慢性UCN2治疗使CRHR2变得不敏感,并改善胰岛素敏感性
Stephen E Flaherty1, Olivier Bezy1, Wei Zheng1
1Internal Medicine Research Unit, Pfizer Inc., 1 Portland Street, Cambridge, MA, USA.
Nature communications
|July 4, 2023
概括
乌洛科丁2 (UCN2) 导致急性胰岛素耐药性,但通过影响小鼠的皮质otropin释放激素受体2 (CRHR2) 信号传递,慢性地改善了葡萄糖耐受性.
科学领域:
- 代谢研究的研究.
- 内分泌学 在内分泌学.
- 分子信号传递是分子信号传递.
背景情况:
- 乌罗皮素2 (UCN2) 是皮质otropin释放激素受体2 (CRHR2) 的一个连接体.
- UCN2对胰岛素敏感性和葡萄糖耐受性的影响是矛盾的.
- 了解UCN2的机制对于代谢健康至关重要.
研究的目的:
- 阐明UCN2对胰岛素敏感性和葡萄糖代谢的双重作用的机制基础.
- 研究CRHR2信号传导在调解UCN2代谢作用中的作用.
- 开发UCN2对代谢调节的影响的统一模型.
主要方法:
- 在雄性小鼠中,急性和慢性给予UCN2.
- 腺病毒介导的UCN2基因传递.
- 对骨肌肉和细胞培养的ex vivo研究.
- 对CRHR2受体招募 (Gs,Gi,β-Arrestin) 和下游信号 (cAMP,胰岛素信号) 的分析.
主要成果:
- 急性UCN2剂量诱导了小鼠和骨肌肉中的全身胰岛素抵抗.
- 慢性UCN2升高解决了代谢并发症,改善了葡萄糖耐受性.
- 根据UCN2度调节的CRHR2信号,在低度处招募Gs,在高度处招募Gi/β-Arrestin.
- 用UCN2进行前期治疗导致CRHR2内部化,减少cAMP和麻木胰岛素信号传递.
结论:
- UCN2对胰岛素敏感性和葡萄糖代谢具有上下文依赖的影响.
- CRHR2的信号动态 (受体的招募和内化) 构成了UCN2对立的代谢作用的基础.
- 一个新的模型调和了UCN2的矛盾效应,提供了对代谢调节的机制性见解.
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