Project Summary/Abstract Our goal is to understand the mechanisms by which obesity, and specifically upper body/visceral obesity (UBO), causes insulin resistance, Type 2 Diabetes and the other health problems. We study what regulates the release of free fatty acids (FFA) from adipose tissue (lipolysis) in humans. For this application we propose to complete the following Specific Aims: 1. We will determine whether impaired insulin-induced suppression of regional lipolysis (measured by IC50) in UBO compared with insulin-sensitive control groups is related to differences in adipocyte lipolysis protein responses. 2. We will determine whether the suppression of regional lipolysis induced by niacin, acting independently of the insulin signaling pathway, is impaired in UBO compared with insulin-sensitive control groups and, if so, if this is related to local differences in adipocyte lipolysis-regulating proteins. 3. We will determine whether stimulated adipose tissue lipolysis resulting from the combination of somatostatin infusion (to suppress insulin secretion) and intravenous epinephrine, is impaired in UBO compared with insulin-sensitive control groups and, if so, if this is related to regional differences in lipolysis and adipocyte lipolysis-regulating proteins. 4. We will determine whether the regional release of FFA relative to glycerol as a measure of intracellular reesterification accounts for the differences in systemic FFA delivery between UBO and non-UBO adults. Combined, we believe these studies will offer insights as to whether adipose tissue lipolysis is abnormal in UBO specifically in response to insulin, or if there are more fundamental issue with metabolic flexibility that relate to adipocyte size. By understanding what is different in the process of lipolysis in UBO we hope to provide guidance as to what therapeutic strategies might be employed to treat adipose dysfunction.