Unraveling the Translational Relevance of β-Hydroxybutyrate as an Intermediate Metabolite and Signaling Molecule

Abstract

β-hydroxybutyrate (BHB) is the most abundant ketone body produced during ketosis, a process initiated by glucose depletion and the β-oxidation of fatty acids in hepatocytes. Traditionally recognized as an alternative energy substrate during fasting, caloric restriction, and starvation, BHB has gained attention for its diverse signaling roles in various physiological processes. This review explores the emerging therapeutic potential of BHB in the context of sarcopenia, metabolic disorders, and neurodegenerative diseases. BHB influences gene expression, lipid metabolism, and inflammation through its inhibition of Class I Histone deacetylases (HDACs) and activation of G-protein-coupled receptors (GPCRs), specifically HCAR2 and FFAR3. These actions lead to enhanced mitochondrial function, reduced oxidative stress, and regulation of inflammatory pathways, with implication for muscle maintenance, neuroprotection, and metabolic regulation. Moreover, BHB's ability to modulate adipose tissue lipolysis and immune responses highlight its broader potential in managing chronic metabolic conditions and aging. While these findings show BHB as a promising therapeutic agent, further research is required to determine optimal dosing strategies, long-term effects, and its translational potential in clinical settings. Understanding BHB's mechanisms will facilitate its development as a novel therapeutic strategy for multiple organ systems affected by aging and disease.

Keywords: inflammation; lipolysis; neurodegenerative diseases; sarcopenia; β-hydroxybutyrate.

Figure 1

Schematic representation of mitochondrial ketogenesis from circulating free fatty acids. Circulating free fatty acids (FFAs) enter the mitochondria and undergo β-oxidation to generate acetyl-CoA. Two acetyl-CoA molecules are condensed by thiolase to form acetoacetyl-CoA, which is subsequently converted to HMG-CoA by HMGCS (3-hydroxy-3-methylglutaryl-CoA synthase). HMGCL (HMG-CoA lyase) then cleaves HMG-CoA to produce acetoacetate. Acetoacetate can be reduced to β-hydroxybutyrate (BHB) by BDH1 (β-hydroxybutyrate dehydrogenase) or spontaneously decarboxylated to acetone. BHB is then exported from the mitochondria for use as an energy substrate by peripheral tissues.

Figure 2

Inter-organ metabolic interactions during ketogenesis induced by exercise. During periods of prolonged exercise, enhanced lipolysis in adipose tissue increases circulating free fatty acids (FFAs), which are taken up by the liver and converted into ketone bodies, primarily β-hydroxybutyrate (BHB). Skeletal muscle utilizes BHB for ATP production, especially when glucose availability is limited. In parallel, the brain adapts to utilize BHB as a major fuel source, preserving glucose for essential biosynthetic pathways. During exercise, high-intensity in particular, myokines released from skeletal muscle and metabolites such as BHB and lactate play roles in dynamic metabolic crosstalk between peripheral tissues and brain in states of ketone-body production.

Figure 3

Proposed effects of ketogenic diet and exercise-induced BHB elevation on skeletal muscle and cognitive function. The ketogenic diet and exercise, high-intensity in particular, both elevate circulating BHB level. Elevated BHB is associated with skeletal muscle health through increased muscle mass, mitochondrial biogenesis and oxidative metabolism, and reduced cellular stress. Recent evidence suggests that exercise-induced BHB elevation may also support cognitive function, particularly in individuals with low baseline BHB levels. Together, these findings highlight the potential of BHB as a metabolic mediator linking lifestyle intervention with musculoskeletal and neurologic benefits.