MECHANISMS OF CARDIOVASCULAR DISEASE IN OBESITY

肥胖引起的心血管疾病的机制

• 批准号: 6012461
• 负责人: DAVID J LOSKUTOFF
• 金额: $ 37.73万
• 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 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6012461
• 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.

关于促进高凝状态和人类肥胖症中心血管疾病风险增加的分子机制的信息很少。 尽管在肥胖人的血浆中，纤溶酶原活化剂抑制剂1（PAI-1）始终如一，显着升高，并且是动脉粥样硬化性疾病的已知危险因素，但控制其肥胖症表达的起源和调节机制仍然有待定义。 我们对肥胖小鼠和培养的脂肪细胞的研究表明，血浆PAI-1的升高是由于脂肪细胞对肿瘤坏死因子 - α和胰岛素的响应而增加的，脂肪细胞可能在人类肥胖症中溶血基因表达中的中心和先前未知的作用。 以下观察结果为肥胖症中的脂肪细胞和PAI-1生物合成提供了更多新颖的见解，并构成了本应用的基础：（1）转化肥胖小鼠脂肪组织中的生长因子β（TGF-BETA）mRNA长期升高，并且是PAI-1在脂肪环境中的强大诱导剂； （2）就PAI-1而言，脂肪细胞是主要的胰岛素反应性细胞； （3）胰岛素继续在代谢性胰岛素脂肪细胞和小鼠中诱导PAI-1。 我们假设肥胖症中的TGF-β和高胰岛素血症增加会改变脂肪细胞的生物合成活性，并促进与这种情况相关的心血管风险。 在AIM 1中，我们将研究肥胖症和脂肪形成过程中TGF-β表达的调节和后果。 TGF-β可以使用TGF-beta的特定抑制剂在体内和体外探索TGF-beta改变脂肪细胞的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AIM 2中，我们将检查其他鼠肥胖的模型，以确定胰岛素对PAI-1的影响的一般性和组织特异性。 我们还将采用胰岛素信号抑制剂来定义控制PAI-1基因表达的途径，并检验以下假设：在脂肪细胞中，葡萄糖稳态和PAI-1基因表达受到不同途径的调节。 这些研究应提供有关TGF-β和胰岛素及其在PAI-1在脂肪细胞中在健康和疾病中调节中的作用的新信息。