Chronic hyperinsulinemia accelerates adipose senescence via mitochondrial dysfunction and cGAS-STING signalling.

Summary

Chronic hyperinsulinemia induces early mitochondrial dysfunction, mtDNA leakage, and activation of cGAS-STING, culminating in adipocyte senescence and adipose dysfunction. Inhibition of cGAS/STING or senolytic therapy (dasatinib plus quercetin) attenuated inflammatory and senescence phenotypes, with corroboration in mouse models and human T2D adipose depots.

Key Findings

• Chronic hyperinsulinemia increased senescence markers and mitochondrial dysfunction in 3T3-L1 and human adipocytes.
• Mitochondrial DNA leakage triggered cGAS-STING activation in insulin-resistant adipocytes and mouse models.
• Temporal analyses showed mitochondrial dysfunction precedes cGAS-STING activation and senescence markers.
• cGAS/STING inhibition and senolytics (dasatinib + quercetin) reduced inflammatory and senescence phenotypes; similar features observed in human T2D adipose.

Clinical Implications

Suggests therapeutic targeting of cGAS-STING or senescent cells to improve insulin resistance and adipose function; underscores the importance of mitigating hyperinsulinemia to preserve adipose tissue quality, relevant to reconstructive and aesthetic outcomes.

Limitations

• Preclinical study without randomized clinical intervention data.
• Potential off-target effects of senolytics and pathway inhibitors require further safety evaluation.

Future Directions

Test cGAS-STING inhibitors and senolytics in translational models and early-phase clinical trials; map cell-type specificity and dose-response in human adipose depots.