A recombinantly produced analogue of murine leptin (MLA) antagonizes leptin-induced signaling in cell lines that express the long form of the leptin receptor. However, the effects of MLA on the activity of leptin-sensitive neurons and on central neural controls of food intake, have not been reported. Here we report effects of MLA on food intake and body weight in adult rats, and on the activity of cultured rat vagal afferent neurons. Daily intracerebroventricular (i.c.v.) co-injection of MLA with exogenous leptin significantly attenuated leptin induced reduction of 48-h food-intake and body weight. Co-injection of MLA with leptin also reduced leptin-induced phosphorylation of STAT3 in the hypothalamus. In addition, chronic i.c.v. MLA infusion over 14 days via osmotic minipumps significantly increased daily food intake, rate of body weight gain, fat-pad mass, and circulating plasma leptin concentrations. Surprisingly, however, MLA did not antagonize leptin-evoked increases in cytosolic calcium concentrations in vagal afferent neurons in primary culture. Rather, MLA itself produced acute activation selectively in leptin responsive vagal afferent neurons. These data suggest that MLA is an antagonist for the central effects of leptin on food intake and body weight, but an agonist at sites were leptin induces acute neuronal activation. This mixed antagonist/agonist action suggests either that (1) the coupling of a single leptin receptor (ObRb) to acute activation of neurons occurs by a signaling mechanism different from those that mediate centrally evoked reductions in food intake and body weight, or 2) that acute neuronal activation and centrally induced reductions of food intake and body weight are mediated by different leptin receptor subtypes.