Fasshauer Mathias, Klein Johannes, Kralisch Susan, Klier Margit, Lossner Ulrike, Bluher Matthias, Paschke Ralf
University of Leipzig, Department of Internal Medicine III, 04103 Leipzig, Germany.
Biochem Biophys Res Commun. 2004 Apr 30;317(2):598-604. doi: 10.1016/j.bbrc.2004.03.090.
During the last 10 years, various adipocytokines have been described which influence insulin sensitivity profoundly and might, therefore, potentially link obesity and insulin resistance. Recently, monocyte chemoattractant protein (MCP)-1 was characterized as a novel adipose-secreted factor upregulated in obesity and insulin resistance that impairs insulin signaling in fat cells in vitro and can be found in atherosclerotic lesions. To clarify expression and regulation of this adipocytokine, MCP-1 mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance. Interestingly, MCP-1 synthesis was significantly downregulated between 43% and 68% during differentiation of 3T3-L1 preadipocytes. Furthermore, 10 ng/ml tumor necrosis factor alpha, 100 nM insulin, 500 ng/ml growth hormone (GH), and 30 ng/ml interleukin (IL)-6-induced MCP-1 mRNA by up to 124-, 23-, 8-, and 2.5-fold, respectively, in a time-dependent fashion with significant stimulation seen at concentrations as low as 0.5 ng/ml GH and 30 ng/ml IL-6. In contrast, the glucocorticoid dexamethasone potently downregulated MCP-1 with significant suppression detectable at concentrations as low as 3 nM and as early as 2h after effector addition. Studies using pharmacological inhibitors suggested that the positive effects of GH and IL-6 on MCP-1 synthesis are at least in part mediated by janus kinase 2 and p44/42 mitogen-activated protein kinase. Taken together, our results show a differential regulation of MCP-1 mRNA by insulin resistance-inducing hormones and support the view that this adipocytokine might be an interesting novel candidate linking insulin resistance, obesity, and atherosclerosis. This adipocytokine could thus be a potential pharmacological target for the treatment of impaired insulin sensitivity.
在过去十年中，人们发现了多种脂肪细胞因子，它们对胰岛素敏感性有深远影响，因此可能是肥胖与胰岛素抵抗之间的潜在联系。最近，单核细胞趋化蛋白（MCP）-1被鉴定为一种新的脂肪分泌因子，在肥胖和胰岛素抵抗中上调，它在体外会损害脂肪细胞中的胰岛素信号传导，并且存在于动脉粥样硬化病变中。为了阐明这种脂肪细胞因子的表达和调控机制，在3T3-L1脂肪细胞分化过程中以及用各种已知可诱导胰岛素抵抗的激素处理后，通过定量实时逆转录-聚合酶链反应测量MCP-1 mRNA。有趣的是，在3T3-L1前脂肪细胞分化过程中，MCP-1的合成显著下调了43%至68%。此外，10 ng/ml肿瘤坏死因子α、100 nM胰岛素、500 ng/ml生长激素（GH）和30 ng/ml白细胞介素（IL）-6分别以时间依赖性方式使MCP-1 mRNA上调高达124倍、23倍、8倍和2.5倍，在低至0.5 ng/ml GH和30 ng/ml IL-6的浓度下即可观察到显著刺激。相比之下，糖皮质激素地塞米松可有效下调MCP-1，在低至3 nM的浓度下以及效应物添加后2小时即可检测到显著抑制。使用药理抑制剂的研究表明，GH和IL-6对MCP-1合成的积极作用至少部分是由janus激酶2和p44/42丝裂原活化蛋白激酶介导的。综上所述，我们的结果显示胰岛素抵抗诱导激素对MCP-1 mRNA有不同的调控作用，并支持这样一种观点，即这种脂肪细胞因子可能是连接胰岛素抵抗、肥胖和动脉粥样硬化的一个有趣的新候选因子。因此，这种脂肪细胞因子可能是治疗胰岛素敏感性受损的潜在药物靶点。
