Elevated mevalonolactone from Ruminococcus torques contributes to metabolically unhealthy obesity development

Obese individuals are categorized as either "Metabolically Unhealthy Obesity" (MUO) or "Metabolically Healthy Obesity" (MHO) based on their insulin resistance and metabolic disorders. However, the intrinsic mechanism remains largely unknown. By examining gut microbiota and fecal metabolome of patients with MUO and MHO, we identified intestinal microorganism Ruminococcus torques (R. torques) and its metabolite mevalonolactone (MVL) as risk factors for insulin resistance and metabolic disorders. Both R. torques and MVL administration result in the MUO phenotype in mice. In general, MVL is an intermediate metabolite in the eukaryotic mevalonate (MVA) pathway; however, we found that the prokaryote R. torques has the potential to produce MVL. We further showed that MVL could directly bind to the transcription factor ZNF384, triggering its nucleation and subsequent binding to the promoter regions of GGPPS. GGPPS enhances Ras prenylation and promotes insulin resistance. In conclusion, the abnormal colonization of R. torques in the gut leads to an increased level of MVL in patients. This, in turn, affects the expression of GGPPSvia ZNF384, ultimately contributing to the development of MUO.