MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY

肥胖引起的心血管疾病的机制

• 批准号: 6537360
• 负责人: DAVID J LOSKUTOFF
• 金额: $ 42.81万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6537360
• 关键词: adipocytes; biological signal transduction; cardiovascular disorder; cell differentiation; cell growth regulation; disease /disorder model; gene expression; glucose metabolism; glucose transport; homeostasis; hormone regulation /control mechanism; hyperinsulinism; insulin; insulin sensitivity /resistance; laboratory mouse; lipid biosynthesis; lipid metabolism; messenger RNA; obesity; plasminogen activator inhibitors; polymerase chain reaction; thromboplastin; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

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.

关于促进人类肥胖症高凝状态和增加心血管疾病风险的分子机制的信息很少。 尽管纤溶酶原激活物抑制剂 1 (PAI-1) 在肥胖人群的血浆中持续显着升高，并且是动脉粥样硬化血栓性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脂肪细胞的研究表明，血浆 PAI-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，并且脂肪细胞可能在人类止血基因表达中发挥着核心且以前未被认识到的作用。肥胖。 以下观察结果为肥胖中的脂肪细胞和 PAI-1 生物合成提供了额外的新见解，并构成了本应用的基础：(1) 转化生长因子 β (TGF-β) mRNA 在肥胖小鼠的脂肪组织中长期升高，并且是一种强大的脂肪细胞中 PAI-1 的诱导剂； (2)就PAI-1而言，脂肪细胞是主要的胰岛素反应细胞； (3) 胰岛素继续在代谢性胰岛素抵抗脂肪细胞和小鼠中诱导 PAI-1。 我们假设肥胖中 TGF-β 的增加和高胰岛素血症会改变脂肪细胞的生物合成活性，并增加与这种情况相关的心血管风险。 在目标 1 中，我们将研究 TGF-β 表达在肥胖和脂肪形成过程中的调节和后果。 将使用 TGF-β 的特异性抑制剂在体内和体外探索 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。 在目标 2 中，我们将检查其他小鼠肥胖模型，以确定胰岛素对 PAI-1 影响的普遍性和组织特异性。 我们还将利用胰岛素信号抑制剂来定义控制 PAI-1 基因表达的途径，并检验脂肪细胞中葡萄糖稳态和 PAI-1 基因表达受不同途径调节的假设。 这些研究应该提供关于 TGF-β 和胰岛素及其各自在健康和疾病中脂肪细胞 PAI-1 调节中的作用的新信息。