PPARy plays a critical role in adipocyte differentiation and glucose metabolism, and thus provides a potential link between obesity and diabetes. The goal of this proposal is to examine the effect of phosphorylation on the metabolic and physiological actions of the nuclear receptor PPARy. This will be accomplished by studying metabolic parameters such as insulin sensitivity and glucose metabolism in mice whose PPARy has been mutated to mimic the less active, phosphorylated state (PPARy-S112D) in the setting of diet-induced obesity.
Specific Aim 1 is to determine the effect of PPARy phosphorylation on glucose homeostasis and insulin resistance in the setting of diet-induced obesity. We hypothesize that PPARy-S112D mice will have impaired glucose homeostasis and increased insulin resistance relative to wild type littermates in the setting of diet-induced obesity. This will be tested by performing provocative metabolic tests and by analyzing expression of key hormones and cytokines involved in insulin resistance and glucose metabolism.
Specific Aim 2 is to determine the effect of PPARy phosphorylation on weight gain and body composition during diet-induced obesity. We hypothesize that PPARy-S1 12D mice will be protected against weight gain when placed on a high fat diet, concomitant with less adipose mass than their wild type littermates. This will be determined by performing measurements of body weight on normal chow and during diet induced obesity, performing non-invasive body fat distribution measurements, and monitoring food intake, energy expenditure and respiratory quotient. These studies will provide insight into the role of phosphorylation of PPARy in metabolic processes, and may provide insight into the development of selective PPARy modulators that elicit the beneficial effects of PPARy activation but with fewer deleterious side effects, which would therefore be beneficial in the treatment of type 2 diabetes

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 #
1F32DK070405-01
Application #
6883854
Study Section
Special Emphasis Panel (ZRG1-F06 (20))
Program Officer
Hyde, James F
Project Start
2004-12-01
Project End
2007-11-30
Budget Start
2004-12-01
Budget End
2005-11-30
Support Year
1
Fiscal Year
2005
Total Cost
$43,976
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Schupp, Michael; Cristancho, Ana G; Lefterova, Martina I et al. (2009) Re-expression of GATA2 cooperates with peroxisome proliferator-activated receptor-gamma depletion to revert the adipocyte phenotype. J Biol Chem 284:9458-64
Schupp, Michael; Lefterova, Martina I; Janke, Jurgen et al. (2009) Retinol saturase promotes adipogenesis and is downregulated in obesity. Proc Natl Acad Sci U S A 106:1105-10