Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, 92037, USA.
Nat Commun. 2022 Feb 1;13(1):608. doi: 10.1038/s41467-022-28271-2.
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.
在肥胖症中，未折叠蛋白反应的 IRE1 臂的信号传导既具有保护作用，也具有有害作用。肝脏或脂肪中 IRE1 调节转录因子 XBP1s 的过表达可预防与肥胖相关的代谢恶化。然而，IRE1 的过度激活会引发 RIDD 和 TRAF2/JNK 促炎信号，从而加速代谢功能障碍。这些病理性的 IRE1 调节过程阻碍了在肥胖相关疾病中利用 IRE1/XBP1s 信号的保护性益处的药理学努力。在这里，我们报告了 XBP1s 选择性药理 IRE1 激活剂 IXA4 在饮食诱导肥胖（DIO）小鼠中的作用。IXA4 可短暂激活肝脏中的保护性 IRE1/XBP1s 信号，而不会诱导 RIDD 或 TRAF2/JNK 信号。IXA4 治疗可通过减少葡萄糖产生和脂肪变性来改善全身葡萄糖代谢和肝脏胰岛素作用，这是通过 IRE1 依赖性肝转录组重构实现的。IXA4 刺激的 IRE1 激活还增强了胰腺功能。我们的研究结果表明，IRE1/XBP1s 信号的系统、短暂激活可产生多种组织益处，从而整合起来减轻肥胖引起的代谢功能障碍。
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