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Ketone bodies effectively compete with glucose for neuronal acetyl‐CoA generation in rat hippocampal slices
Author(s) -
ValenteSilva Paula,
Lemos Cristina,
Köfalvi Attila,
Cunha Rodrigo A.,
Jones John G.
Publication year - 2015
Publication title -
nmr in biomedicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.278
H-Index - 114
eISSN - 1099-1492
pISSN - 0952-3480
DOI - 10.1002/nbm.3355
Subject(s) - ketone bodies , glycolysis , medicine , endocrinology , glutamate receptor , chemistry , hippocampal formation , isotopomers , pyruvic acid , endogeny , biochemistry , metabolism , biology , receptor , organic chemistry , molecule
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. Copyright © 2015 John Wiley & Sons, Ltd.