Leptin is an adipocyte hormone that functions as an afferent signal in a negative feedback loop regulating body weight, and acts by interacting with a receptor in the hypothalamus and other tissues. Leptin treatment has potent effects on lipid metabolism, and leads to a large, specific reduction of adipose tissue mass after several days. Here we show that leptin also acts acutely to increase glucose metabolism, although studies of leptin's effect on glucose metabolism have typically been confounded by the weight-reducing actions of leptin treatment, which by itself could affect glucose homoeostasis. We have demonstrated acute in vivo effects of intravenous and intracerebroventricular administrations of leptin on glucose metabolism. A five-hour intravenous infusion of leptin into wild-type mice increased glucose turnover and glucose uptake, but decreased hepatic glycogen content. The plasma levels of insulin and glucose did not change. Similar effects were observed after both intravenous and intracerebroventricular infusion of leptin, suggesting that effects of leptin on glucose metabolism are mediated by the central nervous system (CNS). These data indicate that leptin induces a complex metabolic response with effects on glucose as well as lipid metabolism. This response is unique to leptin, which suggests that new efferent signals emanate from the CNS after leptin treatment.