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

IF 15.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2025-10-06 DOI:10.1038/s41467-025-63905-1

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,Kenneth King-Yip Cheng

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引用次数: 0

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.

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脂肪细胞fmo3衍生的TMAO通过促进衰老过程中炎性体的激活，诱导WAT功能障碍和代谢紊乱。

三甲胺n-氧化物（TMAO）与心脏代谢疾病有关，肝含黄素单加氧酶3 （FMO3）被认为是其主要来源。在这里，我们证明了脂肪细胞FMO3及其衍生的TMAO升高会引发白色脂肪组织（WAT）功能障碍及其相关的衰老代谢紊乱。在脂肪细胞中，衰老或p53激活上调FMO3和TMAO水平。脂肪细胞特异性消融FMO3可减弱TMAO在WAT和循环中的积累，从而增强衰老和肥胖小鼠的葡萄糖代谢、能量和脂质稳态。这些改善与WAT中衰老、纤维化和炎症的减少有关。蛋白质组学分析确定了脂肪细胞和巨噬细胞中参与炎性体激活的tmao相互作用蛋白。从机制上讲，TMAO与中央炎性体接头蛋白ASC结合，促进caspase-1激活和白细胞介素-1β的产生。我们的发现揭示了脂肪细胞FMO3通过自分泌和旁分泌方式促进衰老过程中炎性体的激活，在调节TMAO产生和WAT功能障碍中的关键作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.