Recent studies in this lab have identified c-Cbl as a key regulator of whole body energy expenditure and adiposity in mice. Ablation of c-Cbl in mice results in a desirable phenotype of reduced adiposity, increased lean body mass, small adipocytes, and increased energy expenditure despite hyperphagia. These mice illustrate a role for c-Cbl in an unknown facet of fuel metabolism that is integrally linked to body weight regulation. The majority of these metabolic changes occur in muscle and fat tissue, therefore the specific aims for this proposal are to 1) identify the tissue type that drives the c-Cbl -/- phenotype and 2) determine the molecular mechanism by which c-Cbl ablation results in increased fatty acid oxidation and reduced adiposity. Dissecting the c-Cbl -/- phenotype will illustrate the role of this protein in the molecular control of energy expenditure and have therapeutic applications in diabetes and obesity. The exciting aspect of these studies is that the molecular control of energy expenditure in mammals is a newly evolving field and the precise wiring diagram for this pathway has yet to be established. This study will identify novel inroads into this pathway and may pave the way for our understanding of mitochondrial energy expenditure.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK075249-03X1
Application #
7559322
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Castle, Arthur
Project Start
2006-04-01
Project End
2009-03-31
Budget Start
2008-04-01
Budget End
2009-03-31
Support Year
3
Fiscal Year
2008
Total Cost
$7,850
Indirect Cost
Name
Garvan Institute of Medical Research
Department
Type
DUNS #
751954603
City
Sydney
State
Country
Australia
Zip Code
2010
Hoehn, Kyle L; Turner, Nigel; Swarbrick, Michael M et al. (2010) Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab 11:70-6
Hoehn, Kyle L; Salmon, Adam B; Hohnen-Behrens, Cordula et al. (2009) Insulin resistance is a cellular antioxidant defense mechanism. Proc Natl Acad Sci U S A 106:17787-92
Hoehn, Kyle L; Hohnen-Behrens, Cordula; Cederberg, Anna et al. (2008) IRS1-independent defects define major nodes of insulin resistance. Cell Metab 7:421-33