MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY

关于促进高凝状态和增加人类肥胖心血管疾病风险的分子机制，目前的信息很少。 尽管纤溶酶原激活物抑制剂1（派-1）在肥胖人群的血浆中持续显著升高，并且是动脉粥样硬化血栓形成疾病的已知危险因素，但控制其在肥胖中表达的起源和调节机制仍有待确定。 我们对肥胖小鼠和培养的脂肪细胞的研究表明，血浆派-1升高是由于脂肪细胞对肿瘤坏死因子-α和胰岛素的反应增加了合成，脂肪细胞可能在人类肥胖症的止血基因表达中起着中心的和以前未被认识的作用。 以下观察结果为肥胖症中的脂肪细胞和派-1生物合成提供了额外的新见解，并形成了本申请的基础：（1）转化生长因子β（2）脂肪细胞是派-1的主要胰岛素反应细胞;（3）胰岛素在代谢性胰岛素抵抗脂肪细胞和小鼠中持续诱导派-1。 我们推测肥胖症患者TGF-β和高胰岛素血症的增加改变了脂肪细胞的生物合成活性，并增加了与此相关的心血管风险。 在目标1中，我们将研究肥胖和脂肪形成过程中TGF-β表达的调节和后果。 TGF-β改变前脂肪细胞生长和分化以及脂肪细胞基因表达、葡萄糖稳态和胰岛素抵抗的可能性将在体内和体外使用TGF-β的特异性抑制剂进行探索。 在目标2中，我们将检查小鼠肥胖的其他模型，以确定胰岛素对派-1的作用的一般性和组织特异性。 我们还将采用胰岛素信号传导抑制剂来确定控制派-1基因表达的途径，并测试脂肪细胞中葡萄糖稳态和派-1基因表达受不同途径调节的假设。 这些研究应该提供新的信息TGF-β和胰岛素及其各自的作用，在健康和疾病的脂肪细胞中的派-1的调节。

Little information is available about the molecular mechanisms that promote the hypercoagulable state and increased risk for cardiovascular disease in human obesity. Although plasminogen activator inhibitor 1 (PAI-1) is consistently and significantly elevated in the plasma of obese humans and is a known risk factor for atherothrombolic disease, the origin and regulatory mechanism(s) that control its expression in obesity remain to be defined. Our studies of obese mice and cultured adipocytes suggest that elevated plasma PAI-1 results from increased synthesis by adipocytes in response to tumor necrosis factor-alpha and insulin, and that the adipocyte may play a central and previously unrecognized role in hemostatic gene expression in human obesity. The following observations provide additional novel insights into adipocytes and PAI-1 biosynthesis in obesity and form the basis of this application: (1) transforming growth factor beta (TGF-beta) mRNA is chronically elevated in adipose tissue of obese mice and is a powerful inducer of PAI-1 in adipocytes; (2) the adipocyte is the primary insulin-responsive cell in terms of PAI-1; and (3) insulin continues to induce PAI-1 in metabolically insulin-resistant adipocytes and mice. We hypothesize that the increased TGF-beta and hyperinsulinemia in obesity alters the biosynthetic activity of adipocytes and promotes the cardiovascular risk associated with this condition. In Aim 1, we will investigate the regulation and consequences of TGF-beta expression in obesity and during adipogenesis. The possibility that TGF-beta alters preadipocyte growth and differentiation as well as adipocyte gene expression, glucose homeostasis, and insulin-resistance will be explored in vivo and in vitro using specific inhibitors of TGF-beta. In Aim 2, we will examine additional models of murine obesity to determine the generality and tissue specificity of the effects of insulin on PAI-1. We will also employ inhibitors of insulin-signaling to define the pathways that control PAI-1 gene expression, and to test the hypothesis that in adipocytes, glucose homeostasis and PAI-1 gene expression are regulated by different pathways. These studies should provide novel information about TGF-beta and insulin and their respective roles in the regulation of PAI-1 in adipocytes in health and disease.