Elevated mevalonolactone from Ruminococcus torques contributes to metabolically unhealthy obesity development

  • J Biol Chem. 2025 Jun;301(6):110281. doi: 10.1016/j.jbc.2025.110281.
Hong-Yu Nie  1 ,  Meng-Fei Zhao  1 ,  Tian-Yu Wu  2 ,  Ming-Jie Zou  1 ,  Yi-Ping Tang  1 ,  Xiao-Chen Wang  1 ,  Nan-Nan Wang  1 ,  Zi-Yue Zhou  1 ,  Yan Bi  1 ,  Yue Zhao  1 ,  Xi-Tai Sun  2 ,  Jing-Zi Zhang  3 ,  Lei Fang  4 ,  Chao-Jun Li  5
Affiliations
  • 1. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School, Nanjing University, Nanjing, Jiangsu Province, China.
  • 2. Department of Hepatobiliary Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China.
  • 3. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School, Nanjing University, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
  • 4. Ministry of Education Key Laboratory of Model Animal for Disease Study, Model Animal Research Center of the Medical School, Nanjing University, Nanjing, Jiangsu Province, China. Electronic address: [email protected].
  • 5. State Key Laboratory of Reproductive Medicine and Offspring Heath, Nanjing Medical University, Nanjing, China. Electronic address: [email protected].
PMID: 40412522 DOI: 10.1016/j.jbc.2025.110281
Abstract

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.

Keywords
Ruminococcus torques (R.torques); geranylgeranyl pyrophosphate (GGPP); metabolically healthy obesity; metabolically unhealthy obesity; mevalonolactone (MVL).
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