Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite.
The ability of the gut hormone ghrelin to promote positive energy balance is mediated by the growth hormone secretagogue receptor (GHSR). GHSR is a G protein-coupled receptor (GPCR) that is found centrally and peripherally and that can signal in a ligand-independent manner basally or when heterodimerized with other GPCRs. However, current Ghsr knockout models cannot dissect ghrelin-dependent and ghrelin-independent signaling, precluding assessment of the physiological importance of these signaling pathways. An animal model carrying a Ghsr mutation that preserves GHSR cell surface abundance, but selectively alters GHSR signaling, would be a useful tool to decipher GHSR signaling in vivo. We used rats with the Ghsr(Q343X) mutation (Ghsr(M/M)), which is predicted to delete the distal part of the GHSR carboxyl-terminal tail, a domain critical for the signal termination processes of receptor internalization and β-arrestin recruitment. In cells, the GHSR-Q343X mutant showed enhanced ligand-induced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination. Ghsr(M/M)rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover, Ghsr(M/M)rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions,Ghsr(M/M)rats showed increased body weight and adiposity and reduced glucose tolerance. Overall, our data stress the physiological role of the distal domain of GHSR carboxyl terminus as a suppressor of ghrelin sensitivity, and we propose using the Ghsr(M/M)rat as a physiological model of gain of function in Ghsr to identify treatments for obesity-related conditions.
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Yacine
Y
Chebani
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Candice
C
Marion
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Philippe
P
Zizzari
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Khadidja
K
Chettab
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Marie
M
Pastor
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Marie
M
Korostelev
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
David
D
Geny
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France. CNRS, Muséum national d'Histoire naturelle, UMR 7179, Mécanismes adaptatifs et évolution, 91800 Brunoy, France.
Jacques
J
Epelbaum
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France.
Virginie
V
Tolle
Centre de Biophysique Moléculaire, CNRS, UPR 4301, Université d'Orléans, 45071 Orléans, France.
Séverine
S
Morisset-Lopez
INSERM, Université Paris Descartes, Sorbonne Paris Cité, UMR-S 894, Centre de Psychiatrie & Neurosciences, 75014 Paris, France. Department of Molecular Physiology and Biophysics, Vanderbilt School of Medicine, Nashville, TN 37232, USA.
Jacques
J
Pantel
D050154:Adiposity / Q000187:drug effects* / Q000235:genetics; D061605:Administration, Intravenous; D000818:Animals; D001066:Appetite / Q000187:drug effects* / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects / Q000235:genetics; D031204:Caloric Restriction; D004435:Eating / Q000187:drug effects / Q000235:genetics; D005260:Female; D054439:Ghrelin / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D005951:Glucose Tolerance Test; D013006:Growth Hormone / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D009154:Mutation; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D054440:Receptors, Ghrelin / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D000071559:beta-Arrestin 1 / Q000235:genetics / Q000378:metabolism
C000605256:Arrb1 protein, rat; D001786:Blood Glucose; D054439:Ghrelin; D009842:Oligopeptides; D054440:Receptors, Ghrelin; D000071559:beta-Arrestin 1; C086184:hexarelin; D013006:Growth Hormone