Abstract
Biased signaling has been suggested as a means of selectively modulating a limited fraction of the signaling pathways for G-protein-coupled receptor family members. Hence, biased ligands may allow modulation of only the desired physiological functions and not elicit undesired effects associatedwith pharmacological treatments. The ghrelin receptor is a highly sought antiobesity target, since the gut hormone ghrelin in humans has been shown to increase both food intake and fat accumulation. However, it also modulates mood, behavior, growth hormone secretion, and gastric motility. Thus, blocking all pathways of this receptor may give rise to potential side effects. In the present study, we describe a highly promiscuous signaling capacity for the ghrelin receptor. We tested selected ligands for their ability to regulate the various pathways engaged by the receptor. Among those, a biased ligand, YIL781, was found to activate the Gaq/11 and Ga12 pathways selectively without affecting the engagement of ß-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gaq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gaq/11, without antagonism at ß-arrestin or other G-protein coupling is sufficient to decrease food intake.
| Translated title of the contribution | Translating biased signaling in the ghrelin receptor system into differential in vivo functions |
|---|---|
| Original language | English |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 115 |
| Issue number | 43 |
| Pages (from-to) | E10255-E10264 |
| Number of pages | 10 |
| ISSN | 0027-8424 |
| DOIs | |
| Publication status | Published - 23 Oct 2018 |