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

作者：Teng Huang, Jia Song, Jia Gao, Jia Cheng, Hao Xie, Lu Zhang, Yuhan Wang, Yu-Han Wang, Zhichao Gao, Xiaohui Wang, Yi Wang, Xiaohui Wang, Jinhan He, Shiwei Liu, Qilin Yu, Shu Zhang, Fei Xiong, Qing Zhou, Cong‐Yi Wang · 发表于：Nature Communications · 年份：2022 · DOI：10.1038/s41467-022-31126-5 · 被引用次数：152 · 研究领域：Tryptophan and brain disorders、Stress Responses and Cortisol、Vitamin D Research Studies

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.