β-Hydroxybutyrate: A Signaling Metabolite

Abstract

Various mechanisms in the mammalian body provide resilience against food deprivation and dietary stress. The ketone body β-hydroxybutyrate (BHB) is synthesized in the liver from fatty acids and represents an essential carrier of energy from the liver to peripheral tissues when the supply of glucose is too low for the body's energetic needs, such as during periods of prolonged exercise, starvation, or absence of dietary carbohydrates. In addition to its activity as an energetic metabolite, BHB is increasingly understood to have cellular signaling functions. These signaling functions of BHB broadly link the outside environment to epigenetic gene regulation and cellular function, and their actions may be relevant to a variety of human diseases as well as human aging.

Keywords: aging; epigenetics; fasting; ketone bodies; metabolism.

Figure 1

Pathways of BHB metabolism and the regulation of key enzymes. Some of the molecules into which BHB is metabolized, such as acetyl-CoA, have signaling activities of their own, as do many of the cofactors involved in BHB metabolism, such as NAD. Abbreviations: BHB, β-hydroxybutyrate; BDH, β-hydroxybutyrate dehydrogenase; CoA, coenzyme A; FGF, fibroblast growth factor; HMGCS, HMG-CoA synthase; MCT, monocarboxylic acid transporter; mTOR, mechanistic target of rapamycin; NAD, nicotinamide adenine dinucleotide; PPARα, proliferator-activated receptor alpha; SIRT, sirtuin; TCA, tricarboxylic acid; VGLUT, vesicular glutamate transporter.

Figure 2

Schematic of direct and indirect signaling functions of the ketone body BHB. Indirect signaling functions require catabolism to other molecules, whereas direct signaling functions are actions of BHB itself. The major downstream effects of signaling functions are noted. Abbreviations: BHB, β-hydroxybutyrate; CoA, coenzyme A; FFAR3, free fatty acid receptor 3; GABA, γ-amino-butyric acid; HDAC, histone deacetylase; HCAR2, hydroxycarboxylic acid receptor 2; NAD, nicotinamide adenine dinucleotide; VGLUT, vesicular glutamate transporter.