Peripheral and central GLP-1 receptor populations mediate the anorectic effects of peripherally administered GLP-1 receptor agonists, liraglutide and exendin-4

Endocrinology. 2011 Aug;152(8):3103-12. doi: 10.1210/en.2011-0174. Epub 2011 Jun 21.


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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Appetite Depressants / pharmacology*
  • Body Weight / drug effects
  • Brain / physiology*
  • Calcitonin / pharmacology
  • Eating / drug effects
  • Exenatide
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide-1 Receptor
  • Liraglutide
  • Male
  • Peptide Fragments / pharmacology
  • Peptides / pharmacology*
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Glucagon / agonists
  • Receptors, Glucagon / physiology*
  • Vagus Nerve / physiology
  • Venoms / pharmacology*


  • Appetite Depressants
  • Glp1r protein, rat
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Peptides
  • Receptors, Glucagon
  • Venoms
  • exendin (9-39)
  • salmon calcitonin
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Calcitonin
  • Exenatide