Abstract
We recently reported that genetic deletion of myeloperoxidase (MPO) alleviates obesity-related insulin resistance in mice in vivo. How MPO impairs insulin sensitivity in adipocytes is poorly characterized. As hypochlorous acid (HOCl) is a principal oxidant product generated by MPO, we evaluated the effects of HOCl on insulin signaling in adipocytes differentiated from 3T3-L1 cells. Exposure of 3T3-L1 adipocytes to exogenous HOCl (200 μmol/l) attenuated insulin-stimulated 2-deoxyglucose uptake, GLUT4 translocation, and insulin signals, including tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and phosphorylation of Akt. Furthermore, treatment with HOCl induced phosphorylation of IRS1 at serine 307, inhibitor κB kinase (IKK), c-Jun NH2-terminal kinase (JNK), and phosphorylation of PKCθ (PKCθ). In addition, genetic and pharmacological inhibition of IKK and JNK abolished serine phosphorylation of IRS1 and impairment of insulin signaling by HOCl. Furthermore, knockdown of PKCθ using siRNA transfection suppressed phosphorylation of IKK and JNK and consequently attenuated the HOCl-impaired insulin signaling pathway. Moreover, activation of PKCθ by peroxynitrite was accompanied by increased phosphorylation of IKK, JNK, and IRS1-serine 307. In contrast, ONOO− inhibitors abolished HOCl-induced phosphorylation of PKCθ, IKK, JNK, and IRS1-serine 307, as well as insulin resistance. Finally, high-fat diet (HFD)-induced insulin resistance was associated with enhanced phosphorylation of PKCθ, IKK, JNK, and IRS1 at serine 307 in white adipose tissues from WT mice, all of which were not found in Mpo knockout mice fed HFDs. We conclude that HOCl impairs insulin signaling pathway by increasing ONOO− mediated phosphorylation of PKCθ, resulting in phosphorylation of IKK/JNK and consequent serine phosphorylation of IRS1 in adipocytes.
Highlights
Insulin resistance, a hallmark of obesity and fundamental cause of type 2 diabetes, is characterized by a diminished ability of insulin to regulate glucose homeostasis in insulinsensitive organs including liver, skeletal muscle, and adipose tissue
2011, Liu et al 2013) on time–action and dose–response curves for insulin-stimulated glucose uptake revealed that stimulation with 100 nmol/l insulin for 15 min could induce maximal insulin action, this dose was used for the entire study to induce glucose uptake and transduction of transduction of insulin signaling in 3T3-L1 adipocytes
Jun NH2-terminal kinase (JNK) siRNA abrogated Hypochlorous acid (HOCl)-impaired insulin signaling, as demonstrated by restoration of insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) and phosphorylation of Akt and GSK3b. These results indicate that phosphorylation of JNK is required for insulin resistance and phosphorylation of IRS1 at Ser307 in 3T3-L1 adipocytes treatment with HOCl
Summary
A hallmark of obesity and fundamental cause of type 2 diabetes, is characterized by a diminished ability of insulin to regulate glucose homeostasis in insulinsensitive organs including liver, skeletal muscle, and adipose tissue. Insulin resistance is partly caused by chronic low-level inflammation and oxidative stress in adipose tissue (Guo 2014). Infiltration of inflammatory cells, which produce cytokines and oxidants, leads to a local inflammatory environment in adipose tissue (Olefsky & Glass 2010). The molecular mechanism and role of HOCl in the pathogenesis of insulin resistance remain to be determined
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