Ketone bodies effectively compete with glucose for neuronal acetyl-CoA generation in rat hippocampal slices

Ketone bodies can be used for cerebral energy generation in situ, when their availability is increased as during fasting or ingestion of a ketogenic diet. However, it is not known how effectively ketone bodies compete with glucose, lactate, and pyruvate for energy generation in the brain parenchyma. Hence, the contributions of exogenous 5.0mM [1-C-13]glucose and 1.0mM [2-C-13]lactate+0.1mM pyruvate (combined [2-C-13]lactate+[2-C-13]pyruvate) to acetyl-CoA production were measured both without and with 5.0mM [U-C-13]3-hydroxybutyrate in superfused rat hippocampal slices by C-13 NMR non-steady-state isotopomer analysis of tissue glutamate and GABA. Without [U-C-13]3-hydroxybutyrate, glucose, combined lactate+pyruvate, and unlabeled endogenous sources contributed (mean +/- SEM) 70 +/- 7%, 10 +/- 2%, and 20 +/- 8% of acetyl-CoA, respectively. With [U-C-13]3-hydroxybutyrate, glucose contributions significantly fell from 70 +/- 7% to 21 +/- 3% (p<0.0001), combined lactate+pyruvate and endogenous contributions were unchanged, and [U-C-13]3-hydroxybutyrate became the major acetyl-CoA contributor (68 +/- 3%) - about three-times higher than glucose. A direct analysis of the GABA carbon 2 multiplet revealed that [U-C-13]3-hydroxybutyrate contributed approximately the same acetyl-CoA fraction as glucose, indicating that it was less avidly oxidized by GABAergic than glutamatergic neurons. The appearance of superfusate lactate derived from glycolysis of [1-C-13]glucose did not decrease significantly in the presence of 3-hydroxybutyrate, hence total glycolytic flux (Krebs cycle inflow+exogenous lactate formation) was attenuated by 3-hydroxybutyrate. This indicates that, under these conditions, 3-hydroxybutyrate inhibited glycolytic flux upstream of pyruvate kinase. Copyright (c) 2015 John Wiley & Sons, Ltd.