| Author: | Ganapathy, Thashma Pemmanda |
| Title: | Potential role of flavin monooxygenase 3 signalling in aging related adipose tissue dysfunction |
| Advisors: | Cheng, K. Y. Kenneth (HTI) |
| Degree: | Ph.D. |
| Year: | 2025 |
| Department: | Department of Health Technology and Informatics |
| Pages: | xxiv, 230 pages : color illustrations |
| Language: | English |
| Abstract: | Cardiometabolic diseases including IR, type 2 diabetes, and cardiovascular disorders, pose a significant public health challenge, particularly in the context of aging. Emerging evidence has identified the gut-derived metabolite trimethylamine N-oxide (TMAO) as a potential key contributor to the pathogenesis of these metabolic diseases. Traditionally, hepatic flavin-containing monooxygenase 3 (FMO3) enzyme was considered the primary source of TMAO production. However, the current study provides compelling evidence that white adipose tissue (WAT) plays a integral role in TMAO-mediated metabolic dysfunction, particularly during the aging process. We first demonstrate that FMO3 expression and TMAO levels are significantly upregulated in the WAT of naturally aging animals and human subjects. This upregulation is not limited to the natural aging process but is also observed in a senescent induced mice model. Interestingly, the increase in FMO3 and TMAO is exhibited due to the activation of the p53 signaling pathway, a well-known regulator of cellular senescence. To further elucidate the functional significance of this WAT-derived TMAO, we utilized the adipocyte-specific FMO3 knockout (KO) mouse model. Remarkably, the ablation of FMO3 in adipocytes led to a significant attenuation of TMAO accumulation in both the WAT and the systemic circulation. The decrease in TMAO levels was associated with significant improvements across multiple metabolic parameters, including enhanced glucose metabolism, improved energy homeostasis, and better regulation of lipid metabolism in both aged and high-fat diet-induced obese mice. To investigate the underlying mechanisms behind the observed metabolic enhancements, we performed detailed analyses of the WAT. Our findings revealed that the metabolic enhancements associated with FMO3 ablation were linked to reduced senescence, fibrosis, and inflammation within the WAT, as well as a decrease in the presence of adipose-resident macrophages. TMAO induce NLRP3 inflammasome activation leading to enhanced caspase-1 activity, and the subsequent production of the proinflammatory cytokine interleukin-1β (IL-1B). The LiP-SMap analysis identified numerous novel TMAO-interacting proteins within white adipocytes and macrophages that are implicated in inflammasome activation. Importantly, TMAO was found to directly bind to the inflammasome adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC). This direct TMAO-ASC interaction serves to facilitate activation of the NLRP3 inflammasome, ultimately leading to the production of the pro-inflammatory cytokine IL-1B. These observations suggest that the adipocyte-derived TMAO plays a pivotal role in promoting age-related WAT dysfunction through the modulation of cellular senescence and inflammation. The insights from our study unveil the pivotal role of the AT-derived TMAO in promoting age-related metabolic dysfunction, challenging the traditional view that the liver is the main source of TMAO. Our study highlights the importance of addressing the FMO3-TMAO axis within the AT as a potential therapeutic target to combat the rising prevalence of metabolic disorders among aging populations. |
| Rights: | All rights reserved |
| Access: | open access |
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