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

Sci Signal. 2016 Apr 19;9(424):ra39. doi: 10.1126/scisignal.aae0374.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity / drug effects*
  • Adiposity / genetics
  • Administration, Intravenous
  • Animals
  • Appetite / drug effects*
  • Appetite / genetics
  • Blood Glucose / metabolism
  • Body Weight / drug effects
  • Body Weight / genetics
  • Caloric Restriction
  • Eating / drug effects
  • Eating / genetics
  • Female
  • Ghrelin / administration & dosage
  • Ghrelin / metabolism
  • Ghrelin / pharmacology*
  • Glucose Tolerance Test
  • Growth Hormone / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Microscopy, Confocal
  • Mutation*
  • Oligopeptides / pharmacology
  • Rats
  • Receptors, Ghrelin / agonists
  • Receptors, Ghrelin / genetics*
  • Receptors, Ghrelin / metabolism
  • Signal Transduction / genetics
  • beta-Arrestin 1 / genetics
  • beta-Arrestin 1 / metabolism


  • Arrb1 protein, rat
  • Blood Glucose
  • Ghrelin
  • Oligopeptides
  • Receptors, Ghrelin
  • beta-Arrestin 1
  • hexarelin
  • Growth Hormone