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

Abstract

β-Hydroxybutyrate (βOHB), 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 βOHB 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. βOHB possesses an intrinsic high heat of combustion, making it an efficient mitochondrial fuel, where it can alter the NAD+/NADH and Q/QH2 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. βOHB 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 βOHB as an efficient neurotherapeutic relies on increasing blood βOHB levels so as to encourage entry of βOHB to the brain. While use of βOHB 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 βOHB have shown great promise, with the approach elevating plasma βOHB while allowing consumption of normal diet. An improved understanding of the mechanisms by which βOHB acts will allow better design of both diet and supplemental interventions.

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Acknowledgements

The authors would like to thank Ben Rowlands of Neuroscience Research Australia and Don Thomas of the UNSW Mark Wainwright Analytical Centre for their assistance in the preparation of this manuscript. The authors would like to acknowledge the lifetime commitment of Professor Mary McKenna to the pursuit of scientific excellence and education in neurochemistry and to dedicate this article to her contributions to this field. We have greatly enjoyed and also benefitted from our interactions over the years.

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Correspondence to Caroline D. Rae.

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Achanta, L.B., Rae, C.D. β-Hydroxybutyrate in the Brain: One Molecule, Multiple Mechanisms. Neurochem Res 42, 35–49 (2017). https://doi.org/10.1007/s11064-016-2099-2

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  • DOI: https://doi.org/10.1007/s11064-016-2099-2

Keywords

  • Ketone body metabolism
  • Histone deacetylase inhibition: K+ channels
  • Brain energy metabolism