Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.

ABSTRACT: In obesity, signaling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects. Overexpression of the IRE1-regulated transcription factor XBP1s in liver or fat protects against obesity-linked metabolic deterioration. However, hyperactivation of IRE1 engages regulated IRE1-dependent decay (RIDD) and TRAF2/JNK pro-inflammatory signaling, which accelerate metabolic dysfunction. These pathologic IRE1-regulated processes have hindered efforts to pharmacologically harness the protective benefits of IRE1/XBP1s signaling in obesity-linked conditions. Here, we report the effects of a XBP1s-selective pharmacological IRE1 activator, IXA4, in diet-induced obese (DIO) mice. IXA4 transiently activates protective IRE1/XBP1s signaling in liver without inducing RIDD

SUBMITTER: Madhavan A 

PROVIDER: S-EPMC8807832 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature