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

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 eIF2a-ATF4 axis of the UPR. This alter-ation in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consump-tion, 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 ap-proaches to treat diseases marked by ER stress.

Automated summary

Chronic endoplasmic reticulum stress and unfolded protein response signaling contribute to type 2 diabetes development in obesity. Restoration of hepatic expression of FKBP11, which is regulated by XBP1s, leads to a rewiring of the unfolded protein response signaling pathway towards NRF2 and promotes glucose homeostasis without affecting ER stress, food consumption, or body weight in obese mice.