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Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3

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Abstract

Objective:

Adipocytes accumulated in the visceral area change their function to induce tumor necrosis factor-α (TNF-α) secretion with concomitant matrix metalloproteinase (MMP)-3 induction in mice. This study was performed to clarify the role of macrophages (Mφ)-secreted MMP on the functional changes in adipocytes using a culture system.

Design:

Cultures of 3T3-L1 adipocytes with THP-1 Mφ or the Mφ-conditioned medium were used to investigate the role of Mφ-MMP on the TNF-α gene in 3T3-L1 adipocytes by the addition of MMP inhibitors. For animal experiments, male C57BL/6J mice were rendered insulin resistant by feeding a high-fat diet, and the expression of an Mφ marker F4/80, and MMP-3 genes in mesenteric and subcutaneous fat tissue specimens were examined.

Results:

Mφ-conditioned media (Mφ-CM) increased the levels of TNF-α mRNA expression in 3T3-L1 adipocytes, and these adipocyte responses were abolished by treatment with GM6001, a broad-spectrum MMP inhibitor, or NNGH (N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid), an MMP-3 inhibitor. The activated form of MMP-3 enhanced glycerol release as well as TNF-α protein secretion from 3T3-L1 adipocytes. The incubation of adipocytes with MMP-3 inhibited insulin-induced glucose uptake in adipocytes. Furthermore, a high-fat intake increased the expression of MMP-3, decreased the insulin-induced glucose uptake of adipocytes and induced expression of F4/80 in mesenteric fat tissue of C57BL/6 mice.

Conclusion:

Mφ may cause a pathological link with surrounding adipocytes through the secretion of MMP-3 followed by TNF-α expression in adipocytes in visceral fat tissue.

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Acknowledgements

This work was partly supported by Grants-in-Aid for Scientific Research to HB and HU from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and Grants-in-Aid for Research Committee to HB and YS from the Ministry of Health, Labor and Welfare, Japan.

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Author notes

  1. H Unoki

    Present address: 4Current address: Laboratory for Diabetic Nephropathy, SNP Research Center, The Institute of Physical and Chemical Research, Kanagawa 230-0045, Japan.,

Authors and Affiliations

  1. Division of Applied Translational Research, Chiba University Graduate School of Medicine, Chiba, Japan

    H Unoki

  2. Department of Genome Research and Clinical Application, Chiba University Graduate School of Medicine, Chiba, Japan

    H Bujo & M Jiang

  3. Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, Chiba, Japan

    T Kawamura, K Murakami & Y Saito

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  1. H Unoki
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  2. H Bujo
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  4. T Kawamura
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  5. K Murakami
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  6. Y Saito
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Correspondence to H Bujo.

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Unoki, H., Bujo, H., Jiang, M. et al. Macrophages regulate tumor necrosis factor-α expression in adipocytes through the secretion of matrix metalloproteinase-3. Int J Obes 32, 902–911 (2008). https://doi.org/10.1038/ijo.2008.7

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  • DOI: https://doi.org/10.1038/ijo.2008.7

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