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NF-κB-Inducing Kinase Provokes Insulin Resistance in Skeletal Muscle of Obese Mice

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Abstract—

Skeletal muscle is crucial for preserving glucose homeostasis. Insulin resistance and abnormalities in glucose metabolism result from a range of pathogenic factors attacking skeletal muscle in obese individuals. To relieve insulin resistance and restore glucose homeostasis, blocking the cell signaling pathways induced by those pathogenic factors seems an attractive strategy. It has been discovered that insulin sensitivity in obese people is inversely linked with the activity of NF-κB inducing kinase (NIK) in skeletal muscle. In order to evaluate NIK’s pathological consequences, mechanism of action, and therapeutic values, an obese mouse model reproduced by feeding a high-fat diet was treated with a NIK inhibitor, B022. C2C12 myoblasts overexpressing NIK were utilized to assess insulin signaling and glucose uptake. B022 thus prevented high-fat diet-induced NIK activation and insulin desensitization in skeletal muscle. The insulin signaling in C2C12 myoblasts was compromised by the upregulation of NIK brought on by oxidative stress, lipid deposition, inflammation, or adenoviral vector. This inhibition of insulin action is mostly due to an inhibitory serine phosphorylation of IRS1 caused by ERK, JNK, and PKC that were activated by NIK. In summary, NIK integrates signals from several pathogenic factors to impair insulin signaling by igniting a number of IRS1-inhibiting kinases, and it also has significant therapeutic potential for treating insulin resistance.

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All data generated or analyzed in the present study are included in this paper.

Abbreviations

NIK:

NF-κB inducing kinase

T2DM:

Type 2 diabetes mellitus

ERK:

Extracellular signal-regulated kinases

JNK:

Jun kinase

PKC:

Protein kinase C

IRS1:

Insulin receptor substrate 1

HFD:

High-fat diet

ELISA:

Enzyme-linked immunosorbent assay

GTT:

Glucose tolerance test

ITT:

Insulin tolerance test

TAG:

Triglyceride

DAG:

Diacylglycerol

MDA:

Malondialdehyde

8-OHdG:

8-Hydroxy-2-deoxyguanosine

TNFα:

Tumor necrosis factor α

DMEM:

Dulbecco's modified Eagle's Medium

2-NBDG:

2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxyglucose

H2O2:

Hydrogen peroxide

PA:

Palmitate

IR:

Insulin receptor

PI3K:

Phosphatidylinositide 3-kinase

PDK1:

Phosphoinositide-dependent protein kinase 1

PKB/Akt:

Protein kinase B

GLUT4:

Glucose transporter 4

S6K:

Ribosomal protein S6 kinase

IKKα:

Inhibitory B kinase α

IKKβ:

Inhibitory B kinase β

mTOR:

Mammalian target of rapamycin

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Funding

This work is supported by the National Natural Science Foundation of China (82170877), Science and Technology Research Project of Henan Province (222102310105), Xinxiang key Laboratory for Epigenetic Molecular Pharmacology, and Shenzhen Science and Technology Innovation Committee (JCYJ20180302173605034).

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Authors and Affiliations

  1. Department of Pharmacology, Pharmacy College, Xinxiang Medical University, Xinxiang, Henan, 453003, China

    Xueqin Chen, Ran Jiang, Kua Hu & Yu Song

  2. Xinxiang key Laboratory for Epigenetic Molecular Pharmacology, Xinxiang, Henan, 453003, China

    Xueqin Chen, Ran Jiang, Kua Hu & Yu Song

  3. Department of Pharmacology, School of Basic Medical Science, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, China

    Xueqin Chen, Zhuoqun Liu, Wenjun Liu & Liang Sheng

  4. Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210100, China

    Shu Wang & Guangxu Xu

  5. Department of Pharmacy, Shenzhen Traditional Chinese Medicine Hospital, The Fourth Clinical Medical College of Guangzhou University of Chinese Medicine, Shenzhen, Guangdong, 518033, China

    Xinhui Kou

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  1. Xueqin Chen
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Contributions

Liang Sheng, Guangxu Xu, Xinhui Kou, and Yu Song initiated the research idea, performed experimental design and got funding support. Xueqin Chen, Zhuoqun Liu, Wenjun Liu performed most of the experiments. Yu Song and Liang Sheng analyzed the data. Shu Wang and Liang Sheng wrote the manuscript. Guangxu Xu and Xinhui Kou critically reviewed the manuscript. Ran Jiang and Kua Hu did a series of pre-experiments.

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Correspondence to Liang Sheng, Guangxu Xu, Xinhui Kou or Yu Song.

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All animal care and experimental procedures were performed in accordance with the guidelines for animal care of Jiangsu province and were approved by the National Experimental Animal Expert Committee.

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Xueqin Chen, Zhuoqun Liu, and Wenjun Liu contributed equally to this work.

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Chen, X., Liu, Z., Liu, W. et al. NF-κB-Inducing Kinase Provokes Insulin Resistance in Skeletal Muscle of Obese Mice. Inflammation 46, 1445–1457 (2023). https://doi.org/10.1007/s10753-023-01820-7

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