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Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes.
J Mol Endocrinol 2015; 54(1):25-37JM

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.

Authors+Show Affiliations

Section of Molecular MedicineBSEB 306A, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.Section of Molecular MedicineBSEB 306A, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.Section of Molecular MedicineBSEB 306A, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA.Section of Molecular MedicineBSEB 306A, Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA ming-hui-zou@ouhsc.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25381390

Citation

Zhou, Jun, et al. "Hypochlorous Acid Via Peroxynitrite Activates Protein Kinase Cθ and Insulin Resistance in Adipocytes." Journal of Molecular Endocrinology, vol. 54, no. 1, 2015, pp. 25-37.
Zhou J, Wang Q, Ding Y, et al. Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes. J Mol Endocrinol. 2015;54(1):25-37.
Zhou, J., Wang, Q., Ding, Y., & Zou, M. H. (2015). Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes. Journal of Molecular Endocrinology, 54(1), pp. 25-37. doi:10.1530/JME-14-0213.
Zhou J, et al. Hypochlorous Acid Via Peroxynitrite Activates Protein Kinase Cθ and Insulin Resistance in Adipocytes. J Mol Endocrinol. 2015;54(1):25-37. PubMed PMID: 25381390.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes. AU - Zhou,Jun, AU - Wang,Qilong, AU - Ding,Ye, AU - Zou,Ming-Hui, Y1 - 2014/11/07/ PY - 2014/11/9/entrez PY - 2014/11/9/pubmed PY - 2015/9/10/medline KW - IRS1 KW - hypochlorous acid KW - insulin resistance KW - peroxynitrite SP - 25 EP - 37 JF - Journal of molecular endocrinology JO - J. Mol. Endocrinol. VL - 54 IS - 1 N2 - 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. SN - 1479-6813 UR - https://www.unboundmedicine.com/medline/citation/25381390/Hypochlorous_acid_via_peroxynitrite_activates_protein_kinase_Cθ_and_insulin_resistance_in_adipocytes_ L2 - https://jme.bioscientifica.com/doi/10.1530/JME-14-0213 DB - PRIME DP - Unbound Medicine ER -