Differences in the Central Anorectic Effects of Glucagon-Like Peptide-1 and Exendin-4 in Rats

Sep 11, 2009Diabetes

Different effects of two appetite-reducing hormones on the brain in rats

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Abstract

Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake.

Ex4's effect on food intake was not affected by antagonism when administered directly into the brain.
In contrast, the effect of Ex4 given peripherally was completely blocked by GLP-1 receptor antagonists.
GLP-1 receptors are essential for Ex4's actions, as shown by the lack of effect in GLP-1 receptor knockout mice.
These findings indicate distinct mechanisms of action for GLP-1 and Ex4 in controlling feeding behavior.

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OBJECTIVE: Glucagon-like peptide (GLP)-1 is a regulatory peptide synthesized in the gut and the brain that plays an important role in the regulation of food intake. Both GLP-1 and exendin (Ex)-4, a long-acting (GLP-1r) agonist, reduce food intake when administered intracerebroventricularly, whereas Ex4 is much more potent at suppressing food intake when given peripherally. It has generally been hypothesized that this difference is due to the relative pharmacokinetic profiles of GLP-1 and Ex4, but it is possible that the two peptides control feeding via distinct mechanisms.

RESEARCH DESIGN AND METHODS: In this study, the effects of intracerebroventricular GLP-1 and Ex4, and the sensitivity of these effects to GLP-1r antagonism, were compared in rats. In addition, the GLP-1r dependence of the anorectic effect of intracerebroventricular Ex4 was assessed in GLP-1r(-/-) mice.

RESULTS: Intracerebroventricular Ex4 was 100-fold more potent than GLP-1 at reducing food intake, and this effect was insensitive to GLP-1r antagonism. However, GLP-1r antagonists completely blocked the anorectic effect of intraperitoneal Ex4. Despite the insensitivity of intracerebroventricular Ex4 to GLP-1r antagonism, intracerebroventricular Ex4 failed to reduce food intake in GLP-1r(-/-) mice.

CONCLUSIONS: These data suggest that although GLP-1rs are required for the actions of Ex4, there appear to be key differences in how GLP-1 and Ex4 interact with central nervous system GLP-1r and in how Ex4 interacts with GLP-1r in the brain versus the periphery. A better understanding of these unique differences may lead to expansion and/or improvement of GLP-1-based therapies for type 2 diabetes and obesity.

Key numbers

100×

Potency Increase

Ex4 is 100× more potent than GLP-1 in reducing food intake.

10.0 μg of GLP-1 vs. 0.1 μg of Ex4

Anorexia Induction

Both doses produce comparable anorexia levels.

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Differences in the Central Anorectic Effects of Glucagon-Like Peptide-1 and Exendin-4 in Rats

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