Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue

营养因素对脂肪组织中巨噬细胞积累的影响

• 批准号: 7899952
• 负责人: ALAN CHAIT
• 金额: $ 41.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899952
• 关键词: Accounting; Address; Adhesions; Adipocytes; Adipose tissue; Amyloid; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonate 5-Lipoxygenase; Attenuated; Cell Nucleus; Cell Surface Receptors; Cells; Chemotactic Factors; Cholesterol; Complex; Dairy Products; Data; Diet; Dietary Cholesterol; Dietary Factors; Dietary Fatty Acid; Docosahexaenoic Acids; Endotoxins; Event; Fatty acid glycerol esters; Fish Oils; Food; Gene Expression; Generations; Genes; Genetic Transcription; Glucose; Grant; Hyaluronan; Hypertrophy; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Lead; Leukotriene B4; Lipids; Macrophage Chemotactic Factors; Meat; Monocyte Chemoattractant Protein-1; Mus; Natural Immunity; Nature; Nutrient; Nutritional; Obesity; Palmitic Acids; Pathway interactions; Pattern recognition receptor; Phosphotransferases; Play; Polyunsaturated Fatty Acids; Predisposition; Preparation; Prevention; Production; Protein Isoforms; Proteins; Proteomics; Reactive Oxygen Species; Regulation; Role; Route; Saturated Fatty Acids; Scheme; Serum; Serum amyloid A protein; Signal Transduction; Stimulus; Sucrose; Testing; Therapeutic; Tissues; Vascular Diseases; Visceral; Weight Gain; adverse outcome; cardiovascular disorder risk; feeding; in vivo; insight; interest; macrophage; monocyte; monocyte chemoattractant protein 1 receptor; novel; oxidation; public health relevance; response; saturated fat; sugar; toll-like receptor 4

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.

描述（由申请人提供）：饮食因素在产生炎症信号方面发挥着重要作用，炎症信号可导致脂肪组织中巨噬细胞积聚。它们通过刺激脂肪细胞中单核细胞趋化因子的表达来实现这一目的，这些趋化因子包括单核细胞趋化蛋白-1 (MCP-1) 和血清淀粉样蛋白 A3 (SAA3)（脂肪细胞产生的 SAA 形式）。这些营养因素包括葡萄糖过量、某些饱和脂肪酸和膳食胆固醇（或食物中胆固醇氧化产生的氧甾醇）。相反，鱼油似乎具有相反的作用，可以防止巨噬细胞在内脏脂肪中积累。在这笔资助中，我们计划测试总体假设，即导致活性氧或其他炎症刺激产生的营养因素将激活脂肪细胞中 NF:B 依赖性趋化途径，导致趋化因子产生、巨噬细胞积累、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节脂肪细胞单核细胞趋化因子表达的机制； (2) 研究可能解释这些效应的几种潜在机制，包括 Toll 样受体 4 (TLR4)、n-3 多不饱和脂肪酸、一种名为 FLAP 的蛋白质（产生强大的脂质趋化因子）和 SAA3 对体内内脏脂肪组织中巨噬细胞积累的作用； (3) 评估膳食胆固醇和膳食氧甾醇导致巨噬细胞在脂肪组织中积聚的潜在机制。总的来说，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积累中的作用的关键信息，并将为如何减少脂肪组织炎症及其下游后果提供治疗见解。公共卫生相关性：脂肪组织中炎症细胞的积累会导致多种不良后果，包括胰岛素抵抗、全身炎症和易患血管疾病。似乎促进炎症细胞积聚的营养因素包括饱和脂肪（主要存在于肉类和乳制品中）、糖形式的营养过剩、膳食胆固醇以及食物储存和制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。