Leptin, a 16-kDa protein, is produced by white adipose tissue (WAT), and is thought to serve as a feedback signal indicating the size of fat stores. Considerable amount of data have shown that leptin can mediate lipid metabolism. However, its possible direct effects on the metabolism of lipids in vivo and the mechanisms involved have not been fully characterized. In this study, we investigated the in vivo effects of leptin on the autonomic nerve activity and lipolysis. We found that intravenous administration of leptin (10 microg/rat) excited the sympathetic nerves innervating WAT, and this effect was abolished by the pretreatment with diphenhydramine, a histamine H(1) receptor antagonist. Moreover, intraperitoneal administration of leptin (130 microg/kg) elevated the levels of plasma glycerol and free fatty acid (FFA). The effect of leptin on plasma FFA was eliminated by pretreatment with diphenhydramine and propranolol, a beta-adrenergic receptor blocker, and disappeared in suprachiasmatic nucleus (SCN)-lesioned rats. Our results suggest that leptin might regulate the lipolytic processes in adipose tissue through facilitation of the sympathetic nerves, driven by histamine neurons through the H(1) receptor, and a beta-adrenergic receptor, probably the beta(3)-receptor, is involved in the lipolytic response to leptin. The actions of leptin in this study are supposed to be controlled by the SCN.