Prevotella copri promotes white adipose browning and ameliorates adiposity.

Patients with obesity showed significantly lower fecal Prevotella copri abundance in a Chinese case-control cohort.

• A case-control analysis of a Chinese cohort was performed comparing obese patients to non-obese controls.
• Fecal P. copri abundance was significantly reduced in the obesity group.
• This finding motivated investigation of P. copri's role in adiposity and fat metabolism.

Administration of P. copri alleviated fat deposition and promoted browning in inguinal white adipose tissue (iWAT) in high-fat diet-induced obese mice.

• Mice were fed a high-fat diet (HFD) to induce adiposity, then treated with P. copri.
• P. copri treatment reduced fat deposition compared to HFD controls.
• Browning markers were upregulated in iWAT following P. copri administration.
• Effects were observed specifically in inguinal white adipose tissue (iWAT).

Succinate was identified as a key metabolite mediating P. copri's effects by activating succinate receptor 1 (SUCNR1).

• Succinate was identified as the key P. copri-derived metabolite responsible for downstream effects.
• Succinate activates SUCNR1 (succinate receptor 1) to mimic the effects of P. copri.
• Treatment with succinate alone recapitulated the browning and anti-adiposity effects observed with P. copri administration.

P. copri or succinate treatment increased iWAT-resident macrophage populations and activated the IL-6-STAT3 pathway.

• Mice treated with either P. copri or succinate showed increased iWAT-resident macrophage populations.
• IL-6-STAT3 pathway activation was observed in iWAT following treatment with P. copri or succinate.
• These findings implicate macrophage-mediated IL-6 signaling as a mechanistic link between P. copri/succinate and adipose browning.

Forkhead box M1 (FOXM1) directly upregulates IL-6 to activate IL-6-STAT3 signaling in P. copri- or succinate-induced iWAT browning.

• FOXM1 was identified as a transcription factor directly upregulating IL-6 expression.
• FOXM1-driven IL-6 upregulation activates the IL-6-STAT3 signaling pathway.
• This mechanism was demonstrated in the context of both P. copri- and succinate-induced iWAT browning.

In human white adipose tissue, P. copri and succinate levels were positively correlated with TBX1 and UCP1 transcription.

• Analysis of human WAT samples was conducted to validate findings from mouse models.
• P. copri levels in human WAT were positively correlated with expression of browning markers TBX1 and UCP1.
• Succinate levels in human WAT were also positively correlated with TBX1 and UCP1 transcription.
• TBX1 and UCP1 are established markers of adipose browning/beige adipocyte identity.