The modern world is in the midst of an obesity epidemic that is continuing to grow to the extent that, in 2003- 2004, 32% of US adults were obese and as many as 50% were considered overweight. This increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes and cardiovascular disease. It is well accepted that the adipocyte is a central player in the development of insulin resistance that leads to type 2 diabetes. It is important, therefore, to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. To this end, during the last funding cycle, we have focused our attention on understanding the role of adipogenic transcription factors, most notably the C/EBPs and PPARgamma, in regulating the formation and function of adipocytes. During the course of these studies, we identified a domain in PPARgamma that facilitates inhibition of the Wnt signaling pathway in order to promote adipogenesis. These studies have now led to a series of novel and exciting preliminary data that represent the core of our future aims. Specifically, we have demonstrated that helix 7 within the ligand-binding domain of PPARgamma is required for its response to endogenous ligands. We also demonstrate that helix 7 regulates expression of a novel subset of adipogenic genes, including the ER oxidoreductase Ero1-Lalpha, that respond to the activity of the NAD-dependent deacetylase, SIRT1. We show that adiponectin secretion from adipocytes is regulated by Ero1-Lalpha and changes in PPARgamma and SIRT1 activity. We propose, therefore, that helix 7 of PPARgamma interacts with specific nuclear coregulators in response to metabolic perturbations to control select adipogenic genes, some of which regulate adiponectin secretion .
The specific aims to test this hypothesis are as follows: 1. To determine the role of posttranslational modification of PPARgamma in regulating expression of the helix 7- associated gene expression. 2. To identify nuclear factors interacting with PPARgamma that function to facilitate helix 7-associated gene expression. 3. To define the mechanisms by which PPARgamma regulates expression of Ero1-l_alpha in response to changes in metabolic status of adipocytes. 4. To define the function of Ero1-Lalpha and associated proteins in regulating adiponectin secretion
