CONTROL OF ADIPOGENESIS AND ENERGY METABOLISM

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DESCRIPTION (provided by applicant): The modern world is in the midst of an obesity epidemic that is growing to the extent that, in 2003-2004, 32% of US adults were obese and >50% were overweight. This increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes. 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, we have focused our attention on understanding the role of adipogenic transcription factors, most notably C/EBPs and PPAR?, in regulating the formation and function of adipocytes. During these studies, we identified a domain in PPAR? that facilitates inhibition of the Wnt signaling pathway in order to promote adipogenesis. These studies have led to a series of novel and exciting data that represent the core of our future aims. Specifically, we have demonstrated that helix 7 within the ligand-binding domain of PPAR? is required for its response to endogenous ligands. We also demonstrate that helix 7 regulates expression of a novel subset (Group 2) of adipogenic genes, including FGF21 and Ero1-La, that respond to the activity of the NAD-dependent deacetylase, SIRT1. We show that adiponectin secretion is regulated by Ero1-La and changes in PPAR? and SIRT1 activity. We have also identified two other subsets of adipogenic genes: Group 3 genes encode inflammatory proteins such as Ccl2/MCP-1 and are down-regulated during adipogenesis in a PPAR?-associated manner; Group 4 genes encode acute-phase reactants such as haptoglobin and are induced during adipogenesis, but are inhibited by the thiazolidinedione family of insulin sensitizers. The goal of these studies is to define the mechanisms by which PPAR? regulates such a physiologically important and diverse program of adipogenic gene expression. The specific aims are: 1. Define the role of SIRT1, HDAC3 and PGC-1a in regulating PPAR? target gene expression during adipogenesis and in mature adipocytes. 2: Identify the transcriptional complexes associating with PPAR? on the promoters/enhancers of select genes in mature adipocytes. 3: Define the role of helix 7 within the ligand- binding domain of PPAR? in controlling adipocyte gene expression. 4: To determine the role of posttranslational modification of PPAR? in regulating expression of adipocyte genes. PUBLIC HEALTH RELEVANCE: The modern world is in the midst of an obesity epidemic that is growing to the extent that, in 2003-2004, 32% of US adults were obese and >50% were overweight and this increase in adiposity has led to a significant increase in the number of individuals with obesity-related disorders including type 2-diabetes. It is well accepted that the adipocyte is a central player in the development of insulin resistance that leads to type 2 diabetes; consequently, it is important to define the mechanisms by which adipocytes regulate insulin responsive processes in the body. To this end, the studies are designed to define the mechanisms by which the `master regulator' of adipocyte formation, PPAR?, regulates expression of the genes coding for select proteins involved in metabolic homeostasis and energy balance including FGF21, ¿Klotho and adiponectin.