Elevated mevalonolactone from Ruminococcus torques contributes to metabolically unhealthy obesity development

Area of Science:

• Microbiome research
• Metabolic disease mechanisms
• Gut-host interactions

Background:

• Obesity is classified into metabolically unhealthy obesity (MUO) and metabolically healthy obesity (MHO), but the underlying mechanisms are unclear.
• Understanding the gut microbiome's role in metabolic health is crucial for developing targeted interventions.

Purpose of the Study:

• To investigate the role of gut microbiota and fecal metabolome in distinguishing MUO from MHO.
• To identify specific microbial and metabolic factors contributing to insulin resistance and metabolic disorders in MUO.

Main Methods:

• Comparative analysis of gut microbiota and fecal metabolome in MUO and MHO individuals.
• Administration of Ruminococcus torques and mevalonolactone in mouse models to assess their impact on obesity phenotype.
• Investigation of the molecular pathway involving mevalonolactone, ZNF384, and GGPPS.

Main Results:

• Ruminococcus torques and its metabolite mevalonolactone (MVL) were identified as risk factors for insulin resistance and metabolic disorders.
• Administration of R. torques or MVL induced a MUO phenotype in mice.
• MVL was found to directly bind to transcription factor ZNF384, influencing GGPPS expression and promoting insulin resistance.

Conclusions:

• Abnormal colonization of R. torques in the gut increases MVL levels, contributing to MUO development.
• The R. torques-MVL-ZNF384-GGPPS pathway is a novel mechanism linking gut microbiota to insulin resistance and metabolic dysfunction.
• Targeting R. torques or MVL may offer therapeutic strategies for managing MUO.