Integrating TMAO into the pathogenesis of obesity and type 2 diabetes: a mini review

Increasing circulating levels of trimethylamine N-oxide (TMAO), a metabolite originating from both dietary sources and microbial metabolism in the gut, have drawn significant attention for their possible contribution to cardiometabolic disorders, such as type 2 diabetes and carotid intima-media thickening in individuals with excess weight. Yet, evidence from longitudinal and retrospective investigations remains inconsistent, with studies often reaching divergent conclusions. Higher circulating TMAO levels have been observed in people with overweight, obesity, and type 2 diabetes who subsequently develop cardiovascular complications, as well as in diabetic individuals who experience renal impairment. Still, the strength and consistency of these links vary considerably between cohorts and are shaped by how thoroughly studies control for underlying confounders. Given that insulin modulates FMO3 activity within hepatocytes, circulating TMAO concentrations might reflect underlying hepatic insulin resistance, offering a possible mechanistic link to its reported associations with diabetes and cardiovascular risk. This mini review summarizes current evidence on TMAO in obesity and type 2 diabetes, highlighting the novel comparison between pediatric and adult findings. This approach may help clarify how TMAO-related mechanisms evolve across the lifespan and inform future risk assessment and prevention strategies.