title: GSK1614343, a novel ghrelin receptor antagonist, produces an unexpected increase of food intake and body weight in rodents and dogs.
abstract: 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.
authors.affiliation: GlaxoSmithKline Medicines Research Centre, Verona, Italy. vivian.costantini@aptuit.com
authors.forename: Vivian J A
authors.initials: VJ
authors.lastname: Costantini
authors.forename: Elena
authors.initials: E
authors.lastname: Vicentini
authors.forename: Fabio M
authors.initials: FM
authors.lastname: Sabbatini
authors.forename: Enzo
authors.initials: E
authors.lastname: Valerio
authors.forename: Stefano
authors.initials: S
authors.lastname: Lepore
authors.forename: Michela
authors.initials: M
authors.lastname: Tessari
authors.forename: Matteo
authors.initials: M
authors.lastname: Sartori
authors.forename: Francesca
authors.initials: F
authors.lastname: Michielin
authors.forename: Sergio
authors.initials: S
authors.lastname: Melotto
authors.forename: Angelo
authors.initials: A
authors.lastname: Bifone
authors.forename: Emilio Merlo
authors.initials: EM
authors.lastname: Pich
authors.forename: Mauro
authors.initials: M
authors.lastname: Corsi
mesh_terms: D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects*; D005260:Female; D054439:Ghrelin / Q000097:blood / Q000494:pharmacology; D006834:Hydrazines / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D017207:Rats, Sprague-Dawley; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors* / Q000235:genetics; D013268:Stimulation, Chemical; D059467:Transcriptome / Q000187:drug effects
chemical_list: D053961:Azabicyclo Compounds; D054439:Ghrelin; D006834:Hydrazines; C556802:N'-(3,5-bis(trifluoromethyl)phenyl)-2-(hexahydropyrrolo(1,2-a)pyrazin-2(1H)-yl)-2-(3-pyridinyl)ethanohydrazide; D054440:Receptors, Ghrelin