Lavanya completed her M.Sc. in Biotechnology and is currently doing her PhD in β-hydroxybutyrate metabolism in the brain with Professor Caroline Rae.
DR MARK SCHIRA
Honorary Senior Research Officer
: +612 9399 1131
ZOEY ISHERWOOD PhD student
BEN ROWLANDS PhD student
The ketone body, β-hydroxybutyrate (βOHB), is metabolised by the brain alongside the mandatory brain fuel glucose. To examine the extent and circumstances by which βOHB can supplement glucose metabolism, we studied guinea pig cortical brain slices using increasing concentrations of [U-(13)C]D-βOHB in conjunction with [1-(13)C]D-glucose under conditions of normo- and hypoglycaemia, as well as under high potassium (40 mmol/L K(+)) depolarization in normo- and hypoglycaemic conditions. The contribution of βOHB to synthesis of GABA was also probed by inhibiting the synthesis of glutamine, a GABA precursor, with methionine sulfoximine (MSO). [U-(13)C]D-βOHB at lower concentrations (0.25 and 1.25 mmol/L) stimulated mitochondrial metabolism, producing greater total incorporation of label into glutamate and GABA but did not have a similar effect in the cytosolic compartment where labelling of glutamine was reduced at 1.25 mmol/L [U-(13)C]D-βOHB. At higher concentrations (2.5 mmol/L) [U-(13)C]D-βOHB inhibited metabolism of [1-(13)C]D-glucose, and reduced total label incorporation and total metabolite pools. When glucose levels were reduced, βOHB was able to partially restore the loss of glutamate and GABA caused by hypoglycaemia, but was not able to supplement levels of lactate, glutamine or alanine or to prevent the increase in aspartate. Under depolarizing conditions glucose was the preferred substrate over βOHB, even in hypoglycaemic conditions where comparatively less βOHB was incorporated except into aspartate isotopomers. Inhibition of glutamine synthesis with MSO had no significant effect on incorporation of label from [U-(13)C]D-βOHB into GABA C2,1 indicating that the majority of this GABA was synthesized in GABAergic neurons from [U-(13)C]D-βOHB rather than from Gln C4,5 imported from astrocytes.
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 Ca(2+) 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.