Environmental Endocrine Disruptors and Adipocyte Biology

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DESCRIPTION (provided by applicant): Rates of obesity and diabetes are reaching epidemic proportions, yet the mechanisms underlying their rapid expansion are incompletely understood. Data showing a correlation between synthetic chemical production and obesity rates has prompted some to propose the "environmental obesogen hypothesis" that suggests a potential causative role for some environmental pollutants in the development of obesity. While some endocrine disrupting chemicals have been shown to promote the differentiation of adipocytes, the exact pathways leading to this phenomenon are incompletely characterized. Previous work studying the impact of endocrine disrupters on the reproductive axis has demonstrated that agents can directly bind to and regulate the nuclear estrogen receptor. Since adipocytes are highly regulated by a number of transcription factors, we will test the hypothesis that endocrine disrupting chemicals impact adipocyte function via direct modulation of nuclear transcription factors and changes in gene/protein expression. Thus, the overarching goal of this application is to define the specific molecular mechanisms by which endocrine disrupting chemicals affect preadipocyte differentiation and mature adipocyte energy homeostasis. A specific focus of this work will be to differentiate the physiological effects of endocrine disruptors mediated through the glucocorticoid receptor as compared to the peroxisome proliferator activator-y, as these two pathways have antagonistic effects on insulin sensitivity in the mature adipocyte. Specific Aim 1 will identify endocrine disruptors that alter the activity of specific nuclear transcription factors in the preadipocyte and determine their effects on differentiation of 3T3-L1 preadipocytes. Particular attention will also be given to potential synergy among endocrine disruptors acting through different pathways that may explain how exposure to low doses of multiple chemicals may result in inappropriate preadipocyte differentiation. Specific Aim 2 will characterize the effects of endocrine disruptors on insulin-mediated energy homeostasis in the mature adipocyte, including activation of insulin signaling cascades and regulation of glucose uptake, lipogenesis, and anti-lipolysis. A special focus of this aim will be to determine whether exposure to endocrine disruptors during specific developmental windows changes the insulin sensitivity of the mature adipocyte. PUBLIC HEALTH RELEVANCE: This work will help characterize the means by which environmental pollutants affect the development and behavior of fat cells in order to understand how synthetic chemicals may contribute to the obesity epidemic; these studies could also provide novel insights into the mechanisms underlying altered fat cell biology in obesity. Finally, these studies could support public health efforts to remediate environmental contamination.