Adipose Tissue-Derived Soluble Fms-Like Tyrosine Kinase 1 Is an Obesity-Relevant Endogenous Paracrine Adipokine
Adipose Tissue-Derived Soluble Fms-Like Tyrosine Kinase 1 Is an Obesity-Relevant Endogenous Paracrine Adipokine
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DOI：
10.1161/hypertensionaha.111.171322
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发表时间：
2011-07-01
期刊：
影响因子：
8.3
通讯作者：
Dechend, Ralf
中科院分区：
文献类型：
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作者：
Herse, Florian;Fain, John N.;Dechend, Ralf
脂肪组织的生长依赖于血管生成。我们检验了脂肪组织产生血管生成相关因子的假设。我们在2个不同的患者队列中获得脂肪活检，培养脂肪源性干细胞并研究成熟脂肪细胞。我们进行了微阵列，RT-PCR和蛋白质印迹，研究了大鼠肥胖/代谢综合征模型，并在瘦素缺陷小鼠中进行了病毒基因转移实验。微阵列鉴定了血管内皮生长因子受体的剪接变体，可溶性fms样酪氨酸激酶1（sFlt-1），作为抗血管生成的候选物。我们验证了表达结果，发现sFlt-1是由分离的成熟人脂肪细胞分泌的。肿瘤坏死因子-α降低成熟脂肪细胞中sFlt-1的表达，而缺氧则没有影响。从脂肪组织中分离细胞表明，最高的sFlt-1表达存在于脂肪组织非脂肪细胞中，而不是脂肪细胞本身。我们还发现，sFlt-1表达和sFlt-1释放脂肪组织外植体与相应患者的体重指数呈负相关，但与脂联素表达直接相关。在肥胖/代谢综合征大鼠模型中，我们观察到循环sFlt-1水平和脂肪组织中的sFlt-1表达也与体重呈负相关。为了进一步模拟我们假定的抗血管生成因子，我们接下来在瘦素缺乏的小鼠遗传模型中通过病毒转移过表达sFlt-1，并观察到转染的小鼠比对照组体重增加更少。我们认为sFlt-1可以作为抑制脂肪组织生长的旁分泌因子。局部sFlt-1可调节血管生成潜力，从而影响脂肪组织质量。（高血压。2011;58：37-42.）。在线补充资料
Adipose tissue growth depends on angiogenesis. We tested the hypothesis that adipose tissue produces factors relevant to angiogenesis. We obtained fat biopsies in 2 different patient cohorts, cultured adipose-derived stem cells and studied mature adipocytes. We performed microarray, RT-PCR, and Western blotting; studied a rat obesity/metabolic syndrome model; and conducted viral gene transfer experiments in leptin-deficient mice. The microarray identified the splice variant of the vascular endothelial growth factor receptor, the soluble fms-like tyrosine kinase 1 (sFlt-1), as an antiangiogenesis candidate. We verified the expression findings and found that sFlt-1 was secreted by isolated mature human adipocytes. Tumor necrosis factor-alpha decreased sFlt-1 expression in mature adipocytes, whereas hypoxia had no effect. Separating cells from adipose tissue showed that the highest sFlt-1 expression was present in adipose-tissue nonfat cells rather than in the adipocytes themselves. We also found that sFlt-1 expression and sFlt-1 release by adipose-tissue explants were inversely correlated with body mass index of the corresponding patients but was directly correlated with adiponectin expression. In the obesity/metabolic syndrome rat model, we observed that circulating sFlt-1 levels and sFlt-1 expression in adipose tissue were also inversely correlated with body weight. To model our putative antiangiogenic factor further, we next overexpressed sFlt-1 by viral transfer in a mouse genetic model of leptin deficiency and observed that the transfected mice gained less weight than controls. We suggest that sFlt-1 could act as a paracrine factor inhibiting adipose tissue growth. Local sFlt-1 may regulate angiogenic potential and thereby influence adipose tissue mass. (Hypertension. 2011;58:37-42.). Online Data Supplement