The central-targets mediating the anorectic and other actions of leptin have yet to be fully identified. Though previous studies have focused on the hypothalamus, leptin also acts on neurons in extra-hypothalamic sites, including the nucleus of the solitary tract (NTS). Moreover, injection of leptin into the NTS of rats suppresses food intake. Within the CNS, glucagon-like peptide (GLP-1) a product of proglucagon, is synthesized almost exclusively in neurons of the NTS. Intracerebroventricular administration of GLP-1 inhibits energy intake and GLP-1 receptor antagonists attenuate the anorexic effects of leptin in rats. To examine if NTS proglucagon neurons are directly regulated by leptin, we performed double GLP-1 and P-STAT3 immunohistochemistry on brain sections from i.p. leptin-treated mice and rats. Leptin induced STAT3 phosphorylation in 100% of GLP-1 cells in the caudal brainstem of mice. In striking contrast, 0% of GLP-1 positive neurons in rats responded to leptin. We then measured regulation of NTS proglucagon mRNA using real time RT-PCR in mice and rats fed ad libitum, fasted, or fasted and treated i.p. with leptin. In mice, proglucagon mRNA fell by fasting and this was prevented by leptin administration. In rats, by contrast, proglucagon mRNA was unaffected by either fasting or leptin. Taken together, our studies reveal direct regulation of proglucagon neurons by leptin in mice but not rats, along with corresponding species differences in the regulation of proglucagon mRNA expression. These data, combined with previous results, suggest a different mechanism of interaction between leptin and NTS proglucagon neurons in mice and rats.