title: Differences in acute anorectic effects of long-acting GLP-1 receptor agonists in rats.
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.
authors.affiliation: Department of Pediatrics, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States. Electronic address: Stephanie.sisley@bcm.edu.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Sisley
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Smith
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors.forename: Darleen A
authors.initials: DA
authors.lastname: Sandoval
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
mesh_terms: D000818:Animals; D000855:Anorexia / Q000139:chemically induced* / Q000378:metabolism; D004435:Eating / Q000187:drug effects*; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006943:Hyperglycemia / Q000139:chemically induced / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000009:adverse effects* / Q000494:pharmacology; D007031:Hypothalamus / Q000378:metabolism; D000069450:Liraglutide; D008297:Male; D010455:Peptides / Q000009:adverse effects* / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018027:Receptors, Glucagon / Q000819:agonists*; D014688:Venoms / Q000009:adverse effects* / Q000494:pharmacology
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D018027:Receptors, Glucagon; D014688:Venoms; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Brain; Exendin-4; GLP-1R; Liraglutide