Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite

Abstract : 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 –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 GhsrQ343X mutation (GhsrM/M), which is predicted to delete the distal part of the GHSR C-terminus tail, a domain critical for the signal termination processes of receptor internalization and beta-arrestin recruitment. In cells, the Q343X GHSR mutant showed enhanced ligand-induced G protein-dependent signaling and blunted activity of processes involved in GPCR signal termination. GhsrM/M rats displayed enhanced responses to submaximal doses of ghrelin or GHSR agonist. Moreover, GhsrM/M rats had a more stable body weight under caloric restriction, a condition that increases endogenous ghrelin tone, whereas under standard housing conditions, GhsrM/M rats showed increased body weight, adiposity and reduced glucose tolerance. Overall, our data stresses the physiological role of the distal domain of GHSR C-terminus as a suppressor of ghrelin sensitivity and we propose using the GhsrM/M rat as a physiological model of gain-of-function in Ghsr to identify treatments for obesity-related conditions.
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Science Signaling, American Association for the Advancement of Science, 2016, 9 (424), pp.ra39. <10.1126/scisignal.aae0374>
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Yacine Chebani, Candice Marion, Philippe Zizzari, Khadidja Chettab, Marie Pastor, et al.. Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite. Science Signaling, American Association for the Advancement of Science, 2016, 9 (424), pp.ra39. <10.1126/scisignal.aae0374>. <inserm-01463897>

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