The pro-inflammatory cytokine tumor necrosis factor alpha (TNF) is implicated as an inciting factor in the insulin resistance of obesity and Type II diabetes. Recent reports including work from our laboratory, indicate that TNF alters adipocyte metabolism and the secretion and gene expression of leptin, the newly discovered cytokine involved in the regulation of adiposity. Preliminary data from our laboratory also appears to show that those alterations are influenced by age. Because elevated TNF is primarily localized to adipose tissue in obesity and Type II diabetes, this cytokine may be a key biological modulator in these diseases, particularly since adipose tissue plays a central role in energy and metabolic homeostasis. However, the precise role of TNF in obesity/diabetes has not been established. The goal of this project is to define changes that occur in adipocyte responsiveness to TNF, with increasing age or disease progression in animals susceptible to obesity and diabetes. We will also compare it with animals that are resistant to those diseases. The rationale for the proposed research is that we believe that defining the effects of TNF on adipocyte metabolism and leptin secretion will provide valuable insights into the pathogenesis of these costly and prevalent diseases may provide a basis of understanding to better approach strategies of avoiding overt disease.