Ketone bodies effectively compete with glucose for neuronal acetyl-CoA generation in rat hippocampal slices.
NMR Biomed.. 2015-07-15; 28(9): 1111-1116
DOI: 10.1002/nbm.3355
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Valente-Silva P(1), Lemos C(1), Köfalvi A(1), Cunha RA(1)(2), Jones JG(1)(3).
Author information:
(1)CNC-Center for Neurosciences and Cell Biology, University of Coimbra, Portugal.
(2)Faculty of Medicine, University of Coimbra, Portugal.
(3)APDP-Portuguese Diabetes Association, Lisbon, Portugal.
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.