A group of neurons in the caudal nucleus of the solitary tract (NTS) processes preproglucagon to glucagon-like peptide 1 (GLP-1), GLP-2 and oxyntomodulin. Whereas the anorectic capacity of all three neuropeptides has been demonstrated, only relatively little is known of preproglucagon mRNA regulation in the brain stem. Using in situ hybridization and fluorescence immunohistochemistry, we examined hindbrain preproglucagon expression in lean and obese Zucker rats under different metabolic perturbations. First, the effect of an acute 48-h fast was examined in male Sprague-Dawley as well as in lean and obese Zucker rats. Whereas fasting had no effect on preproglucagon expression in either genotype, mRNA levels were strongly up regulated in obese Zucker rats. Using a direct immunostaining procedure and a monoclonal GLP-2 antibody, we found a doubling of the immunofluorescence signal emanating from the preproglucagon neurons in caudal brainstem suggesting that indeed the high mRNA levels observed using in situ hybridization histochemistry also reflect a higher translational activity. To investigate the effects of long-term body weight perturbations, lean and obese Zucker rats were either free-fed, voluntarily overfed (chocolate spread enriched chow) or food restricted for 35 days. Preproglucagon levels remained high in the obese Zucker rats irrespective of diet. Finally, in order to functionally validate the apparent hyperactivity in the preproglucagon system in the Zucker rat, we examined the effect of central GLP-1 receptor blockade. ICV administration of 20 microg of the GLP-1 receptor antagonist Des-His-Exendin-9-39 in the morning increased 4-h food intake in obese but not in lean Zucker rats, pointing to an increased activity in central preproglucagon containing pathways in leptin receptor deficient rats. Our data suggest that the preproglucagon neurons in the brainstem are influenced by leptin signaling and point to a role of preproglucagon neurons in the integration of metabolic signals that occurs in the nucleus of the solitary tract.