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The fattening effect of ghrelin
Because secretion of the peptide hormone ghrelin by the stomach is thought to enhance food intake, there is interest in targeting ghrelin or its receptor GHSR to suppress appetite. However, genetic ablation of the genes encoding ghrelin, GHSR, or the enzyme that activates ghrelin does not alter food intake in mice. Chebani et al. found that cells with a truncated form of GHSR had larger responses to ghrelin than cells with the full-length GHSR. Rats bearing this mutant form of GHSR were more sensitive to injected ghrelin and gained more body weight as fat without eating more food than their normal counterparts. Thus, ghrelin promotes the expansion of adipose tissue without affecting appetite. Furthermore, these rats with the mutant GHSR could be used to identify anti-obesity treatments.
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 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 GhsrQ343X mutation (GhsrM/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. 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 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 GhsrM/M rat as a physiological model of gain of function in Ghsr to identify treatments for obesity-related conditions.
