Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York 11030, United States of America.
Mol Med. 2012 Oct 24;18(1):1161-8. doi: 10.2119/molmed.2012.00156.
Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin-1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance.
肥胖是胰岛素抵抗、2 型糖尿病和心血管疾病的一个主要危险因素。肥胖的病理生理学与慢性低度炎症有关。肥胖的脂肪组织被大量分泌细胞因子的巨噬细胞浸润。巨噬细胞与脂肪细胞之间相互作用的机制，导致巨噬细胞激活和细胞因子释放增加，仍有待阐明。我们推测脂肪细胞衍生的因子可能刺激巨噬细胞的激活。我们已经确定色素上皮衍生因子（PEDF）是一种炎症介质，由脂肪细胞分泌，并介导巨噬细胞的激活。重组 PEDF 激活巨噬细胞释放肿瘤坏死因子（TNF）和白细胞介素-1（IL-1）。PEDF 受体脂肪甘油三酯脂肪酶（ATGL）是 PEDF 介导的巨噬细胞激活所必需的。巨噬细胞上 ATGL 的选择性抑制可减弱 PEDF 诱导的 TNF 产生，而 PEDF 增强 p38 和细胞外信号调节激酶 1/2 丝裂原活化蛋白激酶的磷酸化。PEDF 给药大鼠可导致血清 TNF 水平升高和胰岛素抵抗。综上所述，这些发现表明脂肪细胞分泌的 PEDF 有助于肥胖症中慢性炎症的发生和维持，并且可能是改善胰岛素抵抗的治疗靶点。
