Role of the UHRF1-KLHL6-CORO2B axis in obesity-related insulin resistance.

BACKGROUND

Obesity-related insulin resistance (IR) involves mitochondrial dysfunction and ferroptosis dysregulation. Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), an epigenetic regulator of DNA methylation, mediates crucial functions in disease progression, though its mechanisms in IR remain unclear.

METHODS

Using murine IR models and tumor necrosis factor-α (TNF-α)-induced adipocyte systems, UHRF1's regulation of mitophagy and ferroptosis was assessed. Bioinformatics identified downstream targets Kelch-like protein 6 (KLHL6) and coronin 2B (CORO2B), prompting examination of the UHRF1-KLHL6-CORO2B axis in obesity-related IR.

RESULTS

Obesity-related IR mice exhibited increased body weight, impaired glucose and insulin tolerance, adipose tissue inflammation, impaired mitophagy, and alterations in ferroptosis-related parameters, accompanied by reduced UHRF1 expression. In vitro, TNF-α-treated adipocytes showed decreased mitophagy, elevated oxidative stress, and changes consistent with ferroptosis, along with lower UHRF1 levels. UHRF1 overexpression was associated with changes in PINK1/Parkin-related markers, cell viability, oxidative stress indicators, ferroptosis-related parameters, and inflammatory responses. UHRF1 overexpression was associated with increased KLHL6 DNA methylation, decreased KLHL6 expression, and alterations in CORO2B ubiquitination.

CONCLUSIONS

UHRF1 overexpression was associated with decreased KLHL6 expression, altered CORO2B ubiquitination, and changes in autophagy-, ferroptosis-, and inflammation-related markers. These results provide insights into potential pathogenic mechanisms and suggest that UHRF1, KLHL6, and CORO2B may serve as candidate targets for further investigation in obesity-related IR.