دورية أكاديمية
أعرض في EDS

Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.

التفاصيل البيبلوغرافية
العنوان: Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity.
المؤلفون: Flaherty SE 3rd; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Bezy O; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Zheng W; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Yan D; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Li X; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Jagarlapudi S; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Albuquerque B; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Esquejo RM; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Peloquin M; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Semache M; Domain Therapeutics North America, Montréal, QC, Canada., Mancini A; Domain Therapeutics North America, Montréal, QC, Canada., Kang L; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Drujan D; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Breitkopf SB; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Griffin JD; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Jean Beltran PM; Machine Learning and Computational Sciences, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Xue L; Machine Learning and Computational Sciences, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Stansfield J; Biostatistics, Early Clinical Development, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Pashos E; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Shakey Q; Biomedicine design, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Pehmøller C; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Monetti M; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Birnbaum MJ; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Fortin JP; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA., Wu Z; Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA. Zhidan.wu@pfizer.com.
المصدر: Nature communications [Nat Commun] 2023 Jul 04; Vol. 14 (1), pp. 3953. Date of Electronic Publication: 2023 Jul 04.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Insulin Resistance*, Animals ; Male ; Mice ; Corticotropin-Releasing Hormone/genetics ; Corticotropin-Releasing Hormone/metabolism ; Glucose/metabolism ; Insulin ; Ligands ; Receptors, Corticotropin-Releasing Hormone/genetics ; Receptors, Corticotropin-Releasing Hormone/metabolism ; Urocortins/genetics ; Urocortins/metabolism
مستخلص: 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.
(© 2023. The Author(s).)
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المشرفين على المادة: 9015-71-8 (Corticotropin-Releasing Hormone)
IY9XDZ35W2 (Glucose)
0 (Insulin)
0 (Ligands)
0 (Receptors, Corticotropin-Releasing Hormone)
0 (Urocortins)
0 (CRF receptor type 2)
0 (urocortin 2, mouse)
تواريخ الأحداث: Date Created: 20230704 Date Completed: 20230707 Latest Revision: 20230718
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC10319809
DOI: 10.1038/s41467-023-39597-w
PMID: 37402735
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-023-39597-w