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
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
复制标题
DOI：
10.1038/ijo.2010.212
复制
发表时间：
2011-06-01
影响因子：
4.9
通讯作者：
Eckel, J.
中科院分区：
文献类型：
--
作者：
Famulla, S.;Lamers, D.;Eckel, J.
目的：色素上皮衍生因子（PEDF）是一种具有神经营养和抗血管生成作用的多功能蛋白质。最近，PEDF在2型糖尿病患者中上调，并且还导致小鼠的胰岛素抵抗变得明显。在通过二维聚丙烯酰胺凝胶电泳和基质辅助激光解吸/电离-MS表征体外分化的人脂肪细胞的分泌组的过程中，我们发现PEDF是脂肪细胞释放的最丰富的蛋白质之一。本研究的目的是研究PEDF在人脂肪细胞中的调节和自分泌功能，并确定其对人骨骼肌细胞（hSkMC）和人平滑肌细胞（hSMC）的旁分泌作用。人原代脂肪细胞在24小时内从100万个细胞中分泌130 ng ml（-1）PEDF，与脂联素相比非常高，白细胞介素-6（IL-6）或IL-8。PEDF的这种释放显著高于来自其他原代细胞，如脂肪组织定位的巨噬细胞（50倍）、hSkMC和hSMC（5倍）。PEDF蛋白表达在脂肪形成过程中显著增加，这是由PEDF分泌增加引起的。此外，肿瘤坏死因子-α和缺氧显著下调PEDF蛋白水平。曲格列酮和缺氧显着减少PEDF的分泌，而胰岛素显着增加PEDF的分泌。用PEDF处理脂肪细胞和hSkMC在胰岛素刺激的Akt磷酸化水平上诱导脂肪细胞、骨骼肌和平滑肌细胞中的胰岛素抵抗，这是剂量依赖性的并且在脂肪细胞中更突出。此外，PEDF还可诱导炎症性核因子-κ B（NF-κ B）信号传导。结论：PEDF是最丰富的脂肪因子之一，其分泌受胰岛素和缺氧的负调控。PEDF诱导脂肪细胞和hSkMC中的胰岛素抵抗，并导致hSMC中的炎症信号传导。由于这些不同的行动，PEDF是一个关键的脂肪因子，这可能有一个重要的作用，在糖尿病和肥胖相关的疾病。International Journal of Obesity（2011）35，762-772; doi：10.1038/ijo.2010.212; 2010年10月12日在线发表
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-a 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-kappa B (NF-kappa B) signaling was induced by PEDF. In hSMC, PEDF induced proliferation (1.7-fold) and acutely activated proliferative and inflammatory signaling pathways (NF-kappa B, 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. International Journal of Obesity (2011) 35, 762-772; doi:10.1038/ijo.2010.212; published online 12 October 2010