title: Brain activation following peripheral administration of the GLP-1 receptor agonist exendin-4.
abstract: The aim of our study was to investigate the anorectic and brain stimulatory effects of various doses of exendin-4 (Ex-4) and to investigate the role of the vagus nerve in Ex-4-induced brain activation. A dose-related increase in c-fos mRNA expression was observed following Ex-4 administration (0.155-15.5 μg/kg). Doses of Ex-4 that caused anorexia without aversive effects (0.155, 0.775 μg/kg) induced c-fos expression in the hypothalamic arcuate and paraventricular (PVH; parvocellular) nuclei as well as in the limbic and brainstem structures. Doses of Ex-4 that caused aversion (1.55, 15.5 μg/kg) stimulated the same regions (in a more intense way) and additionally activated the magnocellular hypothalamic structures (supraoptic nucleus and PVH magnocellular). The brain c-fos pattern induced by Ex-4 showed both similarities and differences with that induced by refeeding. Subdiaphragmatic vagotomy significantly blunted the stimulation of c-fos mRNA expression induced by Ex-4 in the nodose ganglion, the medial part of nucleus of the solitary tract, and the parvocellular division of the PVH. Pretreatment with Ex-9-39 (330 μg/kg ip) impaired the neuronal activation evoked by Ex-4 in all brain regions and in the nodose ganglion. Effects of Ex-4 on hypothalamic-pituitary-adrenal axis activity were not altered by vagotomy. Results of this study demonstrate and relate the anorectic and brain stimulatory effects of aversive and nonaversive doses of Ex-4 and indicate that the activation of specific central regions induced by the peripheral administration of Ex-4 is, at least in part, dependent on the integrity of the vagus nerve.
authors.affiliation: Merck-Frosst/Canadian Institutes of Health Research Chair in Obesity and Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada.
authors.forename: Elena-Dana
authors.initials: ED
authors.lastname: Baraboi
authors.forename: David H
authors.initials: DH
authors.lastname: St-Pierre
authors.forename: Julie
authors.initials: J
authors.lastname: Shooner
authors.forename: Elena
authors.initials: E
authors.lastname: Timofeeva
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D023421:Models, Animal; D009620:Nodose Ganglion / Q000187:drug effects / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists*; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology / Q000601:surgery; D014688:Venoms / Q000494:pharmacology*
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D016760:Proto-Oncogene Proteins c-fos; D018027:Receptors, Glucagon; D014688:Venoms; D003346:Corticotropin-Releasing Hormone; D000077270:Exenatide