Voluntary overfeeding rapidly induces resistance to the effects of systemic insulin and leptin on liver glucose metabolism. To examine whether central administration of recombinant leptin can restore leptin and insulin action on liver glucose fluxes, we infused leptin in the third cerebral ventricle of conscious overfed rats during pancreatic-insulin clamp studies. The effect of leptin on the phosphorylation of the signal transducer and activator of transcription-3 in the arcuate nuclei of the hypothalamus was similar in animals fed a regular diet or a high-fat diet for 3 days. The infusion of leptin in the third cerebral ventricle markedly inhibited glucose production in rats fed a high-fat diet mainly by decreasing glycogenolysis. The inhibition of glycogenolysis was sufficient to normalize glucose production and was accompanied by leptin-induced decreases in the hepatic expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. Thus central administration of leptin rescues the hepatic insulin resistance induced by short-term hyperphagia.