Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue

描述(由申请人提供)：饮食因素在产生炎症信号方面起着重要作用，炎症信号可能导致脂肪组织中巨噬细胞的聚集。他们通过刺激脂肪细胞中单核细胞趋化因子的表达来达到这一目的，包括单核细胞趋化蛋白-1(MCP-1)和血清淀粉样蛋白A3(SAA3)，这是脂肪细胞产生的SAA的形式。这些营养因素包括葡萄糖过量、某些饱和脂肪酸和饮食中的胆固醇(或食物中胆固醇氧化产生的氧化甾醇)。相反，鱼油似乎具有相反的作用，可能会防止巨噬细胞在内脏脂肪中积聚。在这项拨款中，我们计划测试总体假设，即导致产生活性氧或其他炎症刺激的营养因素将激活脂肪细胞中依赖于NF：B的趋化通路，导致趋化因子的产生、巨噬细胞积聚、胰岛素抵抗和全身炎症。为此，我们提出了三个具体目标：(1)评估营养物质在体外调控脂肪细胞单核细胞趋化因子表达的机制；(2)研究可能解释这些影响的几种潜在机制，包括Toll样受体4(TLR4)、n-3多不饱和脂肪酸、一种名为Flip的蛋白质(它能产生一种强大的脂类趋化因子)和SAA3在体内内脏脂肪组织中巨噬细胞积聚中的作用；(3)评估膳食胆固醇和膳食氧化甾醇导致脂肪组织中巨噬细胞积聚的潜在机制。总而言之，这些研究将提供有关营养物质和营养过剩在脂肪组织中巨噬细胞聚集中的作用的关键信息，并将导致对如何减少脂肪组织炎症及其下游后果的治疗见解。与公共卫生相关：脂肪组织中炎性细胞的积聚会导致几种不良后果，包括胰岛素抵抗、全身炎症和血管疾病的易感性。似乎有助于炎症细胞积累的营养因素包括饱和脂肪(主要存在于肉类和乳制品中)、以糖形式存在的营养过剩、饮食中的胆固醇以及在食物储存和准备过程中由胆固醇形成的一些化合物。这笔赠款将研究这些饮食因素导致这些变化的机制，并将为预防脂肪组织炎症及其后果提供见解。

DESCRIPTION (provided by applicant): Dietary factors play an important role in generating inflammatory signals that can lead to macrophage accumulation in adipose tissue. They do so by stimulating the expression in adipocytes of monocyte chemotactic factors, including monocyte chemoattractant protein-1 (MCP-1) and serum amyloid A3 (SAA3), the form of SAA produced by adipocytes. These nutritional factors include glucose excess, certain saturated fatty acids and dietary cholesterol (or oxysterols that result from cholesterol oxidation in foods). Conversely, fish oils appear to have the opposite effect and may protect against macrophage accumulation in visceral fat. In this grant we plan to test the overall hypothesis that nutritional factors that result in the generation of reactive oxygen species or other inflammatory stimuli will activate NF:B-dependent chemotactic pathways in adipocytes, leading to the generation of chemotactic factors, macrophage accumulation, insulin resistance and systemic inflammation. To this end we propose three specific aims: (1) To evaluate mechanisms by which nutrients regulate the expression of monocyte chemotactic factors by adipocytes in vitro; (2) To investigate several potential mechanism that might account for these effects, including the roles of the toll-like receptor 4 (TLR4), n-3 polyunsaturated fatty acids, a protein called FLAP (which generates a powerful lipid chemotactic factor) and SAA3, on the accumulation of macrophages in visceral adipose tissue in vivo; and (3) To assess potential mechanisms by which dietary cholesterol and dietary oxysterols lead to macrophage accumulation in adipose tissue. Collectively these studies will provide critical information regarding the role of nutrients and nutrient excess in macrophage accumulation in adipose tissue, and will lead to therapeutic insights into how to reduce adipose tissue inflammation and its downstream consequences. PUBLIC HEALTH RELEVANCE: The accumulation of inflammatory cells in fat tissue leads to several adverse consequences, including insulin resistance, systemic inflammation and a predisposition to vascular disease. Nutritional factors that appear to facilitate the accumulation of the inflammatory cells include saturated fats (the type found mainly in meat and dairy products), nutrient excess in the form of sugar, and dietary cholesterol and some compounds that are formed from cholesterol during food storage and preparation. This grant will investigate mechanisms by which these dietary factors cause these changes, and will provide insights into the prevention of adipose tissue inflammation and its consequences.