Obesity and insulin resistance have become public health problems of enormous magnitude. Recent advances in obesity-related areas include new knowledge about the control of fat cell differentiation. Specifically, the nuclear hormone receptor PPAR-gamma (for peroxisome proliferator-activated receptor) has been shown to be a critical determinant in driving adipogenesis. Our lab has recently shown that PPAR-gamma can be phosphorylated by the MAP kinase system in response to several different extracellular growth factors. This phosphorylation inhibits the differentiation of fat cells. In this proposal we describe several experiments to assess the mechanism by which PPAR-gamma phosphorylation inhibits adipogenesis; we also intend to determine the significance of this phenomenon in vivo in various mouse models of obesity. The first studies attempt to discover the effect of PPAR-gamma phosphorylation on ligand binding by this receptor. Later studies are designed to identify proteins which might interact specifically with either phosphorylated or nonphosphorylated PPAR-gamma; such proteins might serve as corepressors or coactivators of PPAR-gamma, respectively. The final series of experiments proposes to identify the relative amounts of each isoform of PPAR-gamma in mice with dietary obesity or after fasting. Additional experiments will be performed in the leptin deficient ob mouse and epidermal growth factor (EGF) treated mice. The insulin sensitizing drugs known as thiazolidinediones are known to be specific, high affinity ligands for PPAR-gamma; this raises the possibility that states of insulin resistance will be characterized by increased PPAR-gamma phosphorylation as well. These studies will help us define how molecular events inside the adipocyte reflect upon the nutritional status of the whole organism.
| Rosen, Evan D; Kulkarni, Rohit N; Sarraf, Pasha et al. (2003) Targeted elimination of peroxisome proliferator-activated receptor gamma in beta cells leads to abnormalities in islet mass without compromising glucose homeostasis. Mol Cell Biol 23:7222-9 |
| Rosen, Evan D; Hsu, Chung-Hsin; Wang, Xinzhong et al. (2002) C/EBPalpha induces adipogenesis through PPARgamma: a unified pathway. Genes Dev 16:22-6 |
| Rosen, E D; Walkey, C J; Puigserver, P et al. (2000) Transcriptional regulation of adipogenesis. Genes Dev 14:1293-307 |
| Rosen, E D; Spiegelman, B M (2000) Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol 16:145-71 |
| Rosen, E D; Sarraf, P; Troy, A E et al. (1999) PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 4:611-7 |
