Ketone bodies are an avidly oxidized cellular fuel source, produced in abundance during the neonatal period, starvation, decompensated diabetes, and by adherence to low-carbohydrate (e.g., Atkins) diets. Ketones are known to be metabolically important for two reasons: first, their accumulation in blood can promote ketoacidosis - elicited by mismatch between rates of ketogenesis and ketone body oxidation. Second, depending on physiological state, ketones supply up to 40% of the carbon backbones that yield high-energy phosphates. While the adverse consequences of ketoacidosis are well-appreciated, experimental models to date have not revealed whether loss of ketone oxidation can be energetically tolerated. Preliminary studies from this laboratory show that germline Oxct1-/- mice, which lack the enzyme critical for ketone body utilization, succinyl-CoA:3-oxo-transferase (SCOT), are not viable after the second postnatal day. The proposed study will test the central hypothesis that ketone bodies serve an obligate energetic role in select physiological states, in that deficiencies of ketone body oxidation create metabolic abnormalities in the neonatal period and during nutrient deprivation in the adult. To specifically examine the energetic effects of ketolytic deficiency, independent of ketoacidosis, this laboratory also recently developed tissue-specific loss-of-SCOT-function mouse models that will be used within the following Specific Aims.
The first aim will demonstrate the tissue- specific energetic requirement for ketone metabolism in the neonatal period. Using skeletal myocyte-, cardiac myocyte-, and neuron-specific Oxct1-/- mice, these experiments are expected to reveal the tissue(s) most dependent on ketones during the neonatal period. Next, using adult mice with loss-of-SCOT-function in skeletal muscle, collectively the largest ketone user and a key determinant of integrated metabolic homeostasis, the second aim will determine the role of ketone body metabolism in whole-body and skeletal muscle metabolism in the fed state and during prolonged nutrient deprivation.
The third aim will use adult mice with loss-of-SCOT-function in heart to explore the role of ketone body metabolism in this high energy-requiring organ in the fed state and in the setting of nutrient deprivation. Because nutrient deprivation decreases glucose availability, elimination of ketone body oxidation is expected to elicit metabolic abnormalities, promote hypoglycemia, and when eliminated in cardiac muscle, contribute to the development of cardiomyopathy. Taken together, these studies will provide fundamental insight into the energetic roles of ketone body metabolism in a mammalian system, and therefore could ultimately influence (i) human newborn screening regimens, which currently do not test discrete disorders of ketone metabolism, (ii) the development of new risk- stratifying biomarkers for adult metabolic disease, and (iii) the development of individualized metabogenomics- guided nutritional regimens.
Ketone body metabolism is an evolutionarily conserved metabolic pathway that is an important contributor to metabolic homeostasis in the neonatal period and in post-absorptive states. Despite numerous experiments that have quantified ketone body utilization, contexts in which ketone bodies are energetically essential have not been described. Novel mouse mutant strains, engineered with tissue-specific deficiencies of ketone body metabolism, are expected to reveal ketoacidosis-independent energetic requirements for ketone metabolism in the neonatal period and during nutrient deprivation in the adult. Therefore, the scope of prospective implications of these studies extends from the prevention of Sudden Infant Death Syndrome to avoiding and treating complications of adult metabolic disease.
|Aubert, Gregory; Martin, Ola J; Horton, Julie L et al. (2016) The Failing Heart Relies on Ketone Bodies as a Fuel. Circulation 133:698-705|
|Youm, Yun-Hee; Nguyen, Kim Y; Grant, Ryan W et al. (2015) The ketone metabolite Î²-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med 21:263-9|
|Cotter, David G; Ercal, Baris; Huang, Xiaojing et al. (2014) Ketogenesis prevents diet-induced fatty liver injury and hyperglycemia. J Clin Invest 124:5175-90|
|Cotter, David G; Ercal, Baris; d'Avignon, D AndrÃ© et al. (2014) Impairments of hepatic gluconeogenesis and ketogenesis in PPARÎ±-deficient neonatal mice. Am J Physiol Endocrinol Metab 307:E176-85|
|Schugar, Rebecca C; Moll, Ashley R; AndrÃ© d'Avignon, D et al. (2014) Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol Metab 3:754-69|
|Huang, Xiaojing; Chen, Ying-Jr; Cho, Kevin et al. (2014) X13CMS: global tracking of isotopic labels in untargeted metabolomics. Anal Chem 86:1632-9|
|Schugar, Rebecca C; Huang, Xiaojing; Moll, Ashley R et al. (2013) Role of choline deficiency in the Fatty liverÂ phenotype of mice fed a low protein, very low carbohydrate ketogenic diet. PLoS One 8:e74806|
|Cotter, David G; Ercal, Baris; d'Avignon, D AndrÃ© et al. (2013) Impact of peripheral ketolytic deficiency on hepatic ketogenesis and gluconeogenesis during the transition to birth. J Biol Chem 288:19739-49|
|Cotter, David G; Schugar, Rebecca C; Wentz, Anna E et al. (2013) Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation. Am J Physiol Endocrinol Metab 304:E363-74|
|Chambers, Kari T; Chen, Zhouji; Lai, Ling et al. (2013) PGC-1Î² and ChREBP partner to cooperatively regulate hepatic lipogenesis in a glucose concentration-dependent manner. Mol Metab 2:194-204|
Showing the most recent 10 out of 17 publications