Translating biased signaling in the ghrelin receptor system into differential in vivo functions

Franziska Mende, Cecilie Hundahl, Bianca Plouffe, Louise Julie Skov, Bjoørn Sivertsen, Andreas Nygaard Madsen, Michael Lückmann, Thi Ai Diep, Stefan Offermanns, Thomas Michael Frimurer, Michel Bouvier*, Birgitte Holst

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E10255-E10264
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number43
Early online date09 Oct 2018
DOIs
Publication statusPublished - 23 Oct 2018
Externally publishedYes

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Keywords

  • Appetite regulation
  • Biased signaling
  • Food intake
  • Gastric emptying
  • Ghrelin receptor

Cite this

Mende, F., Hundahl, C., Plouffe, B., Skov, L. J., Sivertsen, B., Madsen, A. N., Lückmann, M., Diep, T. A., Offermanns, S., Frimurer, T. M., Bouvier, M., & Holst, B. (2018). Translating biased signaling in the ghrelin receptor system into differential in vivo functions. Proceedings of the National Academy of Sciences of the United States of America, 115(43), E10255-E10264. https://doi.org/10.1073/pnas.1804003115