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Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity

Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male...

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Autores principales: Flaherty, Stephen E., Bezy, Olivier, Zheng, Wei, Yan, Dong, Li, Xiangping, Jagarlapudi, Srinath, Albuquerque, Bina, Esquejo, Ryan M., Peloquin, Matthew, Semache, Meriem, Mancini, Arturo, Kang, Liya, Drujan, Doreen, Breitkopf, Susanne B., Griffin, John D., Jean Beltran, Pierre M., Xue, Liang, Stansfield, John, Pashos, Evanthia, Shakey, Quazi, Pehmøller, Christian, Monetti, Mara, Birnbaum, Morris J., Fortin, Jean-Philippe, Wu, Zhidan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319809/
https://www.ncbi.nlm.nih.gov/pubmed/37402735
http://dx.doi.org/10.1038/s41467-023-39597-w
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author Flaherty, Stephen E.
Bezy, Olivier
Zheng, Wei
Yan, Dong
Li, Xiangping
Jagarlapudi, Srinath
Albuquerque, Bina
Esquejo, Ryan M.
Peloquin, Matthew
Semache, Meriem
Mancini, Arturo
Kang, Liya
Drujan, Doreen
Breitkopf, Susanne B.
Griffin, John D.
Jean Beltran, Pierre M.
Xue, Liang
Stansfield, John
Pashos, Evanthia
Shakey, Quazi
Pehmøller, Christian
Monetti, Mara
Birnbaum, Morris J.
Fortin, Jean-Philippe
Wu, Zhidan
author_facet Flaherty, Stephen E.
Bezy, Olivier
Zheng, Wei
Yan, Dong
Li, Xiangping
Jagarlapudi, Srinath
Albuquerque, Bina
Esquejo, Ryan M.
Peloquin, Matthew
Semache, Meriem
Mancini, Arturo
Kang, Liya
Drujan, Doreen
Breitkopf, Susanne B.
Griffin, John D.
Jean Beltran, Pierre M.
Xue, Liang
Stansfield, John
Pashos, Evanthia
Shakey, Quazi
Pehmøller, Christian
Monetti, Mara
Birnbaum, Morris J.
Fortin, Jean-Philippe
Wu, Zhidan
author_sort Flaherty, Stephen E.
collection PubMed
description Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and β-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2.
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spelling pubmed-103198092023-07-06 Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity Flaherty, Stephen E. Bezy, Olivier Zheng, Wei Yan, Dong Li, Xiangping Jagarlapudi, Srinath Albuquerque, Bina Esquejo, Ryan M. Peloquin, Matthew Semache, Meriem Mancini, Arturo Kang, Liya Drujan, Doreen Breitkopf, Susanne B. Griffin, John D. Jean Beltran, Pierre M. Xue, Liang Stansfield, John Pashos, Evanthia Shakey, Quazi Pehmøller, Christian Monetti, Mara Birnbaum, Morris J. Fortin, Jean-Philippe Wu, Zhidan Nat Commun Article Urocortin 2 (UCN2) acts as a ligand for the G protein-coupled receptor corticotropin-releasing hormone receptor 2 (CRHR2). UCN2 has been reported to improve or worsen insulin sensitivity and glucose tolerance in vivo. Here we show that acute dosing of UCN2 induces systemic insulin resistance in male mice and skeletal muscle. Inversely, chronic elevation of UCN2 by injection with adenovirus encoding UCN2 resolves metabolic complications, improving glucose tolerance. CRHR2 recruits Gs in response to low concentrations of UCN2, as well as Gi and β-Arrestin at high concentrations of UCN2. Pre-treating cells and skeletal muscle ex vivo with UCN2 leads to internalization of CRHR2, dampened ligand-dependent increases in cAMP, and blunted reductions in insulin signaling. These results provide mechanistic insights into how UCN2 regulates insulin sensitivity and glucose metabolism in skeletal muscle and in vivo. Importantly, a working model was derived from these results that unifies the contradictory metabolic effects of UCN2. Nature Publishing Group UK 2023-07-04 /pmc/articles/PMC10319809/ /pubmed/37402735 http://dx.doi.org/10.1038/s41467-023-39597-w Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Flaherty, Stephen E.
Bezy, Olivier
Zheng, Wei
Yan, Dong
Li, Xiangping
Jagarlapudi, Srinath
Albuquerque, Bina
Esquejo, Ryan M.
Peloquin, Matthew
Semache, Meriem
Mancini, Arturo
Kang, Liya
Drujan, Doreen
Breitkopf, Susanne B.
Griffin, John D.
Jean Beltran, Pierre M.
Xue, Liang
Stansfield, John
Pashos, Evanthia
Shakey, Quazi
Pehmøller, Christian
Monetti, Mara
Birnbaum, Morris J.
Fortin, Jean-Philippe
Wu, Zhidan
Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
title Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
title_full Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
title_fullStr Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
title_full_unstemmed Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
title_short Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
title_sort chronic ucn2 treatment desensitizes crhr2 and improves insulin sensitivity
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10319809/
https://www.ncbi.nlm.nih.gov/pubmed/37402735
http://dx.doi.org/10.1038/s41467-023-39597-w
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