Obligate Role for Ketone Body Oxidation in Neonatal Metabolic Homeostasis

• Published in: The Journal of biological chemistry Vol. 286; no. 9; pp. 6902 - 6910
• Main Authors: Cotter, David G., d'Avignon, D. André, Wentz, Anna E., Weber, Mary L., Crawford, Peter A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.03.2011; American Society for Biochemistry and Molecular Biology
• Subjects: Adaptation, Physiological - physiology; Animals; Animals, Newborn; Autophagy; Autophagy - physiology; Blood Glucose - metabolism; Brain - metabolism; Brain - pathology; Cell Membrane - metabolism; Coenzyme A-Transferases - genetics; Coenzyme A-Transferases - metabolism; Energy Metabolism; Energy Metabolism - physiology; Glucose Metabolism; Homeostasis - physiology; Hypoglycemia - metabolism; Hypoglycemia - pathology; Ketone Bodies - metabolism; Ketone Body Metabolism; Ketosis - metabolism; Ketosis - pathology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Neonatal Metabolism; NMR; Nuclear Magnetic Resonance, Biomolecular; Oxidation-Reduction; NMR; Ketone Body Metabolism; Energy Metabolism; Autophagy; Glucose Metabolism; Neonatal Metabolism
• DOI: 10.1074/jbc.M110.192369
• ISSN: 0021-9258

To compensate for the energetic deficit elicited by reduced carbohydrate intake, mammals convert energy stored in ketone bodies to high energy phosphates. Ketone bodies provide fuel particularly to brain, heart, and skeletal muscle in states that include starvation, adherence to low carbohydrate diets, and the neonatal period. Here, we use novel Oxct1−/− mice, which lack the ketolytic enzyme succinyl-CoA:3-oxo-acid CoA-transferase (SCOT), to demonstrate that ketone body oxidation is required for postnatal survival in mice. Although Oxct1−/− mice exhibit normal prenatal development, all develop ketoacidosis, hypoglycemia, and reduced plasma lactate concentrations within the first 48 h of birth. In vivo oxidation of 13C-labeled β-hydroxybutyrate in neonatal Oxct1−/− mice, measured using NMR, reveals intact oxidation to acetoacetate but no contribution of ketone bodies to the tricarboxylic acid cycle. Accumulation of acetoacetate yields a markedly reduced β-hydroxybutyrate:acetoacetate ratio of 1:3, compared with 3:1 in Oxct1+ littermates. Frequent exogenous glucose administration to actively suckling Oxct1−/− mice delayed, but could not prevent, lethality. Brains of newborn SCOT-deficient mice demonstrate evidence of adaptive energy acquisition, with increased phosphorylation of AMP-activated protein kinase α, increased autophagy, and 2.4-fold increased in vivo oxidative metabolism of [13C]glucose. Furthermore, [13C]lactate oxidation is increased 1.7-fold in skeletal muscle of Oxct1−/− mice but not in brain. These results indicate the critical metabolic roles of ketone bodies in neonatal metabolism and suggest that distinct tissues exhibit specific metabolic responses to loss of ketone body oxidation.