Decreased carbon shunting from glucose toward oxidative metabolism in diet-induced ketotic rat brain

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-¹³C]glucose or [U-¹³C]acetoacetate tracers. Concentrations and ¹³C-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-¹³C]glucose to acetyl-CoA and amino acids decreased by ∼ 30% in the KG group versus STD, whereas [U-¹³C]acetoacetate contributions were more than two-fold higher. The concentration of GABA remained constant across groups; however, the ¹³C labeling of GABA was markedly increased in the KG group infused with [U-¹³C]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.