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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK091538-02
Application #
8312464
Study Section
Special Emphasis Panel (ZRG1-EMNR-R (02))
Program Officer
Laughlin, Maren R
Project Start
2011-08-05
Project End
2016-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
2
Fiscal Year
2012
Total Cost
$330,600
Indirect Cost
$113,100
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Cotter, David G; Ercal, Baris; d'Avignon, D André et al. (2014) Impairments of hepatic gluconeogenesis and ketogenesis in PPAR?-deficient neonatal mice. Am J Physiol Endocrinol Metab 307:E176-85
Schugar, Rebecca C; Moll, Ashley R; André 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
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; 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
Schugar, Rebecca C; Huang, Xiaojing; Moll, Ashley R et al. (2013) Role of choline deficiency in the Fatty liverýýphenotype of mice fed a low protein, very low carbohydrate ketogenic diet. PLoS One 8:e74806
Cotter, David G; Ercal, Baris; d'Avignon, D Andre 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; Crawford, Peter A (2013) Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 304:H1060-76
Crawford, Peter A; Schaffer, Jean E (2013) Metabolic stress in the myocardium: adaptations of gene expression. J Mol Cell Cardiol 55:130-8
Janardhan, Ajit; Chen, Jane; Crawford, Peter A (2011) Altered systemic ketone body metabolism in advanced heart failure. Tex Heart Inst J 38:533-8

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