A recombinantly produced
murine leptin analog (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 coinjection of MLA with exogenous
leptin significantly attenuated
leptin-induced reduction of 48-h food intake and
body weight. Coinjection of MLA with
leptin also reduced
leptin-induced phosphorylation of
signal transducer and activator of transcription 3 (STAT3) in the hypothalamus. In addition, chronic intracerebroventricular MLA infusion over 14 d 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 where
leptin induces acute neuronal activation. This mixed antagonist/agonist action suggests either 1) that 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.