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<p>Hyperleptinemia and mitochondrial dysfunction in obesity form a vicious cycle, underscoring the need for targeted interventions. This study suggests that berberine reduces leptin synthesis and improves leptin resistance by upregulating adipose tissue pseudokinase TRIB1 expression, promoting COP1-mediated C/EBPα ubiquitination and degradation, enhancing STAT3 phosphorylation, and suppressing SOCS3 expression. Meanwhile, TRIB1 appears to mediate the remodeling of mitochondrial dynamics by increasing the expression of fusion proteins MFN1 and L-OPA1, inhibiting the activity of the fission protein DRP1, reversing mitochondrial fragmentation, improving respiratory metabolic capacity, and thereby enhancing brown adipose tissue (BAT) thermogenesis. In TRIB1 knockout mice, the dual effects of berberine—central reduction of high-fat diet intake and peripheral promotion of lipolysis and thermogenesis—were largely abolished. Collectively, these findings support a model in which TRIB1 serves as a critical mediator through which berberine coordinates leptin signaling and mitochondrial function, providing mechanistic insight that may inform future strategies for obesity intervention.</p> Graphical Abstract <p></p>

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Molecular mechanism of berberine in ameliorating leptin resistance and mitochondrial dysfunction through the TRIB1-C/EBPα axis in obesity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月26日

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  • Xuelian Zhang,
  • Chenyang Zhang,
  • Xiangrui Meng,
  • Jianyuan Tang

摘要

Hyperleptinemia and mitochondrial dysfunction in obesity form a vicious cycle, underscoring the need for targeted interventions. This study suggests that berberine reduces leptin synthesis and improves leptin resistance by upregulating adipose tissue pseudokinase TRIB1 expression, promoting COP1-mediated C/EBPα ubiquitination and degradation, enhancing STAT3 phosphorylation, and suppressing SOCS3 expression. Meanwhile, TRIB1 appears to mediate the remodeling of mitochondrial dynamics by increasing the expression of fusion proteins MFN1 and L-OPA1, inhibiting the activity of the fission protein DRP1, reversing mitochondrial fragmentation, improving respiratory metabolic capacity, and thereby enhancing brown adipose tissue (BAT) thermogenesis. In TRIB1 knockout mice, the dual effects of berberine—central reduction of high-fat diet intake and peripheral promotion of lipolysis and thermogenesis—were largely abolished. Collectively, these findings support a model in which TRIB1 serves as a critical mediator through which berberine coordinates leptin signaling and mitochondrial function, providing mechanistic insight that may inform future strategies for obesity intervention.

Graphical Abstract