PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein
PPARγ ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein
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DOI：
10.2337/diabetes.50.9.2094
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发表时间：
2001-09-01
期刊：
影响因子：
7.7
通讯作者：
Matsuzawa, Y
中科院分区：
文献类型：
--
作者：
Maeda, N;Takahashi, M;Matsuzawa, Y
胰岛素抵抗及其可怕的后果，2型糖尿病，是动脉粥样硬化的主要原因。脂联素是一种脂肪特异性血浆蛋白，具有抗动脉粥样硬化特性，例如抑制血管内皮细胞中粘附分子的表达和巨噬细胞产生细胞因子。伴有胰岛素抵抗的肥胖和2型糖尿病患者血浆脂联素浓度降低。正常化或增加血浆脂联素的治疗方案可能会预防胰岛素抵抗患者的动脉粥样硬化。在这项研究中，我们证明了噻唑烷二酮类（TZDs），这是合成的过氧化物酶体增殖物激活受体γ配体，在人体和啮齿类动物在体内和体外的脂联素的表达和分泌的诱导作用。TZD的给药显著增加了胰岛素抵抗的人和啮齿动物的血浆脂联素浓度，而不影响其体重。脂联素mRNA表达正常化或增加TZDs在肥胖小鼠的脂肪组织。在培养的3 T3-L1脂肪细胞中，TZD衍生物以剂量和时间依赖性方式增强脂联素的mRNA表达和分泌。此外，这些作用是通过TZDs激活启动子介导的。另一方面，在胰岛素抵抗条件下产生更多的TNF-α通过抑制其启动子活性而剂量依赖性地降低脂肪细胞中脂联素的表达。TZDs恢复了TNF-α的这种抑制作用。TZDs可能通过直接作用于脂联素启动子并拮抗TNF-α对脂联素启动子的作用而诱导脂联素的产生，从而预防胰岛素抵抗患者的动脉粥样硬化性血管疾病。
Insulin resistance and its dreaded consequence, type 2 diabetes, are major causes of atherosclerosis. Adiponectin is an adipose-specific plasma protein that possesses anti-atherogenic properties, such as the suppression of adhesion molecule expression in vascular endothelial cells and cytokine production from macrophages. Plasma adiponectin concentrations are decreased in obese and type 2 diabetic subjects with insulin resistance. A regimen that normalizes or increases the plasma adiponectin might prevent atherosclerosis in patients with insulin resistance. In this study, we demonstrate the inducing effects of thiazolidinediones (TZDs), which are synthetic PPAR gamma ligands, on the expression and secretion of adiponectin in humans and rodents in vivo and in vitro. The administration of TZDs significantly increased the plasma adiponectin concentrations in insulin resistant humans and rodents without affecting their body weight. Adiponectin mRNA expression was normalized or increased by TZDs in the adipose tissues of obese mice. In cultured 3T3-L1 adipocytes, TZD derivatives enhanced the mRNA expression and secretion of adiponectin in a dose- and time-dependent manner. Furthermore, these effects were mediated through the activation of the promoter by the TZDs. On the other hand, TNF-a, which is produced more in an insulin-resistant condition, dose-dependently reduced the expression of adiponectin in adipocytes by suppressing its promoter activity. TZDs restored this inhibitory effect by TNF-alpha. TZDs might prevent atherosclerotic vascular disease in insulin-resistant patients by inducing the production of adiponectin through direct effect on its promoter and antagonizing the effect of TNF-alpha on the adiponectin promoter.