Chronic UCN2 treatment desensitizes CRHR2 and improves insulin sensitivity
Nature Communications. 2023 Jul 4;14(1):3953. doi: 10.1038/s41467-023-39597-w.
Stephen E Flaherty 3rd # 1, Olivier Bezy # 1, Wei Zheng 1, Dong Yan 1, Xiangping Li 1, Srinath Jagarlapudi 1, Bina Albuquerque 1, Ryan M Esquejo 1, Matthew Peloquin 1, Meriem Semache 2, Arturo Mancini 2, Liya Kang 1, Doreen Drujan 1, Susanne B Breitkopf 1, John D Griffin 1, Pierre M Jean Beltran 3, Liang Xue 3, John Stansfield 4, Evanthia Pashos 1, Quazi Shakey 5, Christian Pehmøller 1, Mara Monetti 1, Morris J Birnbaum 1, Jean-Philippe Fortin 1, Zhidan Wu 6
Affiliations
1. Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
2. Domain Therapeutics North America, Montréal, QC, Canada.
3. Machine Learning and Computational Sciences, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
4. Biostatistics, Early Clinical Development, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
5. Biomedicine design, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
6. Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA. Zhidan.wu@pfizer.com.
#. Contributed equally.
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.