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The soluble leptin receptor (SLR) is the major, circulating, leptin-binding protein and, in vitro, the SLR inhibits leptin-binding to cell surface receptors. Here we assessed the effects of the SLR on physiological responses to leptin, in vivo.SLR and leptin were given as a single injection (intracerebroventricularly, i.c.v.) or by central (i.c.v.) and peripheral (s.c.) infusion to normal adult F344XBN rats. Phosphorylation of hypothalamic STAT3 (Western blot), food intake and body weight, and the thermogenic response in brown adipose tissue (BAT) were measured.Acute central co-administration of SLR (13.5 μg) and leptin (90 ng) blocked the threefold increase in hypothalamic STAT3 phosphorylation induced by leptin alone, 1 h after the injections. Peripheral leptin infusion (0.1 mg·day−1 for 7 days; s.c.) induced a significant reduction in food intake and body weight, which were partially blocked with a simultaneous central infusion of SLR (4.3 μg·day−1; i.c.v.). In a second experiment, SLR central infusion alone (5.5 μg·day−1) increased food intake and body weight, suggesting that the SLR was able to neutralize endogenous leptin in the brain. This dose of SLR, infused together with a lower dose of peripheral leptin (0.05 mg·day−1), abolished the thermogenic response in BAT, but the anorexic responses and weight reduction were only partially attenuated.These results provide direct evidence that the SLR neutralizes leptin, endogenous or exogenous, in vivo. By neutralizing leptin, the SLR may play a regulatory role in energy homeostasis.