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Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing

Author

Listed:
  • Thashma Ganapathy

    (The Hong Kong Polytechnic University)

  • Juntao Yuan

    (The Hong Kong Polytechnic University)

  • Melody Yuen-man Ho

    (The Hong Kong Polytechnic University)

  • Kelvin Ka-lok Wu

    (The Hong Kong Polytechnic University)

  • Md Moinul Hoque

    (The Hong Kong Polytechnic University)

  • Baomin Wang

    (Zhongshan Hospital Fudan University)

  • Xiaomu Li

    (Zhongshan Hospital Fudan University)

  • Kai Wang

    (The Hong Kong Polytechnic University)

  • Martin Wabitsch

    (German Center for Child and Adolescent Health)

  • Xuejia Feng

    (Shenzhen University of Advanced Technology
    Chinese Academy of Sciences)

  • Yongxia Niu

    (Shenzhen University of Advanced Technology
    Chinese Academy of Sciences)

  • Kekao Long

    (The Hong Kong Polytechnic University)

  • Qizhou Lian

    (Shenzhen University of Advanced Technology
    Chinese Academy of Sciences
    Guangzhou Medical University
    University of Hong Kong)

  • Yuyan Zhu

    (The Hong Kong Polytechnic University)

  • Kenneth King-yip Cheng

    (The Hong Kong Polytechnic University
    The Hong Kong Polytechnic University)

Abstract

Trimethylamine N-oxide (TMAO) contributes to cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) recognized as its primary source. Here we demonstrate that elevated adipocyte FMO3 and its derived TMAO trigger white adipose tissue (WAT) dysfunction and its related metabolic disorders in ageing. In adipocytes, ageing or p53 activation upregulates FMO3 and TMAO levels. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism and energy and lipid homeostasis in ageing and obese mice. These improvements are associated with reduced senescence, fibrosis and inflammation in WAT. Proteomics analysis identified TMAO-interacting proteins involved in inflammasome activation in adipocytes and macrophages. Mechanistically, TMAO binds to the central inflammasome adaptor protein ASC, promoting caspase-1 activation and interleukin-1β production. Our findings uncover a pivotal role for adipocyte FMO3 in modulating TMAO production and WAT dysfunction by promoting inflammasome activation in ageing via an autocrine and paracrine manner.

Suggested Citation

  • Thashma Ganapathy & Juntao Yuan & Melody Yuen-man Ho & Kelvin Ka-lok Wu & Md Moinul Hoque & Baomin Wang & Xiaomu Li & Kai Wang & Martin Wabitsch & Xuejia Feng & Yongxia Niu & Kekao Long & Qizhou Lian , 2025. "Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63905-1
    DOI: 10.1038/s41467-025-63905-1
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