title: The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1.
abstract: The incretin and food intake suppressive effects of intraperitoneally administered glucagon-like peptide-1 (GLP-1) involve activation of GLP-1 receptors (GLP-1R) expressed on vagal afferent fiber terminals. Central nervous system processing of GLP-1R-driven vagal afferents results in satiation signaling and enhanced insulin secretion from pancreatic-projecting vagal efferents. As the vast majority of endogenous GLP-1 is released from intestinal l-cells following ingestion, it stands to reason that paracrine GLP-1 signaling, activating adjacent GLP-1R expressed on vagal afferent fibers of gastrointestinal origin, contributes to glycemic and food intake control. However, systemic GLP-1R-mediated control of glycemia is currently attributed to endocrine action involving GLP-1R expressed in the hepatoportal bed on terminals of the common hepatic branch of the vagus (CHB). Here, we examine the hypothesis that activation of GLP-1R expressed on the CHB is not required for GLP-1's glycemic and intake suppressive effects, but rather paracrine signaling on non-CHB vagal afferents is required to mediate GLP-1's effects. Selective CHB ablation (CHBX), complete subdiaphragmatic vagal deafferentation (SDA), and surgical control rats received an oral glucose tolerance test (2.0 g glucose/kg) 10 min after an intraperitoneal injection of the GLP-1R antagonist, exendin-(9-39) (Ex-9; 0.5 mg/kg) or vehicle. CHBX and control rats showed comparable increases in blood glucose following blockade of GLP-1R by Ex-9, whereas SDA rats failed to show a GLP-1R-mediated incretin response. Furthermore, GLP-1(7-36) (0.5 mg/kg ip) produced a comparable suppression of 1-h 25% glucose intake in both CHBX and control rats, whereas intake suppression in SDA rats was blunted. These findings support the hypothesis that systemic GLP-1R mediation of glycemic control and food intake suppression involves paracrine-like signaling on GLP-1R expressed on vagal afferent fibers of gastrointestinal origin but does not require the CHB.
authors.affiliation: Translational Neuroscience Program, Dept. of Psychiatry, Perelman School of Medicine at the Univ. of Pennsylvania, TRL Bldg., Office 2219, 125 South 31st St., Philadelphia, PA 19104, USA. hayesmr@sas.upenn.edu
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hayes
authors.forename: Scott E
authors.initials: SE
authors.lastname: Kanoski
authors.forename: Bart C
authors.initials: BC
authors.lastname: De Jonghe
authors.forename: Theresa M
authors.initials: TM
authors.lastname: Leichner
authors.forename: Amber L
authors.initials: AL
authors.lastname: Alhadeff
authors.forename: Samantha M
authors.initials: SM
authors.lastname: Fortin
authors.forename: Myrtha
authors.initials: M
authors.lastname: Arnold
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Langhans
authors.forename: Harvey J
authors.initials: HJ
authors.lastname: Grill
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D001069:Appetite Regulation / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D006727:Hormone Antagonists / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D008099:Liver / Q000294:innervation*; D008297:Male; D019899:Paracrine Communication; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery
chemical_list: D001067:Appetite Depressants; D001786:Blood Glucose; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D006727:Hormone Antagonists; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1