Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
Aparajita MadhavanBernard P KokBibiana RiusJulia M D GrandjeanAdekunle AlabiVerena AlbertAra SukiasyanEvan T PowersAndrea GalmozziEnrique SaezR Luke WisemanPublished in: Nature communications (2022)
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 or TRAF2/JNK signaling. IXA4 treatment improves systemic glucose metabolism and liver insulin action through IRE1-dependent remodeling of the hepatic transcriptome that reduces glucose production and steatosis. IXA4-stimulated IRE1 activation also enhances pancreatic function. Our findings indicate that systemic, transient activation of IRE1/XBP1s signaling engenders multi-tissue benefits that integrate to mitigate obesity-driven metabolic dysfunction.
Keyphrases
- endoplasmic reticulum stress
- induced apoptosis
- high fat diet induced
- insulin resistance
- metabolic syndrome
- weight loss
- type diabetes
- transcription factor
- adipose tissue
- weight gain
- immune response
- signaling pathway
- gene expression
- cell death
- bariatric surgery
- skeletal muscle
- lymph node
- physical activity
- dna methylation
- genome wide
- fatty acid
- quality improvement
- nuclear factor
- toll like receptor
- glycemic control