Mitochondrial-generated ROS down regulates insulin signaling via activation of the p38MAPK stress response pathway

Area of Science:

• Biochemistry
• Cell Biology
• Metabolism

Background:

• Hepatic insulin resistance is linked to reactive oxygen species (ROS) and p38 mitogen-activated protein kinase (MAPK) signaling.
• Mitochondrial dysfunction is a potential source of ROS contributing to metabolic disorders.

Purpose of the Study:

• To investigate if ROS from mitochondrial electron transport chain complex I (ETC-CI) dysfunction impairs insulin signaling.
• To determine the role of the p38MAPK pathway in ROS-induced insulin signaling impairment.

Main Methods:

• Primary mouse hepatocytes were treated with Rotenone (ETC-CI inhibitor).
• Effects on insulin signaling proteins (IRS-1, AKT, GSK3β) were assessed with and without antioxidants (NAC) or p38MAPK inhibitors (SB203580, SB202190).

Main Results:

• Rotenone induced IRS-1 phosphorylation, which was blocked by NAC and p38MAPK inhibitors.
• Rotenone inhibited insulin-stimulated AKT and GSK3β phosphorylation, unaffected by NAC or p38MAPK inhibitors.
• These findings indicate distinct mechanisms for proximal and distal insulin signaling impairment.

Conclusions:

• Rotenone-induced hepatic insulin resistance involves p38MAPK-dependent inhibition of proximal insulin signaling (IRS-1).
• A p38MAPK-independent pathway mediates the inhibition of distal insulin signaling (AKT, GSK3β).
• ROS from ETC CI inhibition contribute to hepatic insulin resistance via p38MAPK activation.