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

Area of Science:

• Metabolism
• Endocrinology
• Cellular Biology

Background:

• Prediabetes and Type 2 Diabetes are global health crises.
• Adipose tissue is a key endocrine organ regulating glucose homeostasis.
• Chronic hyperinsulinemic stress is implicated in metabolic dysfunction.

Purpose of the Study:

• To investigate the role of adipocyte senescence and the cGAS-STING pathway in hyperinsulinemia-induced insulin resistance.
• To elucidate the temporal relationship between mitochondrial dysfunction, cGAS-STING activation, and senescence.
• To evaluate therapeutic strategies targeting cGAS-STING or senescence.

Main Methods:

• Induction of insulin resistance and senescence in 3T3-L1 adipocytes and human mesenchymal stem cell-derived adipocytes.
• Analysis of senescence markers, mitochondrial function, and cGAS-STING pathway activation.
• In vivo studies using mouse models and adipose tissue from Type 2 diabetes patients.
• Pharmacological and genetic targeting of cGAS/STING and senolytic treatment (Dasatinib and Quercetin).

Main Results:

• Prolonged hyperinsulinemia increased senescent adipocytes and activated the cGAS-STING pathway.
• Mitochondrial dysfunction preceded cGAS-STING activation and senescence.
• Mitochondrial DNA leakage was identified as a trigger for cGAS-STING.
• Targeting cGAS/STING or using senolytics reduced inflammatory and senescence markers.
• Findings were corroborated in adipose tissue from Type 2 diabetes patients.

Conclusions:

• A progressive model of cellular dysfunction: hyperinsulinemic stress leads to mitochondrial dysfunction, followed by cGAS-STING activation and adipocyte senescence.
• The cGAS-STING pathway and adipocyte senescence are key contributors to adipose tissue dysfunction in insulin resistance and Type 2 Diabetes.
• Targeting the cGAS-STING pathway or employing senolytic therapies shows therapeutic potential for metabolic diseases.