We have evaluated the effects of a 2 week treatment with pioglitazone (Pio, 4 mg/kg.d) on hepatic and peripheral insulin sensitivity, plasma adiponectin, and resistin concentrations in lipid-infused rats. Lipid infusion caused a large (60% in 4 h) decrease in whole-body insulin sensitivity. Hepatic and peripheral insulin resistance contributed about equally to the whole-body insulin resistance. Pio treatment significantly improved whole-body insulin sensitivity due to normalization of hepatic insulin action, whereas peripheral insulin Action remained unchanged and inhibited. Basal plasma resistin levels were similar to 4-fold lower in Pio-treated than in untreated rats. During lipid infusion, resistin levels rose in both Pio-treated and untreated rats, but remained significantly lower in Pio-treated than in untreated rats (P < 0.01). Dot-blot analyses revealed a marked decrease in resistin protein levels in the liver of Pio-treated rats. Resistin levels were higher in muscle tissue in lipid group compared with control and Pio-treated rats (P < 0.05). Fasting plasma adiponectin levels were 1.5-fold higher in Pio-treated than in untreated rats. We conclude that short-term treatment of rats with Pio prevented lipid-induced hepatic insulin resistance and that Pio mediated lowering of blood resistin and raising of adiponectin levels may have contributed to that effect. (c) 2005 Elsevier Inc. All rights reserved.