Adipocyte-derived Kynurenine Promotes Obesity and Insulin Resistance by Activating the AhR/STAT3/IL-6 Signaling

Overview

Journal Nat Commun

Specialty Biology

Date 2022 Jun 17

PMID 35715443

Authors

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

Cong-Yi Wang

Affiliations

Soon will be listed here.

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.

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References

Cheng J, Song J, He X, Zhang M, Hu S, Zhang S . Loss of Mbd2 Protects Mice Against High-Fat Diet-Induced Obesity and Insulin Resistance by Regulating the Homeostasis of Energy Storage and Expenditure. Diabetes. 2016; 65(11):3384-3395. DOI: 10.2337/db16-0151. View

Solon-Biet S, Cogger V, Pulpitel T, Wahl D, Clark X, Bagley E . Branched chain amino acids impact health and lifespan indirectly via amino acid balance and appetite control. Nat Metab. 2019; 1(5):532-545. PMC: 6814438. DOI: 10.1038/s42255-019-0059-2. View

Agudelo L, Femenia T, Orhan F, Porsmyr-Palmertz M, Goiny M, Martinez-Redondo V . Skeletal muscle PGC-1α1 modulates kynurenine metabolism and mediates resilience to stress-induced depression. Cell. 2014; 159(1):33-45. DOI: 10.1016/j.cell.2014.07.051. View

Laurila S, Sun L, Lahesmaa M, Schnabl K, Laitinen K, Klen R . Secretin activates brown fat and induces satiation. Nat Metab. 2021; 3(6):798-809. DOI: 10.1038/s42255-021-00409-4. View

Pan T, Zhou Q, Miao K, Zhang L, Wu G, Yu J . Suppressing Sart1 to modulate macrophage polarization by siRNA-loaded liposomes: a promising therapeutic strategy for pulmonary fibrosis. Theranostics. 2021; 11(3):1192-1206. PMC: 7738894. DOI: 10.7150/thno.48152. View

Munn D, Mellor A . Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2012; 34(3):137-43. PMC: 3594632. DOI: 10.1016/j.it.2012.10.001. View

Teijeiro A, Garrido A, Ferre A, Perna C, Djouder N . Inhibition of the IL-17A axis in adipocytes suppresses diet-induced obesity and metabolic disorders in mice. Nat Metab. 2021; 3(4):496-512. DOI: 10.1038/s42255-021-00371-1. View

Boitano A, Wang J, Romeo R, Bouchez L, Parker A, Sutton S . Aryl hydrocarbon receptor antagonists promote the expansion of human hematopoietic stem cells. Science. 2010; 329(5997):1345-8. PMC: 3033342. DOI: 10.1126/science.1191536. View

Tilg H, Moschen A . Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006; 6(10):772-83. DOI: 10.1038/nri1937. View

10.

Iyer A, Fairlie D, Prins J, Hammock B, Brown L . Inflammatory lipid mediators in adipocyte function and obesity. Nat Rev Endocrinol. 2010; 6(2):71-82. DOI: 10.1038/nrendo.2009.264. View

11.

Wang X, Wang H, Wang H, Zhang F, Wang K, Guo Q . The role of indoleamine 2,3-dioxygenase (IDO) in immune tolerance: focus on macrophage polarization of THP-1 cells. Cell Immunol. 2014; 289(1-2):42-8. DOI: 10.1016/j.cellimm.2014.02.005. View

12.

Stefan N . Causes, consequences, and treatment of metabolically unhealthy fat distribution. Lancet Diabetes Endocrinol. 2020; 8(7):616-627. DOI: 10.1016/S2213-8587(20)30110-8. View

13.

Wang D, Li D, Zhang Y, Chen J, Zhang Y, Liao C . Functional metabolomics reveal the role of AHR/GPR35 mediated kynurenic acid gradient sensing in chemotherapy-induced intestinal damage. Acta Pharm Sin B. 2021; 11(3):763-780. PMC: 7982426. DOI: 10.1016/j.apsb.2020.07.017. View

14.

Seegers N, van Doornmalen A, Uitdehaag J, de Man J, Buijsman R, Zaman G . High-throughput fluorescence-based screening assays for tryptophan-catabolizing enzymes. J Biomol Screen. 2014; 19(9):1266-74. DOI: 10.1177/1087057114536616. View

15.

Rojas I, Moyer B, Ringelberg C, Wilkins O, Pooler D, Ness D . Kynurenine-Induced Aryl Hydrocarbon Receptor Signaling in Mice Causes Body Mass Gain, Liver Steatosis, and Hyperglycemia. Obesity (Silver Spring). 2021; 29(2):337-349. PMC: 10782555. DOI: 10.1002/oby.23065. View

16.

Cussotto S, Delgado I, Anesi A, Dexpert S, Aubert A, Beau C . Tryptophan Metabolic Pathways Are Altered in Obesity and Are Associated With Systemic Inflammation. Front Immunol. 2020; 11:557. PMC: 7174689. DOI: 10.3389/fimmu.2020.00557. View

17.

Yue T, Sun F, Yang C, Wang F, Luo J, Yang P . The AHR Signaling Attenuates Autoimmune Responses During the Development of Type 1 Diabetes. Front Immunol. 2020; 11:1510. PMC: 7426364. DOI: 10.3389/fimmu.2020.01510. View

18.

Zhai L, Bell A, Ladomersky E, Lauing K, Bollu L, Sosman J . Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies. Front Immunol. 2020; 11:1185. PMC: 7308527. DOI: 10.3389/fimmu.2020.01185. View

19.

Green C, Wallace M, Divakaruni A, Phillips S, Murphy A, Ciaraldi T . Branched-chain amino acid catabolism fuels adipocyte differentiation and lipogenesis. Nat Chem Biol. 2015; 12(1):15-21. PMC: 4684771. DOI: 10.1038/nchembio.1961. View

20.

Wang Y, Zhang L, Wu G, Zhou Q, Yue H, Rao L . MBD2 serves as a viable target against pulmonary fibrosis by inhibiting macrophage M2 program. Sci Adv. 2020; 7(1). PMC: 7775789. DOI: 10.1126/sciadv.abb6075. View