Work

Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity

Year: 2022

Type: article

Abstract: ABSTRACT 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.

Source: Nature Communications

DOI: 10.1038/s41467-022-28271-2