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

## TL;DR

Berberine helps reduce obesity-related issues by targeting TRIB1 to improve leptin signaling and mitochondrial function.

## Contribution

The study reveals a novel molecular mechanism of berberine in obesity through the TRIB1-C/EBPα axis.

## Key findings

- Berberine reduces leptin synthesis and improves leptin resistance via TRIB1 upregulation and C/EBPα degradation.
- TRIB1 mediates mitochondrial remodeling by enhancing fusion proteins and inhibiting fission proteins.
- TRIB1 knockout mice show reduced berberine effects on diet intake and thermogenesis.

## Abstract

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.

The online version contains supplementary material available at 10.1186/s13020-025-01296-7.