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The zinc transporter Zip7 is downregulated in skeletal muscle of insulin-resistant cells and in mice fed a high-fat diet

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Norouzi, S, Adulcikas, J ORCID: 0000-0001-9193-6709, Henstridge, DC ORCID: 0000-0003-4988-767X, Sonda, S ORCID: 0000-0001-8152-3425, Sohal, SS ORCID: 0000-0001-9627-6498 and Myers, S ORCID: 0000-0003-4793-3820 2019 , 'The zinc transporter Zip7 is downregulated in skeletal muscle of insulin-resistant cells and in mice fed a high-fat diet' , Cells, vol. 8, no. 7 , p. 663 , doi: 10.3390/cells8070663.

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Abstract

Background: The zinc transporter Zip7 modulates zinc flux and controls cell signaling molecules associated with glucose metabolism in skeletal muscle. The present study evaluated the role of Zip7 in cell signaling pathways involved in insulin-resistant skeletal muscle and mice fed a high-fat diet. Methods: Insulin-resistant skeletal muscle cells were prepared by treatment with an inhibitor of the insulin receptor, HNMPA-(AM)3 or palmitate, and Zip7 was analyzed along with pAkt, pTyrosine and Glut4. Similarly, mice fed normal chow (NC) or a high-fat diet (HFD) were also analyzed for protein expression of Glut4 and Zip7. An overexpression system for Zip7 was utilized to determine the action of this zinc transporter on several genes implicated in insulin signaling and glucose control. Results: We identified that Zip7 is upregulated by glucose in normal skeletal muscle cells and downregulated in insulin-resistant skeletal muscle. We also observed (as expected) a decrease in pAkt and Glut4 in the insulin-resistant skeletal muscle cells. The overexpression of Zip7 in skeletal muscle cells led to the modulation of key genes involved in the insulin signaling axis and glucose metabolism including Akt3, Dok2, Fos, Hras, Kras, Nos2, Pck2, and Pparg. In an in vivo mouse model, we identified a reduction in Glut4 and Zip7 in the skeletal muscle of mice fed a HFD compared to NC controls. Conclusions: These data suggest that Zip7 plays a role in skeletal muscle insulin signaling and is downregulated in an insulin-resistant, and HFD state. Understanding the molecular mechanisms of Zip7 action will provide novel opportunities to target this transporter therapeutically for the treatment of insulin resistance and type 2 diabetes.

Item Type: Article
Authors/Creators:Norouzi, S and Adulcikas, J and Henstridge, DC and Sonda, S and Sohal, SS and Myers, S
Keywords: zinc, zinc transporter, Zip7, insulin signaling pathway, high-fat diet, skeletal muscle, type 2 diabetes, cell signaling
Journal or Publication Title: Cells
Publisher: MDPI AG
ISSN: 2073-4409
DOI / ID Number: 10.3390/cells8070663
Copyright Information:

Copyright 2019 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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