Document Detail


Suppression of food intake by glucagon-like peptide-1 receptor agonists: relative potencies and role of dipeptidyl peptidase-4.
MedLine Citation:
PMID:  23033273     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Lene Jessen; Benedikt A Aulinger; Jonathan L Hassel; Kyle J Roy; Eric P Smith; Todd M Greer; Stephen C Woods; Randy J Seeley; David A D'Alessio
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-10-02
Journal Detail:
Title:  Endocrinology     Volume:  153     ISSN:  1945-7170     ISO Abbreviation:  Endocrinology     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-11-29     Completed Date:  2013-01-31     Revised Date:  2013-12-04    
Medline Journal Info:
Nlm Unique ID:  0375040     Medline TA:  Endocrinology     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5735-45     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adamantane / analogs & derivatives,  pharmacology
Animals
Dipeptidyl Peptidase 4 / physiology*
Eating / drug effects
Gene Deletion
Gene Expression Regulation
Heterozygote
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Models, Biological
Nitriles / pharmacology
Pyrrolidines / pharmacology
Rats
Rats, Long-Evans
Receptors, Glucagon / agonists*
Grant Support
ID/Acronym/Agency:
DK057900/DK/NIDDK NIH HHS; DK56863/DK/NIDDK NIH HHS; R01 DK057900/DK/NIDDK NIH HHS; R01 DK093848/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Nitriles; 0/Pyrrolidines; 0/Receptors, Glucagon; 0/glucagon-like peptide-1 receptor; EC 3.4.14.5/Dipeptidyl Peptidase 4; I6B4B2U96P/vildagliptin; PJY633525U/Adamantane
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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