Pharmacologic IRE1/XBP1s activation promotes systemic adaptive remodeling in obesity

Aparajita Madhavan, Bernard P. Kok, Bibiana Rius, Julia M. D. Grandjean, Adekunle Alabi, Verena Albert, Ara Sukiasyan, Evan T. Powers, Andrea Galmozzi, Enrique Saez () and R. Luke Wiseman ()
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Aparajita Madhavan: The Scripps Research Institute
Bernard P. Kok: The Scripps Research Institute
Bibiana Rius: The Scripps Research Institute
Julia M. D. Grandjean: The Scripps Research Institute
Adekunle Alabi: The Scripps Research Institute
Verena Albert: The Scripps Research Institute
Ara Sukiasyan: The Scripps Research Institute
Evan T. Powers: The Scripps Research Institute
Andrea Galmozzi: The Scripps Research Institute
Enrique Saez: The Scripps Research Institute
R. Luke Wiseman: The Scripps Research Institute

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28271-2

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