Peripheral and Central GLP-1 Receptor Populations Mediate the Anorectic Effects of Peripherally Administered GLP-1 Receptor Agonists, Liraglutide and Exendin-4

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 f...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2011-08, Vol.152 (8), p.3103-3112
Main Authors: Kanoski, Scott E, Fortin, Samantha M, Arnold, Myrtha, Grill, Harvey J, Hayes, Matthew R
Format: Article
Language:English
Subjects:
Animals
Appetite Depressants - pharmacology
Biological and medical sciences
Body Weight - drug effects
Brain - physiology
Calcitonin - pharmacology
Eating - drug effects
Energy Balance-Obesity
Fundamental and applied biological sciences. Psychology
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
Vertebrates: endocrinology
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Summary: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 ip 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 (3rd ICV)] of the GLP-1R antagonist exendin-(9–39) (100 μg), attenuated the intake suppression by ip 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 ip 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.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2011-0174