Peroxisome proliferator-activated receptor gamma2 (PPAR gamma2) has been identified as a key regulator of adipocyte differentiation. Excessive development of adipose tissues leads to obesity, which is a major risk factor for non-insulin dependent diabetes mellitus, hypertension, and coronary artery diseases. The fact that thiazolidione, a new antidiabetic agent in clinical development, is high affinity ligand for PPAR gamma2 strongly suggests it has direct relationship with diabetes. Therefore investigating the molecular mechanisms related to PPAR gamma2 function will improve our ability to control of obesity and diabetes. Key experiments will be proposed to characterize the role and mechanisms of PPAR gamma2 in coordination of the cessation of cell growth to adipocyte differentiation.
The specific aims are: A. To define the changes in cell cycle progression upon ligand-stimulation of PPAR gamma2 in fibroblasts. B. To analyze the effects of ligand-stimulation of PPAR gamma2 on the expression of major cell cycle regulators. C. To identify cell cycle regulators which may interact with PPAR gamma2 in vitro and in vivo to inhibit cell growth.
