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ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Publications at this Location » Publication #319345
Title: Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats

Author
item SISLEY, STEPHANIE - Children'S Nutrition Research Center (CNRC)
item SMITH, KATHLEEN - University Of Cincinnati
item SANDOVAL, DARLEEN - University Of Cincinnati
item SEELEY, RANDY - University Of Cincinnati

Submitted to: Peptides
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/20/2014
Publication Date: 5/29/2014
Citation: Sisley, S., Smith, K., Sandoval, D.A., Seeley, R.J. 2014. Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats. Peptides. 58:1-6.

Interpretive Summary: Two common treatments for type 2 diabetes are liraglutide and exendin-4. Both drugs act through the glucagon-like peptide-1 receptor and also cause weight loss. Although the brain is known to control weight, it is unknown if liraglutide can work in the brain to change body weight or glucose. We gave liraglutide and exendin-4 into the brain of lean rats and found that both could decrease food intake, although exendin-4 was more potent. Neither decreased food intake when given simultaneously with an antagonist to the glucagon-like peptide-1 receptor. Thus, these data show that glucagon-like peptide-1 receptor (GLP-1R) agonists have different abilities to lower food intake in the brain and thus stress the importance of evaluating effects of drugs in the brain to combat childhood obesity and type 2 diabetes.

Technical Abstract: 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.