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

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, Yuyan Zhu and Kenneth King-yip Cheng ()
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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
Yongxia Niu: Shenzhen University of Advanced Technology
Kekao Long: The Hong Kong Polytechnic University
Qizhou Lian: Shenzhen University of Advanced Technology
Yuyan Zhu: The Hong Kong Polytechnic University
Kenneth King-yip Cheng: The Hong Kong Polytechnic University

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63905-1

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