Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity

Stephen E. Flaherty, Olivier Bezy, Wei Zheng, Dong Yan, Xiangping Li, Srinath Jagarlapudi, Bina Albuquerque, Ryan M. Esquejo, Matthew Peloquin, Meriem Semache, Arturo Mancini, Liya Kang, Doreen Drujan, Susanne B. Breitkopf, John D. Griffin, Pierre M. Jean Beltran, Liang Xue, John Stansfield, Evanthia Pashos, Quazi Shakey, Christian Pehmøller, Mara Monetti, Morris J. Birnbaum, Jean-Philippe Fortin and Zhidan Wu ()
Additional contact information
Stephen E. Flaherty: Pfizer Inc.
Olivier Bezy: Pfizer Inc.
Wei Zheng: Pfizer Inc.
Dong Yan: Pfizer Inc.
Xiangping Li: Pfizer Inc.
Srinath Jagarlapudi: Pfizer Inc.
Bina Albuquerque: Pfizer Inc.
Ryan M. Esquejo: Pfizer Inc.
Matthew Peloquin: Pfizer Inc.
Meriem Semache: Domain Therapeutics North America
Arturo Mancini: Domain Therapeutics North America
Liya Kang: Pfizer Inc.
Doreen Drujan: Pfizer Inc.
Susanne B. Breitkopf: Pfizer Inc.
John D. Griffin: Pfizer Inc.
Pierre M. Jean Beltran: Pfizer Inc.
Liang Xue: Pfizer Inc.
John Stansfield: Pfizer Inc.
Evanthia Pashos: Pfizer Inc.
Quazi Shakey: Pfizer Inc.
Christian Pehmøller: Pfizer Inc.
Mara Monetti: Pfizer Inc.
Morris J. Birnbaum: Pfizer Inc.
Jean-Philippe Fortin: Pfizer Inc.
Zhidan Wu: Pfizer Inc.

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39597-w

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