Document Detail

GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.
MedLine Citation:
PMID:  21778696     Owner:  NLM     Status:  MEDLINE    
Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450-1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation.
Vivian J A Costantini; Elena Vicentini; Fabio M Sabbatini; Enzo Valerio; Stefano Lepore; Michela Tessari; Matteo Sartori; Francesca Michielin; Sergio Melotto; Angelo Bifone; Emilio Merlo Pich; Mauro Corsi
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Publication Detail:
Type:  Journal Article     Date:  2011-07-22
Journal Detail:
Title:  Neuroendocrinology     Volume:  94     ISSN:  1423-0194     ISO Abbreviation:  Neuroendocrinology     Publication Date:  2011  
Date Detail:
Created Date:  2011-09-21     Completed Date:  2012-01-12     Revised Date:  2012-06-14    
Medline Journal Info:
Nlm Unique ID:  0035665     Medline TA:  Neuroendocrinology     Country:  Switzerland    
Other Details:
Languages:  eng     Pagination:  158-68     Citation Subset:  IM    
Copyright Information:
Copyright © 2011 S. Karger AG, Basel.
GlaxoSmithKline Medicines Research Centre, Verona, Italy.
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MeSH Terms
Azabicyclo Compounds / pharmacology*
Body Composition / drug effects
Body Weight / drug effects*
Dose-Response Relationship, Drug
Eating / drug effects*
Ghrelin / blood,  pharmacology
Hydrazines / pharmacology*
Hypothalamus / drug effects,  metabolism
Mice, Inbred C57BL
Mice, Knockout
Rats, Sprague-Dawley
Receptors, Ghrelin / antagonists & inhibitors*,  genetics
Stimulation, Chemical
Transcriptome / drug effects
Reg. No./Substance:
0/Azabicyclo Compounds; 0/Ghrelin; 0/Hydrazines; 0/N'-(3,5-bis(trifluoromethyl)phenyl)-2-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-yl)-2-(3-pyridinyl)ethanohydrazide; 0/Receptors, Ghrelin
Erratum In:
Neuroendocrinology. 2012;95(3):247
Note: Bifone, Angelo [added]

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

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