Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y
Department of Internal Medicine and Molecular Science (B5), Graduate School of Medicine, Osaka University, Osaka, Japan.
Diabetes. 2001 Sep;50(9):2094-9. doi: 10.2337/diabetes.50.9.2094.
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 PPARgamma 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-alpha, 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.
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病因。脂联素是一种脂肪组织特异性血浆蛋白，具有抗动脉粥样硬化特性，如抑制血管内皮细胞中黏附分子的表达以及巨噬细胞产生细胞因子。在肥胖和患有胰岛素抵抗的2型糖尿病患者中，血浆脂联素浓度会降低。一种能使血浆脂联素正常化或升高的治疗方案可能会预防胰岛素抵抗患者发生动脉粥样硬化。在本研究中，我们证明了噻唑烷二酮类药物（TZDs），即合成的过氧化物酶体增殖物激活受体γ（PPARγ）配体，在体内和体外对人和啮齿动物脂联素表达和分泌的诱导作用。给予TZDs可显著提高胰岛素抵抗的人和啮齿动物的血浆脂联素浓度，且不影响其体重。在肥胖小鼠的脂肪组织中，TZDs可使脂联素mRNA表达正常化或升高。在培养的3T3-L1脂肪细胞中，TZDs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，在胰岛素抵抗状态下产生更多的肿瘤坏死因子-α（TNF-α）通过抑制其启动子活性，剂量依赖性地降低脂肪细胞中脂联素的表达。TZDs可恢复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诱导其产生，并拮抗TNF-α对脂联素启动子的作用，从而预防胰岛素抵抗患者的动脉粥样硬化性血管疾病。
