Exenatide is a synthetic agonist of the glucagon-like peptide-1 (GLP-1) receptor, which has also been shown to reduce food intake. The goal of this work is to test the hypothesis that exenatide reduces food intake and activates the enteric nervous system (ENS; myenteric and submucosal plexuses) of the gastrointestinal (GI) tract and the areas of the dorsal vagal complex (DVC) of the hindbrain that control food intake. EXPERIMENT 1: Five groups of overnight food-deprived male Sprague Dawley rats were injected with exenatide (0.1, 0.5, 5 and 10 microg/kg) or saline intraperitoneally, and the intake of 10% sucrose solution was measured at 5 min intervals for 120 min. All doses of exenatide reduced sucrose intake following the 20 min time point, and pretreatment with exendin (9-39), a GLP-1 receptor antagonist, reversed this reduction. EXPERIMENTS 2 AND 3: Following overnight food deprivation, five groups of rats were injected with the treatments listed above and sacrificed 90 min following the injections. The myenteric and submucosal plexuses and DVC were processed for detection of Fos-like immunoreactivity (Fos-LI; a marker for neuronal activation). Exenatide increased Fos-LI dose-dependently in the myenteric and submucosal neurons of the duodenum, but not jejunum and ileum, and in the areas of the DVC that regulate food intake e.g. area postrema, nucleus tractus solitaries and dorsal motor nucleus of the vagus. In addition, pretreatment with exendin (9-39) prior to exenatide injection blocked the activation in both locations.
Conclusions: Activation of the enteric neurons by exenatide may be part of the pathway by which this peptide reduces food intake.
Published by Elsevier B.V.