Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Domain Therapeutics North America, Montréal, QC, Canada.
Nat Commun. 2023 Jul 4;14(1):3953. doi: 10.1038/s41467-023-39597-w.
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.
尿皮质素 2（UCN2）作为一种 G 蛋白偶联受体促肾上腺皮质激素释放激素受体 2（CRHR2）的配体。有报道称，UCN2 可改善或恶化体内胰岛素敏感性和葡萄糖耐量。在这里，我们显示 UCN2 的急性给药会在雄性小鼠和骨骼肌中诱导全身胰岛素抵抗。相反，通过注射编码 UCN2 的腺病毒慢性升高 UCN2 可解决代谢并发症，改善葡萄糖耐量。CRHR2 在低浓度 UCN2 下募集 Gs，在高浓度 UCN2 下募集 Gi 和β-Arrestin。在细胞和骨骼肌的体外实验中，UCN2 预处理会导致 CRHR2 的内化，减弱配体依赖性 cAMP 的增加，并减弱胰岛素信号的降低。这些结果为 UCN2 如何调节骨骼肌和体内胰岛素敏感性和葡萄糖代谢提供了机制见解。重要的是，从这些结果中得出了一个工作模型，统一了 UCN2 的矛盾代谢作用。
