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GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.

Authors: Costantini, Vivian J A  Vicentini, Elena  Sabbatini, Fabio M  Valerio, Enzo  Lepore, Stefano  Tessari, Michela  Sartori, Matteo  Michielin, Francesca  Melotto, Sergio  Bifone, Angelo  Pich, Emilio Merlo  Corsi, Mauro 
Citation: Costantini VJ, etal., Neuroendocrinology. 2011;94(2):158-68. doi: 10.1159/000328968. Epub 2011 Jul 22.
Pubmed: (View Article at PubMed) PMID:21778696
DOI: Full-text: DOI:10.1159/000328968

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.


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CRRD Object Information
CRRD ID: 12905045
Created: 2017-06-05
Species: All species
Last Modified: 2017-06-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.