Disruption of the plasminogen activator inhibitor-1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice
Disruption of the plasminogen activator inhibitor-1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice
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DOI：
10.1096/fj.00-0750fje
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发表时间：
2001-06-01
期刊：
影响因子：
4.8
通讯作者：
Loskutoff, DJ
中科院分区：
文献类型：
--
作者：
Schäfer, K;Fujisawa, K;Loskutoff, DJ
在肥胖人类和啮齿动物中经常观察到血浆和脂肪组织纤溶酶原激活物抑制剂-1 (PAI-1) 水平升高。在本报告中，生成了缺乏 PAI-1 基因 (PAI-1(-/-)) 的遗传性肥胖 (ob/ob) 小鼠，然后用于测试 PAI-1 的存在会促进与肥胖相关的高血糖、高胰岛素血症和胰岛素抵抗的假设。与瘦小鼠相比，野生型 (WT) ob/ob 和 PAI-1(-/-) ob/ob 小鼠均出现显着肥胖。然而，PAI-1(-/-) ob/ob 小鼠的体重显着低于 WT ob/ob 小鼠，并且其高血糖和高胰岛素血症显着改善。尽管腹腔注射葡萄糖导致WT ob/ob 小鼠血清胰岛素水平显着增加，但PAI-1(-/-) ob/ob 小鼠的增加相对较小。逆转录聚合酶链反应测定和原位杂交研究表明，在大多数测试年龄的 WT ob/ob 小鼠的脂肪组织中，肿瘤坏死因子 α (TNF-α) mRNA 表达显着增加。然而，在 PAI-1(-/-) ob/ob 小鼠的脂肪组织中，它没有增加，或仅轻微增加。免疫组织化学和 ELISA 显示，与 WT ob/ob 小鼠相比，PAI-1(-/-) ob/ob 小鼠脂肪组织中 TNF-α 蛋白的浓度和分泌率也显着降低。这些结果表明，PAI-1 可能通过促进脂肪组织 TNF-α 基因表达的增加，导致与小鼠肥胖相关的特征性高血糖和高胰岛素血症的发生。
Elevated levels of plasma and adipose tissue plasminogen activator inhibitor-1 (PAI-1) are observed frequently in obese humans and rodents. In this report, genetically obese (ob/ob) mice lacking the PAI-1 gene (PAI-1(-/-)) were generated and then used to test the hypothesis that the presence of PAI-1 promotes the hyperglycemia, hyperinsulinemia, and insulin resistance associated with obesity. Both wild-type (WT) ob/ob and PAI-1(-/-) ob/ob mice developed substantial adiposity compared with their lean counterparts. However, the PAI-1(-/-) ob/ob mice weighed significantly less than the WT ob/ob mice, and their hyperglycemia and hyperinsulinemia improved significantly. Although intraperitoneal glucose administration resulted in a dramatic increase in serum insulin levels in WT ob/ob mice, the increase in PAI-1(-/-) ob/ob mice was relatively small. Reverse transcription polymerase chain reaction assays and in situ hybridization studies demonstrated that tumor necrosis factor alpha (TNF-alpha) mRNA expression increased significantly in the adipose tissue of WT ob/ob mice at most ages tested. However, it was not increased, or only mildly increased, in the adipose tissue of the PAI-1(-/-) ob/ob mice. The concentration and rate of secretion of TNF-alpha protein in adipose tissue from PAI-1(-/-) ob/ob mice also were significantly lower compared with their WT ob/ob counterparts as shown by immunohistochemistry and ELISA. These results suggest that PAI-1 contributes to the development of the characteristic hyperglycemia and hyperinsulinemia associated with murine obesity, possibly by facilitating increased adipose tissue TNF-alpha gene expression.