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Decreased carbon shunting from glucose toward oxidative metabolism in diet‐induced ketotic rat brain
Author(s) -
Zhang Yifan,
Zhang Shenghui,
MarinValencia Isaac,
Puchowicz Michelle A.
Publication year - 2015
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12965
Subject(s) - ketosis , ketone bodies , citric acid cycle , ketogenic diet , medicine , endocrinology , chemistry , neuroprotection , metabolism , oxidative phosphorylation , amino acid , carbohydrate metabolism , biochemistry , biology , diabetes mellitus , neuroscience , epilepsy
The mechanistic link of ketosis to neuroprotection under certain pathological conditions continues to be explored. We investigated whether chronic ketosis induced by ketogenic diet results in the partitioning of ketone bodies toward oxidative metabolism in brain. We hypothesized that diet‐induced ketosis results in increased shunting of ketone bodies toward citric acid cycle and amino acids with decreased carbon shunting from glucose. Rats were fed standard ( STD ) or ketogenic ( KG ) diets for 3.5 weeks and then infused with [U‐ 13 C]glucose or [U‐ 13 C]acetoacetate tracers. Concentrations and 13 C‐labeling pattern of citric acid cycle intermediates and amino acids were analyzed from brain homogenates using stable isotopomer mass spectrometry analysis. The contribution of [U‐ 13 C]glucose to acetyl‐CoA and amino acids decreased by ~ 30% in the KG group versus STD , whereas [U‐ 13 C]acetoacetate contributions were more than two‐fold higher. The concentration of GABA remained constant across groups; however, the 13 C labeling of GABA was markedly increased in the KG group infused with [U‐ 13 C]acetoacetate compared to STD . This study reveals that there is a significant contribution of ketone bodies to oxidative metabolism and GABA in diet‐induced ketosis. We propose that this represents a fundamental mechanism of neuroprotection under pathological conditions.We investigated glucose versus ketone bodies contributions to citric acid (CAC) intermediates and brain amino acids. We found decreased carbon shunting from glucose toward oxidative metabolism in diet‐induced ketotic rat brain, whereas the carbon shunting from ketone bodies toward oxidative metabolism increased, toward gamma‐aminobutyric acid (GABA). The partitioning of ketone bodies toward GABA in ketotic brain represents a fundamental mechanism of neuroprotection under pathological conditions, such as with stroke or seizures.