Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

Jun 1, 2014Peptides

Short-term appetite-suppressing effects of different long-lasting GLP-1 drugs in rats

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Abstract

Direct administration of 0.26 nmol liraglutide resulted in a 50% reduction in food intake in lean Long-Evans rats.

Liraglutide and exendin-4 both activate GLP-1 receptors in the brain, which are involved in controlling food intake.
Exendin-4 reduced food intake at a potency 10 times greater than liraglutide.
Both liraglutide and exendin-4's effects on food intake were blocked by a GLP-1 receptor antagonist.
Exendin-4 caused hyperglycemia when administered before a glucose tolerance test, while liraglutide did not lower glucose levels.
The differences in anorectic effects between the two drugs may explain their varied clinical outcomes.

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Long-acting glucagon-like peptide-1 receptor (GLP-1R) agonists have both glucose- and weight-lowering effects. The brain is poised to mediate both of these actions since GLP-1Rs are present in key areas known to control weight and glucose. Although some research has been performed on the effects of exendin-4 in the brain, little data exists on the central effects of liraglutide, a long-acting GLP-1R agonist with much closer structural homology to native GLP-1. In lean, Long-Evans rats, we found that direct intra-third cerebroventricular (i3vt) administration of 0.26 nmol liraglutide caused a 50% reduction in food intake. However, exendin-4 produced the same reduction in food intake with 10-fold greater potency (0.02 nmol). These data are supported by similar c-Fos immunoreactivity in the hypothalamic paraventricular nuclei by exendin-4 as compared to liraglutide despite differing doses. The anorectic effects of both drugs were blocked with i3vt pre-treatment of a GLP-1R competitive antagonist, exendin(9-39), indicating that both drugs required the GLP-1R for their effects. Exendin-4, and not liraglutide, caused hyperglycemia when given i3vt prior to an oral glucose tolerance test, although liraglutide did not lower glucose. Thus, these data show that GLP-1R agonists have differing anorectic potencies in the CNS, which may account for some of their clinical differences. Additionally, we show here that the glucose lowering properties of acute administration of GLP-1R agonists are not accounted for by their central effects.

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Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

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