PT  - JOURNAL ARTICLE
AU  - Aparajita Madhavan
AU  - Bernard P. Kok
AU  - Julia M.D. Grandjean
AU  - Verena Albert
AU  - Ara Sukiasyan
AU  - Bibiana Rius
AU  - Evan T. Powers
AU  - Andrea Galmozzi
AU  - Enrique Saez
AU  - R. Luke Wiseman
TI  - Pharmacologic IRE1/XBP1s Activation Promotes Systemic Adaptive Remodeling in Obesity
AID  - 10.1101/2020.12.03.408716
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.12.03.408716
4099  - http://biorxiv.org/content/early/2020/12/03/2020.12.03.408716.short
4100  - http://biorxiv.org/content/early/2020/12/03/2020.12.03.408716.full
AB  - In obesity, overexpression of the IRE1-regulated transcription factor XBP1s protects against metabolic dysfunction by stimulating adaptive remodeling of multiple tissues, most notably the liver.1–5 This observation suggests that pharmacologically increasing IRE1/XBP1s signaling might be an attractive approach to mitigate pathologies in obesity and its associated complications.6–8 Here, we tested this notion by treating diet-induced obese (DIO) mice with the pharmacologic IRE1/XBP1s activator IXA4.9 We show that IXA4 treatment selectively activated protective IRE1/XBP1s signaling in livers of DIO mice without inducing obesity-linked pathologies associated with IRE1 hyperactivity, such as liver inflammation and fibrosis.10,11 Chronic IXA4 treatment improved systemic glucose metabolism and feeding-induced insulin action in the liver of DIO mice. These improvements were linked to IRE1/XBP1s-induced remodeling of the liver transcriptome, which dampened glucose production and reduced hepatic steatosis. Further, we show that IXA4 treatment enhanced pancreatic β cell function and insulin homeostasis, indicating that systemic activation of IRE1/XBP1s signaling engendered multi-tissue benefits that integrated to mitigate systemic metabolic dysfunction in DIO mice. Our findings show that selective pharmacological activation of protective IRE1/XBP1s signaling reprograms multiple metabolic tissues, such as liver and pancreas, and represents a potential strategy to correct metabolic alterations in obesity.Competing Interest StatementRLW is an inventor on a patent describing IRE1/XBP1s activating compounds, including IXA4. The authors declare no other competing interests.