COORDINATION OF REGULATORY MECHANISMS IN METABOLISM

Abnormalities of fatty acid metabolisms are considered important contributors to the adverse health consequences of upper body/visceral obesity. Excess hepatic FFA delivery, perhaps originating from visceral adipose tissue lipolysis, could account for the reduced ability of insulin to inhibit hepatic glucose production and for the abnormal VLDL kinetics in visceral obesity. The investigators have found that overnight postabsorptive (basal) hepatic FFA delivery is increased in obesity, but that visceral lipolysis increases in proportion to visceral fat mass only in obese women. The abnormalities of hepatic glucose and lipid metabolism attributed to excess FFA would be expected to be more apparent at times of elevated plasma insulin concentrations. However, there is no information regarding the effects of insulin on splanchnic FFA metabolism in visceral obesity. Excess FFA can also impair insulin mediated glucose disposal in muscle. This could occur through direct or indirect mechanisms; increased FFA is associated with increased intramuscular triglycerides, which are independently associated with insulin resistance. The investigators propose to assess the effects of insulin on splanchnic FFA metabolism in visceral obesity and to investigate intramuscular fatty acid kinetics using a newly developed stable isotope technology. The objectives of this proposal are to determine whether: 1) insulin suppression of splanchnic FFA release is impaired in visceral obesity; 2) visceral lipolysis contributes a greater proportion of hepatic FFA delivery in viscerally obese than in non-obese individuals under hyperinsulinemic conditions; 3) intramuscular triglyceride hydrolysis is increased in visceral obesity compared with trained and sedentary lean humans; 4) insulin inhibits both intramuscular triglyceride hydrolysis and the delivery of fatty acids to pre-oxidative intramuscular pool in lean (trained and sedentary) but not viscerally obese humans; and 5) improved insulin action with respect to glucose metabolism, whether accomplished by exercise training/weight loss or via troglitazone treatment, is associated with improvements in insulin action on FFA and intramuscular fatty acid metabolism in viscerally obese humans. Completion of the studies proposed in this application will better define the role of insulin in regulating visceral lipolysis in high risk obesity and will provide novel information regarding intramuscular fatty acid metabolism in insulin resistant and insulin sensitive states.