Volume 28, Issue 9 p. 1111-1116
Research article

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

Paula Valente-Silva

Paula Valente-Silva

CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal

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Cristina Lemos

Cristina Lemos

CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal

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Attila Köfalvi

Attila Köfalvi

CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal

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Rodrigo A. Cunha

Rodrigo A. Cunha

CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal

Faculty of Medicine, University of Coimbra, Portugal

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John G. Jones

Corresponding Author

John G. Jones

CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal

APDP-Portuguese Diabetes Association, Lisbon, Portugal

Correspondence to: J. G. Jones, CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal. E-mail: [email protected]

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First published: 15 July 2015
Citations: 25

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 [1-13C]glucose and 1.0 mM [2-13C]lactate + 0.1 mM pyruvate (combined [2-13C]lactate + [2-13C]pyruvate) to acetyl-CoA production were measured both without and with 5.0 mM [U-13C]3-hydroxybutyrate in superfused rat hippocampal slices by 13C NMR non-steady-state isotopomer analysis of tissue glutamate and GABA. Without [U-13C]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-13C]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-13C]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-13C]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 [1-13C]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 © 2015 John Wiley & Sons, Ltd.