Polycystic ovary syndrome (PCOS) affects up to 10% of women of reproductive age, and is characterized by elevation in circulating androgen levels, insulin resistance, dyslipidemia and obesity. However, the molecular mechanisms that underlie the development of the metabolic syndrome in PCOS remain unclear. The interplay between PCOS and obstructive sleep apnea (OSA) in women may play a critical but under appreciated role in these pathologies. Despite the recent linkage between OSA and insulin resistance, and the finding that obese women with PCOS are up to 30 times more likely to develop OSA as weight matched women without PCOS, most of the studies on OSA and metabolism have been conducted in men. The central hypothesis of this application is that OSA is a novel risk factor for the development of insulin resistance in adipose tissue in women with PCOS. We will test this hypothesis by measuring insulin sensitivity in primary adipocytes from obese PCOS women with OSA, before and after therapeutic intervention for the OSA. Insulin signal transduction and regulation of lipid metabolism will be assayed in vitro and compared to values obtained in vivo. Additionally, we will determine the role alterations in circulating glucocorticoids and the localized activation of glucocorticoids in adipocytes by the enzyme 110- HSD1 on adipocytic insulin action. Finally, the effects of modulating reducing endogenous ovarian androgen production on insulin signaling in adipocytes from obese PCOS women with OSA will be determined, as will the effects of giving exogenous estrogen or progesterone to patients. Together, these studies will comprise an integral part of a larger SCOR application that will undertake a comprehensive examination of the role of OSA and circulating androgen on the development on insulin resistance, obesity and the metabolic syndrome in women with PCOS. Relevance: Women with PCOS suffer from obesity, metabolic syndrome, dysregulation of sex steroid synthesis and obstructive sleep apnea. However, the inter connections between these various disorders is not well understood. As part of an integrative collaborative project, this application will directly investigate the effects of OSA and androgens on insulin sensitivity in adipocyte biopsies from PCOS patients before and after therapeutic interventions.