and facing unpredictable periods of food shortage. Paradoxically, the brain of modern, regularly fed humans whose ordinary blood KBs are ~0.1 mM, has access to much fewer circulating sources of energy than that of their distant ancestors. KBs can modify certain proteins post-translationally, for example, histones through lysine-butyrylation. KBs could act as short- or long-term epigenetic messengers. These properties of KBs might allow a fetus to directly sense maternal starvation and adapt their cerebral metabolism to this situation, possibly preparing for nutritional constraints in extra-uterine life. KB transcriptional and epigenetic properties could also enable the postnatal organism to retain a molecular memory of its own starvation episodes. No other energy substrate, such as glucose or lactate, has such capacities. Medicine turned its attention to KBs a century ago. Indeed, KBs are the only energy substrates whose circulating levels can be increased, and nutritional interventions can alter them under free-living conditions. This property opens broad prospects for ketogenic diets (KDs) to prevent or rescue neurodegenerative diseases characterized by glucose hypometabolism, notably Alzheimer’s disease (AD). However, KDs have not yet found real medical applications, for reasons that are discussed. Full article

The transition from energy sufficiency to deficiency triggers complex metabolic and immune adaptations that have traditionally been viewed through a reductionist pathological lens. During early lactation, coordinated mobilization of adipose tissue, muscle protein, and bone minerals supports milk synthesis, with ketogenesis specifically arising from hepatic oxidation of non–esterified fatty acids. This review introduces the Keto–Inflammatory Network (KIN), a novel framework positioning ketonemia as an evolutionarily conserved adaptive response rather than inherent metabolic dysfunction. The KIN integrates β–hydroxybutyrate (BHB) signaling with immune modulation, epigenetic regulation, circadian rhythms, and microbiota interactions. Through mechanisms including NLRP3 inflammasome inhibition, HDAC–mediated epigenetic modifications, and HCAR2 receptor activation, ketone bodies orchestrate anti–inflammatory responses while maintaining metabolic flexibility. Building upon important precedent work recognizing beneficial roles of ketones in ruminant metabolism, this review synthesizes recent advances in immunometabolism and systems biology into an integrated framework. The KIN encompasses calcium–ketone integration through the Calci–Keto–Inflammatory Code (CKIC), temporal regulation via the Ketoinflammatory Clock, and trans–kingdom signaling through microbiota interactions. In dairy cattle, this perspective reframes periparturient ketonemia as existing on a continuum from adaptive to pathological, with biological meaning determined by integrated metabolic–inflammatory patterns rather than absolute ketone concentrations. The CKIC paradigm, while requiring prospective validation, suggests novel therapeutic approaches leveraging ketone signaling for inflammatory diseases, autoimmune conditions, and metabolic disorders while challenging traditional threshold–based ketosis management strategies. This systems–level understanding opens new avenues for precision interventions that work with, rather than against, evolved adaptive mechanisms refined through millions of years of mammalian evolution. By distinguishing ketonemia (measurable ketone elevation) from pathological ketosis (dysregulated ketone accumulation), and by integrating evidence from both ruminant and monogastric models, this review provides a comprehensive framework for next–generation metabolic medicine. Full article

Background: Survivors with chronic sequelae of carbon monoxide (CO) poisoning after the 1963 Miike–Mikawa coal mine disaster can exhibit persistent higher brain dysfunction in late life. We examined whether serum metabolic alterations remained detectable ~60 years later and assessed serum brain-derived neurotrophic factor (BDNF). Methods: In this cross-sectional case–control study, outpatients with chronic CO-poisoning sequelae (CO; n = 14) and former miners without CO exposure (CON; n = 16), all aged ≥ 75 years, underwent targeted serum metabolomics (1183 metabolites) and clinical assessments. Between-group differences were evaluated using Welch’s t-test, and age-matched propensity-score matching (1:1) served as a sensitivity analysis. BDNF was additionally compared using a linear regression/ analysis of covariancemodel adjusting for age and Mini–Mental State Examination (MMSE). Results: Relative to controls, the CO group showed higher valine, alanine, and betaine and lower 3-hydroxybutyric acid, inosine, and hypoxanthine; these contrasts persisted with concordant direction after matching. Serum BDNF was lower in the CO group (unadjusted trend) and was significantly reduced after age/MMSE adjustment (p = 0.0252). Exploratory correlations between clinical measures and selected metabolites/BDNF were attenuated after accounting for group. Conclusions: Six decades after exposure, chronic CO sequelae were associated with a reproducible serum profile combining amino-acid elevations with relative suppression of ketone-body and purine-related metabolites, suggesting enduring alterations in systemic substrate handling and bioenergetics. If replicated in larger cohorts, such signatures—potentially alongside BDNF—should be regarded as hypothesis-generating; biomarker development would require external validation, longitudinal tracking, and assessment of intervention responsiveness before any clinical use is considered. Full article

Background/Objectives: Obesity is characterized by dysregulated hypothalamic energy homeostasis and reduced central responsiveness to the anorexigenic hormones leptin and insulin. β-Hydroxybutyrate (β-HB), a major ketone body, has recently garnered attention as a signaling metabolite. However, its effects on hypothalamic leptin and insulin responsiveness remain unclear. This study aimed to investigate the effects of β-HB on hypothalamic hormone responsiveness and the associated molecular mechanisms, primarily using a high-fat diet (HFD)-induced obese mouse model. Methods: Male mice were fed an HFD to induce obesity and treated with β-HB via oral or intracerebroventricular (ICV) administration. Feeding behavior following leptin and insulin administration was evaluated, and activation of hypothalamic leptin-induced STAT3 signaling and insulin-induced Akt signaling was analyzed. In addition, mRNA expression of inflammation-related and appetite-regulating genes was assessed by quantitative PCR. Normal mice also received chronic ICV administration of β-HB from the onset of HFD feeding, and changes in body weight and cumulative food intake were measured. Results: Both oral and ICV administration of β-HB significantly enhanced the anorexigenic responses to leptin and insulin in HFD-induced obese mice. At the molecular level, leptin-induced STAT3 phosphorylation and insulin-induced Akt phosphorylation were enhanced in the hypothalamus. Gene expression analysis revealed reduced SOCS3 and TNFα expression and increased POMC expression. Furthermore, chronic ICV administration of β-HB from the onset of HFD feeding significantly suppressed body weight gain and the increase in cumulative food intake. Conclusions: This study demonstrates that β-HB improves hypothalamic leptin and insulin responsiveness in obese mice and modulates the associated molecular environment. These findings suggest that β-HB acts as a metabolically responsive signaling molecule regulating hypothalamic function, providing a basis for novel metabolic intervention strategies against obesity. Full article

Starvation elicits profound metabolic adaptations in skeletal muscle, enabling survival during nutrient scarcity. While global proteomic changes underpinning muscle atrophy have been studied, the role of lysine β-hydroxybutyrylation (Kbhb), a novel metabolite-derived post-translational modification linked to ketone metabolism, remains largely unexplored. In this study, we subjected mice to 72 h of food deprivation and performed integrative quantitative proteomics and Kbhb-modified peptide profiling on gastrocnemius muscle. Starvation induced significant body weight and muscle mass loss, accompanied by increased systemic β-hydroxybutyrate levels and widespread Kbhb modification of muscle proteins. Proteomic analysis revealed extensive downregulation of ribosomal and translation-associated proteins, coupled with upregulation of autophagy and lipid catabolism pathways, highlighting a coordinated shift from anabolic processes to catabolic and oxidative metabolism. Deep Kbhb profiling identified over 7500 modified lysine sites across 2000 proteins, with starvation triggering a global increase in Kbhb on key metabolic enzymes involved in glycolysis, TCA cycle, fatty acid β-oxidation, and amino acid metabolism. Notably, starvation-enhanced Kbhb preferentially targeted evolutionarily conserved lysines proximal to catalytic or cofactor-binding domains, implicating a regulatory role in enzymatic activity modulation. Conversely, Kbhb on structural and contractile proteins was downregulated, suggesting functional reprioritization of muscle physiology during fasting. Our findings uncover lysine β-hydroxybutyrylation as a dynamic, metabolically responsive PTM mediating gastrocnemius muscle adaptation to energy deficiency, expanding the paradigm of potentially metabolite-driven epigenetic and non-epigenetic regulatory mechanisms in muscle metabolism. Full article