Back to Search
Start Over
Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation.
- Source :
-
American journal of physiology. Endocrinology and metabolism [Am J Physiol Endocrinol Metab] 2013 Feb 15; Vol. 304 (4), pp. E363-74. Date of Electronic Publication: 2012 Dec 11. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Adaptation, Physiological
Animals
Animals, Newborn
Caloric Restriction adverse effects
Coenzyme A-Transferases biosynthesis
Coenzyme A-Transferases genetics
Heterozygote
Hypoglycemia etiology
Ketone Bodies blood
Ketosis blood
Ketosis etiology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Muscle, Skeletal metabolism
Myocytes, Cardiac metabolism
Nerve Tissue Proteins biosynthesis
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neurons metabolism
Organ Specificity
Oxidation-Reduction
Aging
Coenzyme A-Transferases metabolism
Ketone Bodies metabolism
Ketosis physiopathology
Muscle, Skeletal enzymology
Myocytes, Cardiac enzymology
Neurons enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1555
- Volume :
- 304
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Endocrinology and metabolism
- Publication Type :
- Academic Journal
- Accession number :
- 23233542
- Full Text :
- https://doi.org/10.1152/ajpendo.00547.2012