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

Abstract

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 5.0 mM [1-(13)C]glucose and 1.0 mM [2-(13)C]lactate + 0.1 mM pyruvate (combined [2-(13)C]lactate + [2-(13)C]pyruvate) to acetyl-CoA production were measured both without and with 5.0 mM [U-(13)C]3-hydroxybutyrate in superfused rat hippocampal slices by (13)C NMR non-steady-state isotopomer analysis of tissue glutamate and GABA. Without [U-(13)C]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-(13)C]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-(13)C]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-(13)C]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-(13)C]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.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…Further development of these intriguing results is required, because the improvement in endurance exercise performance was predominantly driven by a robust response to the KE in 2/8 subjects. Nonetheless, these results do support classical studies that indicate a preference for ketone oxidation over other substrates (GARLAND et al, 1962; Hasselbaink et al, 2003; Stanley et al, 2003; Valente-Silva et al, 2015), including during exercise, and that trained athletes may be more primed to utilize ketones (Johnson et al, 1969a; Johnson and Walton, 1972; Winder et al, 1974; Winder et al, 1975). Finally, the mechanisms that might support improved exercise performance following equal caloric intake (differentially distributed among macronutrients) and equal oxygen consumption rates remain to be determined.…”

New insights into the mechanisms of the ketogenic diet

“…In neurons BHB can compete with glucose for energy generation by inhibiting glycolytic flux upstream of pyruvate kinase [12 • ]. KDs can thereby shunt ketones into oxidative metabolism in the brain, which also enhances the capacity to produce amino acids such as GABA [13].…”

1′-Acetoxychavicol acetate ameliorates age-related spatial memory deterioration by increasing serum ketone body production as a complementary energy source for neuronal cells

“…The brain does not oxidize fatty acids, because fatty acids except for omega-3 fatty acid docosahexaenoic acid cannot across the blood-brain barrier [33]. b-Hydroxybutyric acid substituted for glucose as an energy substrate and preserved neuronal integrity and stability in rat hippocampal slices [37,38]. Cerebral activity of 3-hydroxybutyric acid dehydrogenase, the gateway enzyme for ketone body utilization, is constitutive and is not significantly influenced by nutritional state or dietary composition [39].…”