title: Decreased carbon shunting from glucose toward oxidative metabolism in diet-induced ketotic rat brain.
abstract: 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.
authors.affiliation: Department of Biomedical Engineering, School of Medicine, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shenghui
authors.initials: S
authors.lastname: Zhang
authors.forename: Isaac
authors.initials: I
authors.lastname: Marin-Valencia
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Puchowicz
mesh_terms: D000090:Acetoacetates / Q000378:metabolism; D000818:Animals; D001923:Brain Chemistry; D002244:Carbon / Q000378:metabolism*; D055423:Diet, Ketogenic; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism*; D007657:Ketone Bodies / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D056693:Propionic Acidemia / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
chemical_list: D000090:Acetoacetates; D007657:Ketone Bodies; C016635:acetoacetic acid; D005680:gamma-Aminobutyric Acid; D002244:Carbon; D005947:Glucose
keywords: GABA; brain amino acids; citric acid cycle; glucose; ketone bodies; oxidative metabolism