Perfluorooctane sulfonate-induced insulin resistance is mediated by protein kinase B pathway

Area of Science:

• Environmental Health
• Cell Biology
• Metabolic Diseases

Background:

• Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant linked to insulin resistance.
• The precise mechanisms underlying PFOS-induced insulin resistance require further elucidation.

Purpose of the Study:

• To investigate the molecular mechanisms by which PFOS induces insulin resistance in human hepatoma HepG2 cells.
• To explore the role of protein kinase B (AKT) signaling and cellular processes like autophagy and lipid metabolism in PFOS-induced hepatic insulin resistance.

Main Methods:

• Treatment of human hepatoma HepG2 cells with PFOS.
• Assessment of AKT phosphorylation and activation.
• Measurement of gluconeogenic gene (PEPCK) mRNA levels.
• Evaluation of insulin-stimulated glucose uptake.
• Analysis of autophagy markers and mTORC2 activity.
• Quantification of cellular triglyceride levels.

Main Results:

• PFOS inhibited the phosphorylation and activation of AKT, a key regulator of insulin sensitivity.
• PFOS increased the mRNA levels of the gluconeogenic gene PEPCK, leading to reduced insulin-stimulated glucose uptake.
• PFOS exposure disturbed autophagy and increased triglyceride accumulation in HepG2 cells, contributing to AKT inhibition.
• These molecular disturbances collectively resulted in insulin resistance in PFOS-treated cells.

Conclusions:

• PFOS inhibits AKT activation through mechanisms involving disrupted autophagy, potentially via mTORC2 inhibition, and hepatic lipid accumulation.
• These effects contribute to the development of hepatic insulin resistance.
• The study provides new mechanistic insights into how PFOS exposure leads to insulin resistance.