β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms

beta-Hydroxybutyrate (beta OHB), a ketone body, is oxidised as a brain fuel. Although its contribution to energy metabolism in the healthy brain is minimal, it is an interesting metabolite which is not only oxidised but also has other direct and collateral effects which make it a molecule of interest for therapeutic purposes. In brain beta OHB can be produced in astrocytes from oxidation of fatty acids or catabolism of amino acids and is metabolised in the mitochondria of all brain cell types although uptake across the blood brain barrier is a metabolic control point. beta OHB possesses an intrinsic high heat of combustion, making it an efficient mitochondrial fuel, where it can alter the NAD(+)/NADH and Q/QH(2) couples and reduce production of mitochondrial reactive oxygen species. It can directly interact as a signalling molecule influencing opening of K+ channels and regulation of Ca2+ channels. beta OHB is an inhibitor of histone deacetylases resulting in upregulation of genes involved in protection against oxidative stress and regulation of metabolism. It interacts with an inflammasome in immune cells to reduce production of inflammatory cytokines and reduce inflammation. Use of beta OHB as an efficient neurotherapeutic relies on increasing blood beta OHB levels so as to encourage entry of beta OHB to the brain. While use of beta OHB as a sole therapeutic is currently limited, with employment of a ketogenic diet a more widely used approach, recent development and testing of esterified forms of beta OHB have shown great promise, with the approach elevating plasma beta OHB while allowing consumption of normal diet. An improved understanding of the mechanisms by which beta OHB acts will allow better design of both diet and supplemental interventions.