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Research ArticleArticle

Autophagy-Mediated Insulin Receptor Down-Regulation Contributes to Endoplasmic Reticulum Stress-Induced Insulin Resistance

Lijun Zhou, Jingjing Zhang, Qichen Fang, Meilian Liu, Xianling Liu, Weiping Jia, Lily Q. Dong and Feng Liu
Molecular Pharmacology September 2009, 76 (3) 596-603; DOI: https://doi.org/10.1124/mol.109.057067
Lijun Zhou
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Jingjing Zhang
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Qichen Fang
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Meilian Liu
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Xianling Liu
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Weiping Jia
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Lily Q. Dong
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Feng Liu
Departments of Biochemistry (L.Z., F.L.), Pharmacology (J.Z., M.L., X.L., F.L.), and Cellular and Structural biology (L.Q.D.), University of Texas Health Science Center at San Antonio, San Antonio, Texas; and Shanghai Diabetes Institute and Department of Endocrinology and Metabolism, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, China (Q.F., W.J.)
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Abstract

Endoplasmic reticulum (ER) stress is associated with obesity-induced insulin resistance, yet the underlying mechanisms remain to be fully elucidated. Here we show that ER stress-induced insulin receptor (IR) down-regulation may play a critical role in obesity-induced insulin resistance. The expression levels of IR are negatively associated with the ER stress marker C/EBP homologous protein (CHOP) in insulin target tissues of db/db mice and mice fed a high-fat diet. Significant IR down-regulation was also observed in fat tissue of obese human subjects and in 3T3-L1 adipocytes treated with ER stress inducers. ER stress had little effect on IR tyrosine phosphorylation per se but greatly reduced IR downstream signaling. The ER stress-induced reduction in IR cellular levels was greatly alleviated by the autophagy inhibitor 3-methyladenine but not by the proteasome inhibitor N-benzoyloxycarbonyl (Z)-Leu-Leu-leucinal (MG132). Inhibition of autophagy prevented IR degradation but did not rescue IR downstream signaling, consistent with an adaptive role of autophagy in response to ER stress-induced insulin resistance. Finally, chemical chaperone treatment protects cells from ER stress-induced IR degradation in vitro and obesity-induced down-regulation of IR and insulin action in vivo. Our results uncover a new mechanism underlying obesity-induced insulin resistance and shed light on potential targets for the prevention and treatment of obesity-induced insulin resistance and type 2 diabetes.

Footnotes

    • Received April 15, 2009.
    • Accepted June 18, 2009.
  • This work was supported by National Institutes of Health National Institute on Aging [Grant AG26043]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant DK76902] (to F.L.); and a Career Development Award from the American Diabetes Association (to L.Q.D.).

  • ABBREVIATIONS: ER, endoplasmic reticulum; IR, insulin receptor; PI3K, phosphatidylinositol 3-kinase; IRS, insulin receptor substrate; JNK, c-Jun N-terminal protein kinase; 3-MA, 3-methyladenine; TUDCA, tauroursodeoxycholic acid; SP600125, anthra[1,9-cd]pyrazol-6(2H)-one 1,9-pyrazoloanthrone; H&E, hematoxylin and eosin; WAT, white adipose tissue; HFD, high-fat diet; CHOP, C/EBP homologous protein; TG, thapsigargin; LC3, light chain 3; eIF2α, eukaryotic initiation factor 2α.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 76 (3)
Molecular Pharmacology
Vol. 76, Issue 3
1 Sep 2009
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Research ArticleArticle

Autophagy-Mediated Insulin Receptor Down-Regulation Contributes to Endoplasmic Reticulum Stress-Induced Insulin Resistance

Lijun Zhou, Jingjing Zhang, Qichen Fang, Meilian Liu, Xianling Liu, Weiping Jia, Lily Q. Dong and Feng Liu
Molecular Pharmacology September 1, 2009, 76 (3) 596-603; DOI: https://doi.org/10.1124/mol.109.057067

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Research ArticleArticle

Autophagy-Mediated Insulin Receptor Down-Regulation Contributes to Endoplasmic Reticulum Stress-Induced Insulin Resistance

Lijun Zhou, Jingjing Zhang, Qichen Fang, Meilian Liu, Xianling Liu, Weiping Jia, Lily Q. Dong and Feng Liu
Molecular Pharmacology September 1, 2009, 76 (3) 596-603; DOI: https://doi.org/10.1124/mol.109.057067
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