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

TY - JOUR

T1 - Translating biased signaling in the ghrelin receptor system into differential in vivo functions

AU - Mende, Franziska

AU - Hundahl, Cecilie

AU - Plouffe, Bianca

AU - Skov, Louise Julie

AU - Sivertsen, Bjørn

AU - Madsen, Andreas Nygaard

AU - Lückmann, Michael

AU - Diep, Thi Ai

AU - Offermanns, Stefan

AU - Frimurer, Thomas Michael

AU - Bouvier, Michel

AU - Holst, Birgitte

PY - 2018/10/23

Y1 - 2018/10/23

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1804003115

DO - 10.1073/pnas.1804003115

M3 - Journal article

C2 - 30301804

SN - 0027-8424

VL - 115

SP - E10255-E10264

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 43

ER -