Severe obesity affects 4.7% of the U.S. population. A significant number of these individuals suffer from impaired glucose tolerance and type II diabetes due to insulin resistance (IR). Although it is generally accepted that the accumulation of intraabdominal (IA) fat increases the risk of developing IR, the mechanisms responsible for this phenomenon are not yet understood. In addition, the role of subcutaneous (SC) fat towards the etiology of IR - protective, inert or detrimental - is still under debate. This is because SC adipose tissue releases adipocytokines (IL-6, leptin, TNF- ) that have been demonstrated to impair insulin action. In individuals who are severely obese, hyperinsulinemia may induce an exaggerated production of adipocytokines from IA compared to SC fat stores. Our specific aims are: (1) to determine relative contribution of abdominal SC fat versus IA fat to systemic levels of IL-6, leptin and TNF- in lean and in severely obese individuals; (2) to determine the effects of systemic adipocytokine concentrations on whole body as well as tissue sensitivity to insulin. Hypothesis: (a) In the context of severe obesity, IA fat produces increased quantities of IL-6, leptin and TNF- compared to SC fat; (b) In severely obese patients undergoing weight loss, whole body and tissue IR can be predicted by changes in systemic adipocytokines. Methods: Adipose tissue content of IL-6, leptin and TNF- will be determined by ELISA in biopsies obtained from IA and SC fat stores in lean and severely obese patients. Computer tomography-determined areas of IA and SC fat will be related to changes in systemic adipocytokines at baseline and 6-mo following weight loss therapy. Changes in systemic IL-6, leptin and TNF- will be assessed from measurements made at baseline and following 6-mo weight loss. For this time period we will also determine changes in whole body (via IVGTT) and tissue sensitivity to insulin (via glucose uptake into muscle and fat). Relationships between systemic adipocytokines and IR will be assessed using uni- and multivariate correlation analysis. These novel studies will determine whether hypersecretion of adipocytokines by IA versus SC adipose tissue induces IR in patients with severe obesity.