@article{80c8e2fd30da464bbe2bc6eb81451d7d,
title = "FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity",
abstract = "Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (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 many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.",
keywords = "ER stress, FKBP11, NRF2, UPR signaling, glucose intolerance, insulin resistance, obesity, type 2 diabetes",
author = "Hilde Herrema and Dongxian Guan and Choi, {Jae Won} and Xudong Feng and {Salazar Hernandez}, {Mario Andres} and Farhana Faruk and Thomas Auen and Eliza Boudett and Rongya Tao and Hyonho Chun and Umut Ozcan",
note = "Funding Information: This work was mainly supported by the funds provided to U.O. from the Department of Medicine, the Smith President's Innovation Award from Boston Children's Hospital, and grants R01DK081009, R01DK098496, and R56DK098496 provided to U.O. by the National Institutes of Health. U.O. came up with the idea to investigate role of FKBP11 in the regulation of ER stress and glucose homeostasis. H.H. J.W.C. D.G. and U.O. designed the experiments. H.H. performed the initial experiments under the direction of U.O. that identified the role of FKBP11 in glucose homeostasis. J.W.C. performed the experiments under the direction of U.O. that showed differential activation of UPR signaling arms. D.G. performed promoter analysis and other experiments and completed the revision. H.C. performed microarray analysis and created and analyzed the volcano plots. X.F. M.A.S.H. F.F. E.B. T.A. and R.T. helped in performing experiments. Raw data of the experiments were mainly analyzed by H.H. and J.W.C. The manuscript was written by U.O. J.W.C. and H.H. U.O. is a founder of ERX Pharmaceuticals and a member of its scientific advisory board and board of directors. ERX Pharmaceuticals does not have any relation to the work reported in this article. Funding Information: This work was mainly supported by the funds provided to U.O. from the Department of Medicine , the Smith President{\textquoteright}s Innovation Award from Boston Children's Hospital , and grants R01DK081009 , R01DK098496 , and R56DK098496 provided to U.O. by the National Institutes of Health . Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = jul,
day = "5",
doi = "https://doi.org/10.1016/j.cmet.2022.06.007",
language = "English",
volume = "34",
pages = "1004--1022.e8",
journal = "Cell metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "7",
}