Acute Oxidative Stress Can Reverse Insulin Resistance by Inactivation of Cytoplasmic JNK

Abstract

Chronic oxidative stress results in decreased responsiveness to insulin, eventually leading to diabetes and cardiovascular disease. Activation of the JNK signaling pathway can mediate many of the effects of stress on insulin resistance through inhibitory phosphorylation of insulin receptor substrate 1. By contrast, exercise, which acutely increases oxidative stress in the muscle, improves insulin sensitivity and glucose tolerance in patients with Type 2 diabetes. To elucidate the mechanism underlying the contrasting effects of acute versus chronic oxidative stress on insulin sensitivity, we used a cellular model of insulin-resistant muscle to induce either chronic or acute oxidative stress and investigate their effects on insulin and JNK signaling. Chronic oxidative stress resulted in increased levels of phosphorylated (activated) JNK in the cytoplasm, whereas acute oxidative stress led to redistribution of JNK-specific phosphatase MKP7 from the nucleus into the cytoplasm, reduction in cytoplasmic phospho-JNK, and a concurrent accumulation of phospho-JNK in the nucleus. Acute oxidative stress restored normal insulin sensitivity and glucose uptake in insulin-resistant muscle cells, and this effect was dependent on MKP7. We propose that the contrasting effects of acute and chronic stress on insulin sensitivity are driven by changes in subcellular distribution of MKP7 and activated JNK.Chronic oxidative stress is one of the major sources of metabolic abnormalities associated with Type 2 diabetes (1-3). High glucose and fatty acid levels lead to increased production of reactive oxygen species (ROS), 2 which can cause insulin resistance in peripheral metabolic tissues. This leads to decreased glucose uptake in muscle and adipose tissue, and eventually, pancreatic ␤ cell failure, glucose intolerance, and frank diabetes (4 -8).The mechanistic link between increased ROS levels and insulin resistance is activation of several signaling pathways, primarily mitogen-activated protein kinases (MAPK) pathways. JNK (Jun N-terminal kinases) are MAP kinases activated by cellular stresses, including oxidative stress, and play a role in apoptosis and survival, stress resistance, and immune response (9). Upstream signaling leading to JNK activation involves stress-induced MAPK kinases MEKK4 and MEKK7, as well as scaffold protein JIP (JNK-interacting protein) (10). Activation of JNK leads to dimerization followed by translocation into the nucleus, where it can phosphorylate its downstream target c-Jun, leading to activation of stress response and apoptotic pathways. JNKs are specifically dephosphorylated and inactivated by MAP kinase phosphatase 7 (MKP7), which also acts as a shuttle protein and was proposed to be involved in JNK nucleocytoplasmic translocation (11).Obesity increases JNK activation in muscle and adipose tissue in mice. Genetic ablation or pharmacological inhibition of JNK results in marked improvement of insulin sensitivity in mouse models of diet-induced obesity and insulin resistance (6, 12, 13). Mechanistically, J...

Quantitative Analysis of Orphan Nuclear Receptors in Insulin-Resistant C2C12 Skeletal Muscle Cells

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Hypoxia Potentiates Palmitate-induced Pro-inflammatory Activation of Primary Human Macrophages

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