Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

Research output: Contribution to journal › Letter › Research › peer-review

Standard

Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. / Kizilkaya, Hüsün S.; Sørensen, Kimmie V.; Madsen, Jakob S.; Lindquist, Peter; Douros, Jonathan D.; Bork-Jensen, Jette; Berghella, Alessandro; Gerlach, Peter A.; Gasbjerg, Lærke S.; Mokrosiński, Jacek; Mowery, Stephanie A.; Knerr, Patrick J.; Finan, Brian; Campbell, Jonathan E.; D’Alessio, David A.; Perez-Tilve, Diego; Faas, Felix; Mathiasen, Signe; Rungby, Jørgen; Sørensen, Henrik T.; Vaag, Allan; Nielsen, Jens S.; Holm, Jens Christian; Lauenborg, Jeannet; Damm, Peter; Pedersen, Oluf; Linneberg, Allan; Hartmann, Bolette; Holst, Jens J.; Hansen, Torben; Wright, Shane C.; Lauschke, Volker M.; Grarup, Niels; Hauser, Alexander S.; Rosenkilde, Mette M.

In: Nature Metabolism, Vol. 6, 2024, p. 1268–1281.

Research output: Contribution to journal › Letter › Research › peer-review

Harvard

Kizilkaya, HS, Sørensen, KV, Madsen, JS, Lindquist, P, Douros, JD, Bork-Jensen, J, Berghella, A, Gerlach, PA, Gasbjerg, LS, Mokrosiński, J, Mowery, SA, Knerr, PJ, Finan, B, Campbell, JE, D’Alessio, DA, Perez-Tilve, D, Faas, F, Mathiasen, S, Rungby, J, Sørensen, HT, Vaag, A, Nielsen, JS, Holm, JC, Lauenborg, J, Damm, P, Pedersen, O, Linneberg, A, Hartmann, B, Holst, JJ, Hansen, T, Wright, SC, Lauschke, VM, Grarup, N, Hauser, AS & Rosenkilde, MM 2024, 'Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes', Nature Metabolism, vol. 6, pp. 1268–1281. https://doi.org/10.1038/s42255-024-01061-4

APA

Kizilkaya, H. S., Sørensen, K. V., Madsen, J. S., Lindquist, P., Douros, J. D., Bork-Jensen, J., Berghella, A., Gerlach, P. A., Gasbjerg, L. S., Mokrosiński, J., Mowery, S. A., Knerr, P. J., Finan, B., Campbell, J. E., D’Alessio, D. A., Perez-Tilve, D., Faas, F., Mathiasen, S., Rungby, J., ... Rosenkilde, M. M. (2024). Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. Nature Metabolism, 6, 1268–1281. https://doi.org/10.1038/s42255-024-01061-4

Vancouver

Kizilkaya HS, Sørensen KV, Madsen JS, Lindquist P, Douros JD, Bork-Jensen J et al. Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. Nature Metabolism. 2024;6:1268–1281. https://doi.org/10.1038/s42255-024-01061-4

Author

Kizilkaya, Hüsün S. ; Sørensen, Kimmie V. ; Madsen, Jakob S. ; Lindquist, Peter ; Douros, Jonathan D. ; Bork-Jensen, Jette ; Berghella, Alessandro ; Gerlach, Peter A. ; Gasbjerg, Lærke S. ; Mokrosiński, Jacek ; Mowery, Stephanie A. ; Knerr, Patrick J. ; Finan, Brian ; Campbell, Jonathan E. ; D’Alessio, David A. ; Perez-Tilve, Diego ; Faas, Felix ; Mathiasen, Signe ; Rungby, Jørgen ; Sørensen, Henrik T. ; Vaag, Allan ; Nielsen, Jens S. ; Holm, Jens Christian ; Lauenborg, Jeannet ; Damm, Peter ; Pedersen, Oluf ; Linneberg, Allan ; Hartmann, Bolette ; Holst, Jens J. ; Hansen, Torben ; Wright, Shane C. ; Lauschke, Volker M. ; Grarup, Niels ; Hauser, Alexander S. ; Rosenkilde, Mette M. / Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes. In: Nature Metabolism. 2024 ; Vol. 6. pp. 1268–1281.

Bibtex

@article{cfffb9a5197f464baed5d57409ee0976,

title = "Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes",

abstract = "Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.",

author = "Kizilkaya, {H{\"u}s{\"u}n S.} and S{\o}rensen, {Kimmie V.} and Madsen, {Jakob S.} and Peter Lindquist and Douros, {Jonathan D.} and Jette Bork-Jensen and Alessandro Berghella and Gerlach, {Peter A.} and Gasbjerg, {L{\ae}rke S.} and Jacek Mokrosi{\'n}ski and Mowery, {Stephanie A.} and Knerr, {Patrick J.} and Brian Finan and Campbell, {Jonathan E.} and D{\textquoteright}Alessio, {David A.} and Diego Perez-Tilve and Felix Faas and Signe Mathiasen and J{\o}rgen Rungby and S{\o}rensen, {Henrik T.} and Allan Vaag and Nielsen, {Jens S.} and Holm, {Jens Christian} and Jeannet Lauenborg and Peter Damm and Oluf Pedersen and Allan Linneberg and Bolette Hartmann and Holst, {Jens J.} and Torben Hansen and Wright, {Shane C.} and Lauschke, {Volker M.} and Niels Grarup and Hauser, {Alexander S.} and Rosenkilde, {Mette M.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

doi = "10.1038/s42255-024-01061-4",

language = "English",

volume = "6",

pages = "1268–1281",

journal = "Nature Metabolism",

issn = "2522-5812",

publisher = "Springer",

}

RIS

TY - JOUR

T1 - Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes

AU - Kizilkaya, Hüsün S.

AU - Sørensen, Kimmie V.

AU - Madsen, Jakob S.

AU - Lindquist, Peter

AU - Douros, Jonathan D.

AU - Bork-Jensen, Jette

AU - Berghella, Alessandro

AU - Gerlach, Peter A.

AU - Gasbjerg, Lærke S.

AU - Mokrosiński, Jacek

AU - Mowery, Stephanie A.

AU - Knerr, Patrick J.

AU - Finan, Brian

AU - Campbell, Jonathan E.

AU - D’Alessio, David A.

AU - Perez-Tilve, Diego

AU - Faas, Felix

AU - Mathiasen, Signe

AU - Rungby, Jørgen

AU - Sørensen, Henrik T.

AU - Vaag, Allan

AU - Nielsen, Jens S.

AU - Holm, Jens Christian

AU - Lauenborg, Jeannet

AU - Damm, Peter

AU - Pedersen, Oluf

AU - Linneberg, Allan

AU - Hartmann, Bolette

AU - Holst, Jens J.

AU - Hansen, Torben

AU - Wright, Shane C.

AU - Lauschke, Volker M.

AU - Grarup, Niels

AU - Hauser, Alexander S.

AU - Rosenkilde, Mette M.

PY - 2024

Y1 - 2024

N2 - Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

AB - Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR–GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

U2 - 10.1038/s42255-024-01061-4

DO - 10.1038/s42255-024-01061-4

M3 - Letter

C2 - 38871982

AN - SCOPUS:85196101926

VL - 6

SP - 1268

EP - 1281

JO - Nature Metabolism

JF - Nature Metabolism

SN - 2522-5812

ER -

ID: 395996330