From Carbohydrates to Ketones: Mitochondrial Reprogramming via β-Hydroxybutyrate Signaling for Non-Pharmacological Treatment of Metabolic Syndrome

Metabolic syndrome (MetS) encompasses central adiposity, dyslipidemia, insulin resistance, and hypertension, predisposing individuals to cardiovascular and hepatic disease. Ketogenic diets (KD), through carbohydrate restriction and induction of nutritional ketosis, have re-emerged as metabolic interventions capable of modulating multiple pathways relevant to MetS. Evidence from clinical and experimental studies indicates that KD consistently lowers triglycerides, improves glycemic control and insulin sensitivity, and reduces visceral adiposity, while LDL-C responses remain heterogeneous and largely dependent on dietary fat quality. Mechanistically, β-hydroxybutyrate functions as both an alternative energy substrate and a signaling metabolite, inhibiting histone deacetylases and the NLRP3 inflammasome, enhancing mitochondrial biogenesis via AMPK–SIRT3–PGC-1α activation, and promoting fatty acid oxidation through PPARα. These molecular adaptations translate into improved metabolic flexibility, reduced hepatic steatosis, and an attenuated inflammatory tone. Hormonal mediators such as FGF21 and GDF15 further support energy balance and substrate partitioning, whereas modifications in bile acid pools and the gut microbiota contribute to improved lipid handling and reduced caloric absorption. Clinical implementation requires careful supervision, lipid and hepatic monitoring, and an emphasis on unsaturated fat sources to ensure cardiometabolic safety. Long-term controlled trials incorporating multi-omic biomarkers are warranted to determine durability, responder phenotypes, and mechanistic predictability. Collectively, KD represents both a viable therapeutic strategy and a translational model for nutrient-driven metabolic reprogramming in MetS.