Principal Investigator, Dr. Robert Sargis, endeavors to become an independent investigator at the interface of the fields of environmental endocrine disruption, obesity, and metabolism. In particular Dr. Sargis will examine the effects of environmental pollutants on adipocyte metabolism and insulin signaling in order to understand the molecular mechanisms by which these compounds contribute to the burgeoning obesity and diabetes epidemics. Rooted in endocrine disruptor research demonstrating that chemical pollutants can alter endocrine signaling, the "environmental obesogen hypothesis" posits a causative link between the exponential rise in synthetic chemical production and the obesity epidemic. The central hypothesis of this application is that inappropriate modulation of glucocorticoid receptor activity by environmental endocrine disruptors will adversely affect adipocyte metabolism and insulin signaling. Understanding the molecular mechanisms by which environmental chemicals alter glucocorticoid receptor activation could significantly advance our knowledge of the pathophysiology of these metabolic derangements. Preliminary data suggest that specific endocrine disruptors activate the glucocorticoid signaling cascade, stimulate adipocyte differentiation, and induce insulin resistance in the mature adipocyte. To investigate the role of environmental endocrine disruption in adipocyte metabolism and insulin signaling, the following studies are proposed: 1) to examine the effects of environmental endocrine disruptors on insulin signaling in mature adipocytes to identify the molecular targets of these chemicals;2) to determine the mechanisms by which glucocorticoid-like endocrine disruptors inappropriately activate the glucocorticoid receptor and thereby induce insulin resistance;and 3) to characterize alterations in adipocyte gene expression induced by endocrine disruptors. In sum, the proposed studies will greatly enhance our understanding of the role of environmental endocrine disruptors in the perturbation of adipocyte metabolism that may in part underlie the scourges of obesity and diabetes. The proposed project will be conducted by Dr. Sargis under the guidance of Dr. Matthew Brady and a Research Advisory Committee in the Section of Endocrinology, Diabetes, and Metabolism at the University of Chicago. This application has been specifically designed to enable Dr. Sargis's transition to independence as an Assistant Professor at the completion of this 5-year award. A career development plan has been devised to help Dr. Sargis meet this goal through the acquisition of new research skills in biochemistry and molecular biology as well as selected coursework. Collectively, these experiences will expand Dr. Sargis's knowledge base in order to perform these cutting-edge studies at the unique interface of molecular metabolism and environmental health. The University of Chicago provides a rich and dynamic environment in which to complete this career development award, and Dr. Brady, as well as numerous other skilled investigators, is deeply committed to helping Dr. Sargis achieve his goal of becoming an independent scientist. PUBLIC HEALTH RELEVANCE: The burgeoning obesity and diabetes epidemics are placing enormous strains on our healthcare system;however, the precise factors responsible for these diseases are incompletely understood. The proposed studies will characterize the molecular mechanisms by which environmental endocrine disrupting chemicals contribute to the development of obesity and diabetes through disruption of adipocyte metabolism and insulin signaling with particular focus on alterations in glucocorticoid signaling. Understanding the potential contribution of environmental pollutants to the development of obesity and diabetes will provide the scientific foundation upon which to develop sound public policy directed at mitigating the effects of environmental depredation on the metabolic scourges of our time.