title: Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4.
abstract: The long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists, exendin-4 and liraglutide, suppress food intake and body weight. The mediating site(s) of action for the anorectic effects produced by peripheral administration of these GLP-1R agonists are not known. Experiments addressed whether food intake suppression after i.p. delivery of exendin-4 and liraglutide is mediated exclusively by peripheral GLP-1R or also involves direct central nervous system (CNS) GLP-1R activation. Results showed that CNS delivery [third intracerebroventricular (3(rd) ICV)] of the GLP-1R antagonist exendin-(9-39) (100 μg), attenuated the intake suppression by i.p. liraglutide (10 μg) and exendin-4 (3 μg), particularly at 6 h and 24 h. Control experiments show that these findings appear to be based neither on the GLP-1R antagonist acting as a nonspecific competing orexigenic signal nor on blockade of peripheral GLP-1R via efflux of exendin-(9-39) to the periphery. To assess the contribution of GLP-1R expressed on subdiaphragmatic vagal afferents to the anorectic effects of liraglutide and exendin-4, food intake was compared in rats with complete subdiaphragmatic vagal deafferentation and surgical controls after i.p. delivery of the agonists. Both liraglutide and exendin-4 suppressed food intake at 3 h, 6 h, and 24 h for controls; for subdiaphragmatic vagal deafferentation rats higher doses of the GLP-1R agonists were needed for significant food intake suppression, which was observed at 6 h and 24 h after liraglutide and at 24 h after exendin-4.
  
  
  CONCLUSIONS
  Food intake suppression after peripheral administration of exendin-4 and liraglutide is mediated by activation of GLP-1R expressed on vagal afferents as well as direct CNS GLP-1R activation.
authors.affiliation: Department of Psychology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. kanoski@sas.upenn.edu
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kanoski
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Fortin
authors.forename: Myrtha
authors.initials: M
authors.lastname: Arnold
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Grill
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hayes
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000502:physiology*; D002116:Calcitonin / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D000069450:Liraglutide; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001067:Appetite Depressants; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; C083773:exendin (9-39); C028815:salmon calcitonin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D002116:Calcitonin; D000077270:Exenatide