β-Cell-Derived TMAO Regulates Senescence and Inflammation via FMO3
TMAO is typically generated via the gut microbiota-liver axis, but pancreatic β-cells also produce it through flavin-containing monooxygenase 3 (FMO3). This production helps suppress NF-κB-mediated senescence and inflamm
Human cells utilize gut microbiota-derived metabolites to control systemic metabolism. The authors of this paper show that pancreatic β-cells produce trimethylamine N-oxide (TMAO) as an autocrine and intracellular metabolite to maintain β-cell function. This production is via flavin-containing monooxygenase 3 (FMO3), a machinery that deteriorates in humans and rodents under diabetic and ageing conditions. In mice, β-cell-specific deletion of FMO3 leads to senescence, inflammation, and defective glucose-stimulated insulin secretion, causing age-dependent glucose intolerance. Loss of FMO3 triggers nuclear factor kappa-B (NF-κB) activation, promoting senescent and inflammatory responses. Mechanistically, TMAO binds to inhibitor of kappa B alpha (IκBα), which inhibits IκBα degradation and NF-κB nuclear translocation, thereby blocking NF-κB-mediated transcription of senescent and inflammatory programs. Replenishment of FMO3 reduces NF-κB activation and senescence in aged human islets. This regulatory mechanism highlights the protective role of β-cell-derived TMAO against ageing-related β-cell dysfunction in mice.