Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing
Circulating trimethylamine N-oxide (TMAO) participates in the pathogenesis of cardio-metabolic diseases, with hepatic flavin-containing monooxygenase 3 (FMO3) originally regarded as the primary source of TMAO production. Here, we demonstrate that white adipose tissue (WAT) expressed FMO3 and its derived metabolic product TMAO causatively contribute to the systemic elevation of TMAO levels, WAT dysfunction, and metabolic diseases in ageing. We showed that FMO3 expression and TMAO levels are upregulated in WAT of naturally ageing animals and human subjects, as well as in a DNA damage-induced senescent adipocyte model, but not in the liver. This upregulation is due to p53 activation in mice and could be mitigated by calorie restriction in humans. Adipocyte-specific ablation of FMO3 attenuates TMAO accumulation in WAT and circulation, leading to enhanced glucose metabolism, energy homeostasis, and lipid regulation in aged and high-fat diet-induced obese mice. Transcriptomic and histological analysis link these metabolic improvements to reduced senescence, fibrosis, and inflammation in WAT as well as a decrease in adipose-resident macrophages. LiP-small molecule mapping (LiP-SMap) analysis identified numerous novel TMAO-interacting proteins implicated in inflammasome activation within white adipocytes and macrophages. Mechanistically, TMAO facilitates inflammasome activation by binding to the inflammasome adaptor protein apoptosis-associated speck-like protein containing A CARD (ASC), thereby inducing its expression, caspase-1 activation, and subsequent interleukin-1ß (IL-1ß) 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. Overall design: To investigate the role of adipo-FMO3 during aging, we isolated epididymal adipose tissue (eWAT) from 105-week-old wild-type (WT) and adipo-FMO3 knockout (KO) mice on a C57BL/6 background. The isolated tissues were subjected to transcriptome sequencing to analyse gene expression profiles and elucidate the functional implications of adipo-FMO3 in the aging process.