Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity.
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DOI：
10.1038/s41467-022-28271-2
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发表时间：
2022-02-01
影响因子：
16.6
通讯作者：
Wiseman RL
中科院分区：
文献类型：
--
作者：
Madhavan A;Kok BP;Rius B;Grandjean JMD;Alabi A;Albert V;Sukiasyan A;Powers ET;Galmozzi A;Saez E;Wiseman RL
在肥胖症中，未折叠蛋白反应中通过 IRE1 臂发出的信号既发挥保护作用，也发挥有害作用。肝脏或脂肪中 IRE1 调节的转录因子 XBP1 的过度表达可以防止与肥胖相关的代谢恶化。然而，IRE1 的过度激活会参与受调节的 IRE1 依赖性衰变 (RIDD) 和 TRAF2/JNK 促炎症信号传导，从而加速代谢功能障碍。这些病理性 IRE1 调节过程阻碍了在肥胖相关疾病中从药理学角度利用 IRE1/XBP1 信号传导的保护作用的努力。在这里，我们报告了 XBP1s 选择性药理学 IRE1 激活剂 IXA4 对饮食诱导肥胖 (DIO) 小鼠的影响。 IXA4 短暂激活肝脏中的保护性 IRE1/XBP1s 信号传导，而不诱导 RIDD 或 TRAF2/JNK 信号传导。 IXA4 治疗通过 IRE1 依赖性肝脏转录组重塑来改善全身葡萄糖代谢和肝脏胰岛素作用，从而减少葡萄糖产生和脂肪变性。 IXA4 刺激的 IRE1 激活还可增强胰腺功能。我们的研究结果表明，IRE1/XBP1s 信号传导的系统性瞬时激活可产生多组织益处，这些益处可整合以减轻肥胖驱动的代谢功能障碍。通过未折叠蛋白反应的 IRE1 臂发出的信号对肥胖症既具有保护作用，也具有有害作用。作者在此报告称，IRE1/XBP1s 信号传导的选择性药理学激活剂可刺激饮食诱导的肥胖小鼠肝脏和胰腺的适应性重塑，并减轻与肥胖相关的全身代谢功能障碍。
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. Signalling through the IRE1 arm of the unfolded protein response exerts both protective and harmful effects in obesity. Here the authors report that a selective pharmacologic activator of IRE1/XBP1s signalling stimulates an adaptive remodelling of liver and pancreas in diet-induced obese mice and mitigates obesity-linked systemic metabolic dysfunction.
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影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
14.8
作者：
Grandjean JMD;Madhavan A;Cech L;Seguinot BO;Paxman RJ;Smith E;Scampavia L;Powers ET;Cooley CB;Plate L;Spicer TP;Kelly JW;Wiseman RL
通讯作者：
Wiseman RL
影响因子：
11.8
作者：
Rutkowski, D. Thomas;Wu, Jun;Back, Sung-Hoon;Callaghan, Michael U.;Ferris, Sean P.;Iqbal, Jahangir;Clark, Robert;Miao, Hongzhi;Hassler, Justin R.;Fornek, Jamie;Katze, Michael G.;Hussain, M. Mahmood;Song, Benbo;Swathirajan, Jayanth;Wang, Junying;Yau, Grace D. -Y.;Kaufman, Randal J.
通讯作者：
Kaufman, Randal J.
影响因子：
2
作者：
Kaneko, M;Niinuma, Y;Nomura, Y
通讯作者：
Nomura, Y
DOI：
10.1073/pnas.1115623109
发表时间：
2012-04-10
影响因子：
11.1
作者：
Cross, Benedict C. S.;Bond, Peter J.;Harding, Heather P.
通讯作者：
Harding, Heather P.