Adipocyte-derived kynurenine promotes obesity and insulin resistance by activating the AhR/STAT3/IL-6 signaling

Teng Huang, Jia Song, Jia Gao, Jia Cheng, Hao Xie, Lu Zhang, Yu-Han Wang, Zhichao Gao, Yi Wang, Xiaohui Wang, Jinhan He, Shiwei Liu, Qilin Yu, Shu Zhang, Fei Xiong (), Qing Zhou () and Cong-Yi Wang ()
Additional contact information
Teng Huang: Huazhong University of Science and Technology
Jia Song: Huazhong University of Science and Technology
Jia Gao: Huazhong University of Science and Technology
Jia Cheng: Huazhong University of Science and Technology
Hao Xie: Huazhong University of Science and Technology
Lu Zhang: Huazhong University of Science and Technology
Yu-Han Wang: Huazhong University of Science and Technology
Zhichao Gao: Huazhong University of Science and Technology
Yi Wang: Huazhong University of Science and Technology
Xiaohui Wang: Huazhong University of Science and Technology
Jinhan He: West China Hospital, Sichuan University
Shiwei Liu: Third Hospital of Shanxi Medical University
Qilin Yu: Huazhong University of Science and Technology
Shu Zhang: Huazhong University of Science and Technology
Fei Xiong: Huazhong University of Science and Technology
Qing Zhou: Huazhong University of Science and Technology
Cong-Yi Wang: Huazhong University of Science and Technology

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Aberrant amino acid metabolism is a common event in obesity. Particularly, subjects with obesity are characterized by the excessive plasma kynurenine (Kyn). However, the primary source of Kyn and its impact on metabolic syndrome are yet to be fully addressed. Herein, we show that the overexpressed indoleamine 2,3-dioxygenase 1 (IDO1) in adipocytes predominantly contributes to the excessive Kyn, indicating a central role of adipocytes in Kyn metabolism. Depletion of Ido1 in adipocytes abrogates Kyn accumulation, protecting mice against obesity. Mechanistically, Kyn impairs lipid homeostasis in adipocytes via activating the aryl hydrocarbon receptor (AhR)/Signal transducer and activator of transcription 3 /interleukin-6 signaling. Genetic ablation of AhR in adipocytes abolishes the effect of Kyn. Moreover, supplementation of vitamin B6 ameliorated Kyn accumulation, protecting mice from obesity. Collectively, our data support that adipocytes are the primary source of increased circulating Kyn, while elimination of accumulated Kyn could be a viable strategy against obesity.

Date: 2022
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DOI: 10.1038/s41467-022-31126-5

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