Hypochlorous acid via peroxynitrite activates protein kinase Cθ and insulin resistance in adipocytes
Authors: Jun Zhou
Qilong Wang
Ming-Hui Zou
Ye Ding
Journal: Journal of Molecular Endocrinology (2015)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: IRS1; hypochlorous acid; insulin resistance; peroxynitrite.
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 .

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. 

Retracted: Yes

PubPeer comments:
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 #1 We thank you for your comments. We have sent all original data, along with your comments, to the editors of J Mol Endo and Diabetes. , 
 #3 We thank you for your comments. We have sent all original data, along with your comments, to the editors of JEM and Diabetes , 
 https: retractionwatch.com 2019 07 08 georgia-state-researcher-has-two-papers-retracted-eight-flagged-hes-not-happy-about-it , 
 2021 retraction notice. https: jme.bioscientifica.com view journals jme 66 2 JME-14-0213r.xml This article has been retracted at the request of the University of Oklahoma Health Sciences Center (OUHSC), with the knowledge and consent of the authors. The request for this retraction was received on 7 December 2020. The retraction follows the conclusion of an OUHSC investigation that u2018determined that the first author, Dr Jun Zhou, carried out knowing and intentional falsification of multiple Western blot figuresu2019 and that u2018significant falsification of data in multiple figures invalidate the scientific findings and conclusions of this articleu2019. The editors of the Journal of Molecular Endocrinology were first made aware of concerns about the article in June 2019. After correspondence with the authors failed to resolve the concern, the editors asked OUHSC to investigate in July 2019. At that time, OUHSC initiated a confidential investigation that concluded in November 2020 resulting in this retraction request. This retraction notice was published 25 January 2021. , 
 https: retractionwatch.com 2020 05 20 associate-vp-for-research-at-georgia-state-is-up-to-10-retractions ,