title: Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4.
abstract: Administration of the glucagon-like peptide-1 (GLP-1) receptor agonists GLP-1 and exendin-4 (Ex-4) directly into the central nervous system decreases food intake. But although Ex-4 potently suppresses food intake after peripheral administration, the effects of parenteral GLP-1 are variable and not as strong. A plausible explanation for these effects is the rapid inactivation of circulating GLP-1 by dipeptidyl peptidase-4 (DPP-4), an enzyme that does not alter Ex-4 activity. To test this hypothesis, we assessed the relative potency of Ex-4 and GLP-1 under conditions in which DPP-4 activity was reduced. Outbred rats, wild-type mice, and mice with a targeted deletion of DPP-4 (Dpp4(-/-)) were treated with GLP-1 alone or in combination with the DPP-4 inhibitor vildagliptin, Ex-4, or saline, and food intake was measured. GLP-1 alone, even at high doses, did not affect feeding in wild-type mice or rats but did reduce food intake when combined with vildagliptin or given to Dpp4(-/-) mice. Despite plasma clearance similar to DPP-4-protected GLP-1, equimolar Ex-4 caused greater anorexia than vildagliptin plus GLP-1. To determine whether supraphysiological levels of endogenous GLP-1 would suppress food intake if protected from DPP-4, rats with Roux-en-Y gastric bypass and significantly elevated postprandial plasma GLP-1 received vildagliptin or saline. Despite 5-fold greater postprandial GLP-1 in these animals, vildagliptin did not affect food intake in Roux-en-Y gastric bypass rats. Thus, in both mice and rats, peripheral GLP-1 reduces food intake significantly less than Ex-4, even when protected from DPP-4. These findings suggest distinct potencies of GLP-1 receptor agonists on food intake that cannot be explained by plasma pharmacokinetics.
authors.affiliation: Division of Endocrinology, University of Cincinnati, Cincinnati, OH 45237, USA.
authors.forename: Lene
authors.initials: L
authors.lastname: Jessen
authors.forename: Benedikt A
authors.initials: BA
authors.lastname: Aulinger
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Hassel
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Roy
authors.forename: Eric P
authors.initials: EP
authors.lastname: Smith
authors.forename: Todd M
authors.initials: TM
authors.lastname: Greer
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Woods
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Seeley
authors.forename: David A
authors.initials: DA
authors.lastname: D'Alessio
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D004435:Eating / Q000187:drug effects; D017353:Gene Deletion; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor; D006579:Heterozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009570:Nitriles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D020318:Rats, Long-Evans; D018027:Receptors, Glucagon / Q000819:agonists*; D000077597:Vildagliptin
chemical_list: C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D009570:Nitriles; D011759:Pyrrolidines; D018027:Receptors, Glucagon; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane