美国波士顿儿童医院Umut Ozcan、Hilde Herrema等研究人员合作发现，FKBP11重塑UPR信号来促进2型糖尿病和肥胖症的葡萄糖稳态。2022年7月5日，国际知名学术期刊《细胞—代谢》发表了这一成果。

研究人员表示，慢性内质网（ER）压力和未折叠蛋白反应（UPR）信号的持续激活导致了肥胖症中2型糖尿病的发生。UPR信号传导是一个复杂的信号传导途径，在许多不同的细胞过程中仍在探索。

研究人员证明了受XBP1转录调节的FK506结合蛋白11（FKBP11）在肥胖小鼠的肝脏中严重减少。在肥胖小鼠中恢复肝脏FKBP11的表达，启动了一个非经典的UPR信号通路，标志着PERK信号向NRF2的重连，并远离了UPR的eIF2α-ATF4轴。在不改变肝脏ER压力、食物消耗或体重的情况下，这种UPR信号的改变建立了葡萄糖的平衡。

研究人员认为，肥胖期间的ER压力可以被有益地重连，进而促进葡萄糖稳态。这些发现可能为开发治疗以ER压力为标志的疾病的新方法提供了新的途径。

附：英文原文

Title: FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity

Author: Hilde Herrema, Dongxian Guan, Jae Won Choi, Xudong Feng, Mario Andres Salazar Hernandez, Farhana Faruk, Thomas Auen, Eliza Boudett, Rongya Tao, Hyonho Chun, Umut Ozcan

Issue&Volume: 2022/07/05

Abstract: Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded proteinresponse (UPR) signaling contribute to the development of type 2 diabetes in obesity.UPR signaling is a complex signaling pathway, which is still being explored in manydifferent cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11),which is transcriptionally regulated by XBP1s, is severely reduced in the livers ofobese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypicalUPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away fromthe eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucosehomeostasis without changing hepatic ER stress, food consumption, or body weight.We conclude that ER stress during obesity can be beneficially rewired to promote glucosehomeostasis. These findings may uncover possible new avenues in the development ofnovel approaches to treat diseases marked by ER stress.

DOI: 10.1016/j.cmet.2022.06.007

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00227-3