Ketone Body Signaling is the role of ketone bodies, particularly beta-hydroxybutyrate (βOHB), as critical signaling molecules that communicate metabolic and environmental status to the cell, extending beyond their traditional function as alternative energy substrates. Produced by the liver during states of carbohydrate restriction or fasting, these molecules act as metabolic messengers that influence gene expression, inflammation, and cellular protection. This signaling mechanism represents a powerful, evolutionarily conserved pathway linking nutritional status directly to fundamental processes of healthspan and resilience. Optimizing this signaling is a key focus in metabolic and neurological wellness.
Origin
The term emerged from the evolving understanding of metabolism, which traditionally viewed ketones solely as fuel for extrahepatic tissues like the brain and heart during starvation. Recent endocrinology and longevity research shifted this perspective, recognizing βOHB’s non-metabolic, regulatory roles. This conceptual expansion established ketone bodies as pleiotropic signaling mediators that actively participate in cellular homeostasis.
Mechanism
The signaling mechanism is multi-faceted, involving both receptor-mediated and epigenetic pathways. βOHB acts as a ligand for G protein-coupled receptors (GPCRs), such as GPR109A, which inhibits lipolysis in adipose tissue, thus regulating fatty acid release. Crucially, βOHB also functions as an endogenous inhibitor of Histone Deacetylases (HDACs), which are enzymes that typically repress gene transcription. By inhibiting HDACs, βOHB promotes the acetylation of histones, thereby increasing the expression of protective genes involved in stress resistance, antioxidant defense, and energy metabolism, directly linking nutrient status to the epigenome.
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