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.

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.

Fig. 1.

Cumulative chow intake at 1 h and 3 h (A), at 6 h and 24 h (B), and δ body weight at 24 h (C) after ICV (vehicle or exendin-(9–39), 100 μg) and ip (vehicle, liraglutide, 10 μg/kg; or exendin-4, 3.0 μg/kg) drug coadministration (* denotes significant difference compared with ICV vehicle/ip vehicle treatment; † denotes significant difference compared with ICV vehicle/ip liraglutide treatment; ‡ denotes significant difference compared with ICV vehicle/ip exendin-4 treatment). P < 0.05 = significant difference; data are mean ± sem.

Fig. 2.

Cumulative chow intake at 1 h, 3 h, 6 h, and 24 h in rats that received ip exendin-(9–39) (0, 25, and 75 μg) combined with ip liraglutide (10 μg/kg) coadministration (panels A and B) and in rats that received ip exendin-(9–39) (0, 25, and 75 μg) combined with ip exendin-4 (3 μg/kg) coadministration (panels C and D) (* denotes significant difference compared with ICV vehicle/ip vehicle treatment; † denotes significant difference compared with ICV vehicle/ip liraglutide treatment; ‡ denotes significant difference compared with ICV vehicle/ip exendin-4 treatment). P < 0.05 = significant difference; data are mean ± sem.

Fig. 3.

Cumulative chow intake in rats with SDA and control rats at 1 h and 3 h (A), at 6 h, and 24 h (B), and δ body weight at 24 h (C) after vehicle, ip liraglutide (10, 25, or 50 μg/kg), or exendin-4 (1.0, or 3.0 μg/kg) treatment (* denotes significant difference compared with vehicle treatment). P < 0.05 = significant difference; data are mean ± sem.