Previous studies supported by this grant have elucidated a central role played by free fatty acids (FFA) in the regulation of glucose output by the liver. In the competitive renewal the potential significance of this interrelationship between adipocytes and liver function to the metabolic syndrome (Syndrome "X") will be investigated. We examine the hypothesis that overproduction of FFA by the visceral adipose depot is responsible for hepatic insulin resistance in the face of visceral adiposity. Animal model is the conscious dog, either lean, or with central adiposity induced by moderate (2g/kg/day) or enhanced (6g/kg/day) fat feeding. These diets produce an animal with central adiposity and insulin resistance, but with limited increase in body weight which represents central obesity but not morbid obesity. We will measure the flux of FFA and cytokines (leptin, TNF-alpha, IL-6) from the visceral adipose depot to liver under lean and fat fed conditions. Specific aims include 1) The individual roles of the direct (i.e., antiglucagon) versus indirect (i.e., via suppression of lipolysis) effects of insulin on glucose production will be assessed. Dose-response effects will be examined for basal, fasting insulin levels as well elevated levels achieved after meals. 2) Release of glucose from the gut as well as insulin secretion into portal blood will be measured after oral glucose. Changes in portal glucose and insulin will be induced, alone or together, by direct intraportal infusion and direct versus indirect effect of insulin on liver glucose output will be determined. 3) Changes in intraportal flux of FFA as well as cytokines measured in lean vs. obese animals will be simulated by direct infusion of Liposyn or cytokines into portal veins to examine the chronic effects of visceral release of these compounds to liver and peripheral insulin resistance. 4) We have identified powerful oscillations in lipolysis from the central adipose depot, and shown that they are driven by the sympathetic nervous system. We will examine the importance of sympathetic drive of central oscillations in extended fasting as well as changes in sympathetic drive as a function of time of day. These studies will reveal the importance of the "visceral-hepatic axis" in the pathogenesis of liver insulin resistance in the metabolic syndrome, and may reveal the linkage between central adiposity, insulin resistance and risk for Type 2 diabetes mellitus.