Nesfatin-1 Inhibits Gastric Acid Secretion via a Central Vagal

34 Nesfatin-1, a novel hypothalamic peptide, inhibits nocturnal feeding behavior and 35 gastrointestinal motility in rodents. The effects of nesfatin-1 on gastrointestinal secretory 36 function, including gastric acid production, have not been evaluated. Nesfatin-1 was injected 37 into the 4 intracerebral ventricle (4V) of chronically cannulated rats to identify a nesfatin dose 38 sufficient to inhibit food intake. Nesfatin-1 (2μg) inhibited dark-phase food intake, in dose 39 dependent fashion, for over 3 hours. Evaluation of gastric acid production was conducted in 40 urethane-anesthetized rats. Nesfatin-1 (2μg) was introduced via 4V following endocrine 41 stimulation of gastric acid secretion by pentagastrin (2μg/kg/h, I.V.), vagal stimulation with 242 deoxy-D-glucose (200mg/kg, S.C.), or no stimulus. Gastric secretions were collected via gastric 43 cannula and neutralized by titration to determine acid content. Basal and pentagastrin-stimulated 44 gastric acid secretion were unaffected by nesfatin-1, whereas 2-deoxy-D-glucose-stimulated 45 gastric acid production was inhibited by nesfatin-1 in a dose-dependent manner. C-Fos 46 immunofluorescence in brain sections was used to evaluate in vivo neuronal activation by 4V 47 nesfatin-1. Nesfatin-1 caused activation of efferent vagal neurons, as evidenced by a 16-fold 48 increase in the mean number of c-Fos positive DMNV neurons in nesfatin-1 treated animals vs. 49 controls, p<0.01. Finally, nesfatin-induced calcium signaling was evaluated in primary cultured 50 DMNV neurons from neonatal rats. Nesfatin-1 caused dose-dependent calcium increments in 51 95% of cultured DMNV neurons. These studies demonstrate that central administration of 52 nesfatin-1, at doses sufficient to inhibit food intake, results in inhibition of vagally-stimulated 53 secretion of gastric acid. Nesfatin-1 activates DMNV efferent vagal neurons in vivo and triggers 54 calcium signaling in cultured DMNV neurons. 55