Adipocyte FMO3-derived TMAO induces WAT dysfunction and metabolic disorders by promoting inflammasome activation in ageing
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ABSTRACT:
PROVIDER: PRJNA1251598 | ENA |
REPOSITORIES: ENA
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Project description: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-1β (IL-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.
2025-08-23 | PXD066391 | Pride
Project description: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-1β (IL-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.
2025-07-17 | GSE294785 | GEO
Project description: Not available
| S-EPMC12501297 | biostudies-literature
Project description:Stroke is a kind of cerebrovascular disease with high mortality. TMAO has been shown to aggravate stroke outcomes, but its mechanism remains unclear. Mice were treated with TMAO in normal saline by oral gavage for 14 consecutive days. Then, mice were made into MCAO models. Neurological score, infarct volume, neuronal damage and markers associated with inflammation were assessed. Since microglia played a crucial role in stroke, microglia of MCAO mice were isolated for high-throughput sequencing to identify the most differentially expressed gene following TMAO treatment. Afterward, the downstream pathways of TMAO were investigated using primary microglia. Our results demonstrated that TMAO promoted the release of inflammatory cytokines in the brain of MCAO mice and promoted the activation of OGD/R microglial inflammasome, thereby exacerbating stroke outcomes. FTO/IGF2BP2 inhibited NLRP3 inflammasome activation in OGD/R microglia by downregulating the m6A level of NLRP3, TMAO can inhibit the expression of FTO and IGF2BP2, thus promoting the activation of NLRP3 inflammasome in OGD/R microglia. In conclusion, these results demonstrated that TMAO promotes NLRP3 inflammasome activation of microglia aggravating neurological injury in stroke through FTO/IGF2BP2.
2023-09-06 | GSE216349 | GEO
Project description:TMAO is gut microbiota dependent metabolite catalyzed by monooxygenase FMO3 from TMA. TMAO is positively assocaited with different metabolic diseases such as diabetes, chronic kidney disease, and atherosclerosis. We used microarray to analyze the genes regulated by TMAO treatment in primary rat hepatocytes to further understand the mechanistic view of TMAO action.
2019-08-22 | GSE135856 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation.
2014-12-19 | GSE64326 | GEO
Project description:Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide(TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT), and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation. To identify potential regulators of macrophage reverse cholesterol transport (RCT), liver was isolated from two independent mouse models where the non-biliary RCT pathway known as transintestinal cholesterol excretion (TICE) was either chronically (NPC1L1-liver-transgenic mice) or acutely (ACAT2 antisense oligonucleotide treatment) stimulated. Total RNA was isolated and gene expression levels were profiled on the Affymetrix GeneAtlas MG-430 PM Array Strip (Affymetrix; Santa Clara, CA, USA)
2014-12-19 | E-GEOD-64326 | biostudies-arrayexpress
Project description:TMAO promoted TREM-1 expression through NLRP3 inflammasome
| PRJNA1054027 | ENA
Project description:To investigate the impact of TMAO on Myeloid cells. An RNA-seq analysis of myeloid cells was performed with and without TMAO treatment.
2023-12-18 | GSE250419 | GEO
Project description:β-Cell dysfunction, manifested as impaired glucose-stimulated insulin secretion (GSIS), and β-cell loss, which presents as dedifferentiation, inhibited transcriptional identity and death, are the hallmarks of type 2 diabetes. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has been shown to play a role in cardiovascular disease. Here, we found that plasma TMAO levels are elevated in both diabetic mice and human subjects and that TMAO at a similar concentration to that found in diabetes could directly decrease β-cell GSIS in both MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels through choline diet feeding impairs GSIS, the β-cell proportion, and glucose tolerance. TMAO inhibits calcium transients through NLRP3 inflammasome-related inflammatory cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production through either genetic knockdown or antisense oligomers of Fmo3, the TMAO-producing enzyme, improves β-cell GSIS, the β-cell proportion, and glucose tolerance in both db/db and choline diet-fed mice. These observations elucidate a novel role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be a new approach for the treatment of type 2 diabetes.
2024-02-23 | GSE243083 | GEO