12/15 Lipoxygenases Role in Inflammation and Angiogenesis in Human Adipose Tissue

描述（由申请人提供）：越来越多的证据表明，由于与胰岛素抵抗、血脂异常、 2糖尿病和CVD。肥胖症中内脏脂肪组织的快速扩张伴随着血管生长不足，导致缺氧和炎症，这与肥胖症中胰岛素抵抗的发展密切相关。作为抵消缺氧的补偿机制，触发新血管的形成-血管生成。有趣的是，在皮下脂肪组织中，血管生成反应是足够的，平衡缺氧。然而，在内脏脂肪组织中，血管生成不能充分补偿组织生长，导致组织缺氧持续和炎症恶化。这种储库特异性效应的机制尚不完全清楚，但可能部分解释了肥胖的心血管代谢并发症与内脏脂肪组织的关系。脂氧合酶途径是肥胖和胰岛素抵抗动物模型中脂肪组织炎症的关键参与者。12/15脂氧合酶是胰岛素抵抗发展所必需的，其靶向基因缺失可预防肥胖症中的胰岛素抵抗。然而，脂氧合酶在人体脂肪组织中的功能作用尚不清楚。我们以前已经表明，12/15脂肪氧合酶亚型在人体皮下和网膜（内脏）脂肪组织中具有不同的表达模式，并且主要由非脂肪细胞表达。在这个建议中，我们的目的是详细研究酶的表达和活性在不同的细胞组成的人AT，并确定调节缺氧。此外，我们想研究12/15脂氧合酶途径在内皮细胞缺氧血管生成反应中的作用，并建立不同仓库之间的差异。我们还旨在确定12/15脂氧合酶途径在脂肪组织巨噬细胞炎症中的作用，以响应缺氧，并确定负责产生炎症介质的关键基因。在患有肥胖症和糖尿病的人中，减肥手术后的体重减轻导致胰岛素敏感性的改善和糖尿病的消退。然而，脂肪组织炎症对该临床结局的贡献尚不清楚。在这个建议中，我们将检查12/15脂氧合酶的表达和活性的变化与接受减肥手术的受试者的体重和胰岛素抵抗的变化之间的相关性。我们将在有或无糖尿病的受试者中纵向和横断面研究相关性。了解12/15 ALOX亚型在人AT的不同细胞组分中的功能以及肥胖和胰岛素抵抗中的储库特异性途径调节可能导致治疗糖尿病和预防CVD死亡的靶向创新疗法。该项目还为本科生、研究生和医学生提供了各种生物化学、细胞和分子生物学技术的培训机会。

DESCRIPTION (provided by applicant): Growing evidence indicates that visceral adiposity is particularly detrimental to health, due to associations with insulin resistance, dyslipidemia, Type 2 diabetes and CVD. Rapid expansion of visceral adipose tissue in obesity is accompanied by insufficient vascular growth leading to hypoxia and inflammation that are closely linked to development of insulin resistance in obesity. As a compensatory mechanism to counteract hypoxia, formation of new blood vessels- angiogenesis is triggered. Interestingly, in subcutaneous adipose tissue, angiogenic responses are adequate, balancing hypoxia. However, in visceral adipose tissue, angiogenesis is not adequately compensating tissue growth leading to persistence of tissue hypoxia and exacerbation of inflammation. The mechanisms responsible for this depot specific effect are incompletely understood but may explain in part why associations of cardio- metabolic complications of obesity were linked mostly to visceral adipose tissue. The lipoxygenase pathway is a key player in adipose tissue inflammation in animal models of obesity and insulin resistance. 12/15 lipoxygenases are required for development of insulin resistance and their targeted genetic deletion prevents insulin resistance in obesity. However, functional roles of lipoxygenase enzymes in human adipose tissue are not known. We have shown previously that 12/15 lipoxygenase isoforms have a distinct pattern of expression in subcutaneous and omental (visceral) adipose tissue in humans and are mostly expressed by non-adipose cells. In this proposal we aim to investigate in detail enzymes expression and activity in different cells component of human AT and to determine modulation by hypoxia. Further, we want to investigate the role of 12/15 lipoxygenase pathway in endothelial cells angiogenic response to hypoxia and establish differences between different depots. We also aim to determine the role of 12/15 lipoxygenase pathway in adipose tissue macrophage inflammation in response to hypoxia and identify key genes responsible for production of inflammatory mediators. In humans with obesity and diabetes, weight loss following bariatric surgery leads to improved insulin sensitivity and resolution of diabetes. However, the contribution of adipose tissue inflammation to this clinical outcome is not known. In this proposal we will examine correlations between changes in 12/15 lipoxygenases expression and activity and changes in body weight and insulin resistance in subjects undergoing bariatric surgery. We will study correlations both longitudinally and cross-sectionally in subjects with or without diabetes. Understanding of the functions of 12/15 ALOX isoforms in different cells component of human AT and the depot- specific pathway modulation in obesity and insulin resistance may lead to targeted innovative therapy to treat diabetes and to prevent CVD mortality. This project also provides excellent opportunities for training of undergraduate, graduate and medical students in a variety of biochemical, cellular and molecular biology techniques.