. Sympathetic denervation does not prevent a reduction in fat pad size of rats or mice treated with peripherally administered leptin. Am J Physiol Regul Integr Comp Physiol 289: R92-R102, 2005; doi:10.1152/ajpregu.00858.2004.-Leptin increases sympathetic nervous system (SNS) activity in brown adipose tissue and renal nerves. Experiments described here tested whether SNS innervation is required for peripheral, physiological concentrations of leptin to reduce body fat. In experiment 1, one epididymal (EPI) fat pad was sympathectomized by local injection of 6-hydroxydopamine (6OHDA) in C57BL/6 mice that were then infused for 13 days with PBS or 10 g leptin/day from an intraperitoneal miniosmotic pump. Surprisingly, EPI denervation increased total body fat of PBS-infused mice but leptin decreased the size of both injected and noninjected EPI pads in 6OHDA mice. Experiment 2 was identical except for the use of male Sprague-Dawley rats that were infused with 50 g leptin/day. Leptin had little effect on EPI weight or norepinephrine (NE) content, but denervation of one EPI pad decreased the effect of leptin on intact EPI, inguinal and retroperitoneal (RP) fat and increased the size of the mesenteric fat pad. Experiment 3 included groups in which either one EPI or one RP pad was denervated. RP denervation reduced RP NE content but did not prevent a leptin-induced reduction in fat pad mass. Therefore, the SNS is not required for low doses of leptin to reduce body fat. EPI denervation significantly increased adipocyte number in contralateral EPI and RP fat pads and this was prevented by leptin. These changes in intact pads of rats with one denervated fat pad imply communication between fat depots and suggest that both leptin and the SNS regulate the size of individual depots. peripheral leptin infusion; norepinephrine; body weight IT IS WELL ESTABLISHED THAT administration of leptin to experimental animals results in a selective decrease in body fat mass while protecting lean body mass (24). A similar response has been observed in obese humans on a weight-reducing diet and receiving daily injections of leptin (26). The loss of body fat may be accompanied by hypophagia (18) but can occur in the absence of any sustained inhibition of food intake if low doses of leptin are infused peripherally into wild-type mice (4, 24). The mechanisms responsible for this specific reduction in body fat by physiological concentrations of leptin have not been fully elucidated. Leptin inhibits adipose tissue fatty acid synthesis (6, 21) and this is associated with a downregulation of expression of transcription factors and enzymes that promote lipogenesis (37,46). In addition, in vivo and in vitro studies have shown that very high concentrations of leptin promote lipolysis from adipocytes in wild-type mice (15) and rats (16), whereas physiological concentrations of leptin (10 ng/ml) have no effect on the lipolytic rate in isolated adipocytes (16). The lipolysis that is induced by leptin is unusual because a simultaneous stimulation of fat cel...