REGULATION OF TRIACYLGLYCEROL METABOLISM IN OBESITY

This application focuses on the hypertriglyceridemia associated with upper body obesity. The investigator hypothesizes that increased triglycerides in upper body obesity result from increased availability of free fatty acids to the liver due to resistance to insulin mediated inhibition of peripheral lipolysis. Furthermore, hyperglycemia-induced inhibiton of hepatic fatty acid oxidation results in diversion of hepatic free fatty acids into esterification for triglycerides. The investigator further proposes that the relative importance of either increased hepatic free fatty acid availability or reduced hepatic fatty acid oxidation in abnormal triglyceride production depends on feeding. To investigate these hypotheses, the investigator proposes quantification of whole body and regional (leg and splanchnic) free fatty acid kinetics and oxidation and VLDL triglycerides secretion and clearance rates in both upper body and lower body obese individuals. These measures are to be made both fasting and fed. The investigator will also manipulate free fatty acid concentrations by adjustments with nicotinic acid, lipid and, heparin infusions. The studies employ stable and radioactive isotopes for kinetic measurements and involve detailed physiologic and kinetic mathematical modeling.