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Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells

International Journal of Obesity volume 35, pages 762–772 (2011)Cite this article

Subjects

Abstract

Objective:

Pigment epithelium-derived factor (PEDF) is a multifunctional protein with neurotrophic and anti-angiogenic properties. More recently it became evident that PEDF is upregulated in patients with type 2 diabetes and also contributes to insulin resistance in mice. During characterization of the secretome of in vitro differentiated human adipocytes by two-dimensional polyacrylamide gel electrophoresis and matrix-assisted laser desorption/ionization-MS, we found that PEDF is one of the most abundant proteins released by adipocytes. The aim of this study was to investigate the regulation and autocrine function of PEDF in human adipocytes and to determine its paracrine effects on human skeletal muscle cells (hSkMC) and human smooth muscle cells (hSMC).

Methods and results:

Human primary adipocytes secrete 130 ng ml−1 PEDF over 24 h from 1 million cells, which is extremely high as compared with adiponectin, interleukin-6 (IL-6) or IL-8. This release of PEDF is significantly higher than from other primary cells, such as adipose-tissue located macrophages (50-times), hSkMC and hSMC (5-times). PEDF protein expression significantly increases during adipogenesis, which is paralleled by increased PEDF secretion. Furthermore, tumor necrosis factor-α and hypoxia significantly downregulate PEDF protein levels. PEDF secretion was significantly reduced by troglitazone and hypoxia and significantly increased by insulin. Treatment of adipocytes and hSkMC with PEDF induced insulin resistance in adipocytes, skeletal and smooth muscle cells at the level of insulin-stimulated Akt phosphorylation, which was dose dependent and more prominent in adipocytes. Furthermore, inflammatory nuclear factor-κB (NF-κB) signaling was induced by PEDF. In hSMC, PEDF induced proliferation (1.7-fold) and acutely activated proliferative and inflammatory signaling pathways (NF-κB, p38 mitogen-activated protein kinase and mammalian target of rapamycin).

Conclusion:

PEDF is one of the most abundant adipokines and its secretion is inversely regulated by insulin and hypoxia. PEDF induces insulin resistance in adipocytes and hSkMC and leads to inflammatory signaling in hSMC. Because of these diverse actions, PEDF is a key adipokine, which could have an important role in diabetes and obesity-related disorders.

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Acknowledgements

This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, the Deutsche Forschungsgemeinschaft (SE 1922/2-1), the Commission of the European Communities (Collaborative Project ADAPT, contract number HEALTH-F2-2008-201100), and EU COST Action BM0602. We thank Professor Liebau and her team, Department of Plastic Surgery, Florence-Nightingale-Hospital Düsseldorf, and PD Dr Andree and his team, Department of Plastic Surgery and Breast Reconstruction, Sana Hospital Düsseldorf-Gerresheim, for support in obtaining adipose tissue samples. The secretarial assistance of Birgit Hurow is gratefully acknowledged.

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  1. S Famulla and D Lamers: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Düsseldorf, Germany

    S Famulla, D Lamers, S Hartwig, W Passlack, A Horrighs, A Cramer, S Lehr, H Sell & J Eckel

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Famulla, S., Lamers, D., Hartwig, S. et al. Pigment epithelium-derived factor (PEDF) is one of the most abundant proteins secreted by human adipocytes and induces insulin resistance and inflammatory signaling in muscle and fat cells. Int J Obes 35, 762–772 (2011). https://doi.org/10.1038/ijo.2010.212

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