During states of low
carbohydrate intake, mammalian
ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial
enzyme coenzyme A (
CoA)
transferase [
succinyl-CoA:3-oxoacid
CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of
ketone bodies and that germline SCOT-knockout (KO) mice die within 48 h of birth because of hyperketonemic
hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that
ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during
starvation in the adult. Although transgene-mediated restoration of myocardial
CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic
hypoglycemia in the neonatal period, mice lacking
CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal
CoA transferase deficiency exhibit increased cerebral glycolysis and
glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop
hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate
starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1(+/-) mice demonstrates that global diminution of
ketone body oxidation yields hyperketonemia, but
hypoglycemia emerges only during a protracted state of low
carbohydrate intake. Together, these data suggest that, at the tissue level,
ketone bodies are not a required energy substrate in the newborn period or during
starvation, but rather that integrated
ketone body metabolism mediates adaptation to ketogenic nutrient states.