Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss

The current study was undertaken to investigate fatty acid metabolism by sk eletal muscle to examine potential mechanisms that could lead to increased muscle triglyceride in obesity. Sixteen lean and 40 obese research voluntee rs had leg balance measurement of glucose and free fatty acid (FFA) uptake (fractional extraction of [9,10 H-3]oleate) and indirect calorimetry across the leg to determine substrate oxidation during fasting and insulin-stimul ated conditions. Muscle obtained by percutaneous biopsy had lower carnitine palmitoyl transferase (CPT) activity and oxidative enzyme activity in obes ity (P < 0.05). During fasting conditions, obese subjects had an elevated l eg respiratory quotient (RQ, 0.83 +/- 0.02 vs. 0.90 +/- 0.01; P < 0.01) and reduced fat oxidation but similar FFA uptake across the leg. During insuli n infusions, fat oxidation by leg tissues was suppressed in lean but not ob ese subjects; rates of FFA uptake were similar. Fasting values for leg RQ c orrelated with insulin sensitivity (r = -0.57, P < 0.001). Thirty-two of th e obese subjects were restudied after weight loss (WL, -14.0 +/- 0.9 k.g); insulin sensitivity and insulin suppression of fat oxidation improved (P < 0.01), but fasting leg RQ (0.90 +/- 0.02 vs. 0.90 +/- 0.02, pre-WL vs, post -WL) and muscle CPT activity did not change. The findings suggest that trig lyceride accumulation in skeletal muscle in obesity derives from reduced ca pacity for fat oxidation and that inflexibility in regulating fat oxidation , more than fatty acid uptake, is related to insulin resistance.