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Hypertrophic Adipocyte–Derived Exosomal miR‐802‐5p Contributes to Insulin Resistance in Cardiac Myocytes Through Targeting HSP60
Author(s) -
Wen Zhongyuan,
Li Junfeng,
Fu Yalin,
Zheng Yuyang,
Ma Mingke,
Wang Changhua
Publication year - 2020
Publication title -
obesity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.438
H-Index - 199
eISSN - 1930-739X
pISSN - 1930-7381
DOI - 10.1002/oby.22932
Subject(s) - medicine , insulin resistance , endocrinology , exosome , myocyte , insulin , downregulation and upregulation , heat shock protein , adipocyte , gene knockdown , insulin receptor , microvesicles , biology , microbiology and biotechnology , chemistry , adipose tissue , microrna , cell culture , biochemistry , genetics , gene
Objective This study aimed to elucidate the mechanism by which hypertrophic adipocytes regulate insulin signaling in cardiac myocytes. Methods Palmitate was used to induce hypertrophic 3T3‐L1 adipocytes. Exosomes were purified from normal control or hypertrophic 3T3‐L1 adipocyte‐associated conditioned medium. Exosome‐exposed neonatal rat ventricular myocytes were stimulated with insulin to investigate the effects of exosomes on insulin signaling. Small interfering RNA techniques were used to downregulate protein levels, and their efficiency was evaluated by Western blot. Results Hypertrophic adipocyte–derived exosomes highly expressed miR‐802‐5p. Insulin sensitivity of neonatal rat ventricular myocytes was negatively regulated by miR‐802‐5p. TargetScan and luciferase reporter assays revealed that heat shock protein 60 (HSP60) was a direct target of miR‐802‐5p. HSP60 silencing was found to induce insulin resistance and to mitigate the insulin‐sensitizing effects of adiponectin. In addition, HSP60 depletion significantly increased the expression levels of C/EBP‐homologous protein and enhanced oxidative stress, accompanied by the increases in the phosphorylation of JNK and IRS‐1 Ser307. Moreover, the effects of HSP60 knockdown on C/EBP‐homologous protein and oxidative stress were abolished by the inhibition of either miR‐802‐5p or endocytosis. Conclusions Hypertrophic adipocyte–derived exosomal miR‐802‐5p caused cardiac insulin resistance through downregulating HSP60. These findings provide a novel mechanism by which epicardial adipose tissue impairs cardiac function.