The common hepatic branch of the vagus is not required to mediate the glycemic and food intake suppressive effects of glucagon-like-peptide-1

Am J Physiol Regul Integr Comp Physiol. 2011 Nov;301(5):R1479-85. doi: 10.1152/ajpregu.00356.2011. Epub 2011 Aug 17.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Appetite Depressants / administration & dosage
  • Appetite Depressants / pharmacology*
  • Appetite Regulation / drug effects*
  • Behavior, Animal / drug effects*
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Eating / drug effects*
  • Glucagon-Like Peptide 1 / administration & dosage
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Glucose Tolerance Test
  • Hormone Antagonists / pharmacology
  • Injections, Intraperitoneal
  • Liver / innervation*
  • Male
  • Paracrine Communication
  • Peptide Fragments / administration & dosage
  • Peptide Fragments / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / antagonists & inhibitors
  • Receptors, Glucagon / metabolism
  • Time Factors
  • Vagotomy
  • Vagus Nerve / drug effects*
  • Vagus Nerve / metabolism
  • Vagus Nerve / surgery

Substances

  • Appetite Depressants
  • Blood Glucose
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Hormone Antagonists
  • Peptide Fragments
  • Receptors, Glucagon
  • exendin (9-39)
  • Glucagon-Like Peptide 1