Translating biased signaling in the ghrelin receptor system into differential in vivo functions
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Translating biased signaling in the ghrelin receptor system into differential in vivo functions. / Mende, Franziska; Hundahl, Cecilie; Plouffe, Bianca; Skov, Louise Julie; Sivertsen, Bjørn; Madsen, Andreas Nygaard; Lückmann, Michael; Diep, Thi Ai; Offermanns, Stefan; Frimurer, Thomas Michael; Bouvier, Michel; Holst, Birgitte.
I: Proceedings of the National Academy of Sciences of the United States of America, Bind 115, Nr. 43, 2018, s. E10255-E10264.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › fagfællebedømt
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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
Y1 - 2018
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 associated with 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 Gαq/11 and Gα12 pathways selectively without affecting the engagement of β-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gαq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gαq/11, without antagonism at β-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 associated with 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 Gαq/11 and Gα12 pathways selectively without affecting the engagement of β-arrestin or other G proteins. YIL781 was further characterized for its in vivo physiological functions. In combination with the use of mice in which Gαq/11 was selectively deleted in the appetite-regulating AgRP neurons, this biased ligand allowed us to demonstrate that selective blockade of Gαq/11, without antagonism at β-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
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
SN - 0027-8424
IS - 43
ER -
ID: 209112490