Peroxisome proliferator—activated receptor (PPAR)-α agonists lower circulating lipids, but the consequences for muscle lipid metabolism and insulin sensitivity are not clear. We investigated whether PPAR-αactivation improves insulin sensitivity in insulin-resistant rats and compared the effects with PPAR-γ activation. Three-week high fat-fed male Wistar rats were untreated or treated with the specific PPAR-α agonist WY14643 or the PPAR-γ agonist pioglitazone (both 3 mg · kg^-1· day^-1) for the last 2 weeks of high-fat feeding. Like pioglitazone, WY14643 lowered basal plasma levels of glucose, triglycerides(-16% vs. untreated), and leptin (-52%), and also muscle triglyceride (-34%)and total long-chain acyl-CoAs (LCACoAs) (-41%) (P < 0.05). In contrast to pioglitazone, WY14643 substantially reduced visceral fat weight and total liver triglyceride content (P < 0.01) without increasing body weight gain. WY14643 and pioglitazone similarly enhanced wholebody insulin sensitivity (clamp glucose infusion rate increased 35 and 37% and glucose disposal 22 and 15%, respectively, vs. untreated). Both agents enhanced insulin-mediated muscle glucose metabolic index (Rg') and reduced muscle triglyceride and LCACoA accumulation (P < 0.05). Although pioglitazone had more potent effects than WY14643 on muscle insulin sensitization, this was associated with its greater effect to reduce muscle LCACoA accumulation. Overall insulin-mediated muscle Rg' was inversely correlated with the content of LCACoAs (r = -0.74, P =0.001) and with plasma triglyceride levels (r = -0.77, P< 0.001). We conclude that even though WY14643 and pioglitazone,representing PPAR-α and PPAR-γ activation, respectively, may alter muscle lipid supply by different mechanisms, both significantly improve muscle insulin action in the high fat—fed rat model of insulin resistance, and this effect is proportional to the degree to which they reduce muscle lipid accumulation.