To test the roles of lipid oversupply versus oxidation in causing tissue lipid accumulation associated with insulin resistance/obesity, we studied in vivo fatty acid (FA) metabolism in obese (Obese) and lean (Lean) Zucker rats. Indices of local FA utilization and storage were calculated using the partially metabolizable [9,10-3H]-(R)-2-bromopalmitate (3H-R-BrP) and [U-14C]-palmitate (14C-P) FA tracers, respectively. Whole-body FA appearance ( ) was estimated from plasma 14C-P kinetics. Whole-body FA oxidation rate ( ) was assessed using 3H2O production from 3H-palmitate infusion, and tissue FA oxidative capacity was evaluated ex vivo. In the basal fasting state Obese had markedly elevated FA levels and , associated with elevated FA utilization and storage in most tissues. Estimated rates of muscle FA oxidation were not lower in obese rats and were similarly enhanced by contraction in both lean and obese groups. At comparable levels of FA availability, achieved by nicotinic acid, was lower in Obese than Lean. In Obese rats, FA oxidative capacity was 35% higher than that in Lean in skeletal muscle, 67% lower in brown fat and comparable in other organs. In conclusion, lipid accumulation in non-adipose tissues of obese Zucker rats appears to result largely from systemic FA oversupply. 1. Introduction Disturbances in fatty acid metabolism may cause several key features of the insulin resistance syndrome, including impaired glucose regulation, dyslipidemia, and obesity. Thus systemic free fatty acid (FA) oversupply can decrease insulin-stimulated glucose uptake in skeletal muscle [1, 2], reduce insulin suppression of hepatic glucose production [3], and alter glucose-stimulated insulin secretion [4]. Furthermore, an oversupply of FA to liver may cause dyslipidemia, including hypertriglyceridemia and the atherogenic lipoprotein profile [5]. With regard to FA utilization, reductions in mitochondrial content and diminished fatty acid oxidation capacity in skeletal muscle and adipose tissue have been linked with obesity and insulin resistance [6–14]. Additionally, in conditions of impaired insulin action there is also a reduced ability to appropriately switch between glucose and lipid fuels (i.e., metabolic inflexibility), postulated to play an important role in the development of obesity [15]. The obese Zucker rat is an animal model possessing major metabolic features seen in conditions of human insulin resistance, including glucose metabolic insulin resistance, hypertriglyceridemia, and elevated nonadipose tissue lipid levels [16, 17], which have been implicated
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