Dissociating ghrelin-dependent G protein from β-arrestin–2 signaling in transgenic rats

The gut-derived hormone ghrelin regulates growth hormone release, appetite, metabolism, and immune function through its receptor, the growth hormone secretagogue receptor 1a (GHSR1a). In this issue of Science Signaling, Chebani et al decode GHSR1a signaling by using transgenic rats with a mutation in GHSR1a that prevents its interaction with β-arrestin. These mutant rats are more responsive to endogenous ghrelin, resulting in increased fat deposition and insulin resistance without affecting food intake.