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: 8277088
• 负责人: ALAN CHAIT
• 金额: $ 41.09万
• 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/8277088
• 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 Products; 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; response; saturated fat; sugar; toll-like receptor 4

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.

饮食因素在产生炎症信号中起着重要作用，这些炎症信号可导致巨噬细胞 在脂肪组织中积累。它们通过刺激脂肪细胞中单核细胞 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（SAA 3）， 由脂肪细胞产生的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化固醇）。相反地， 鱼油似乎具有相反的效果，可以防止内脏脂肪中的巨噬细胞积聚。 在这项资助中，我们计划测试的总体假设，即营养因素，导致在反应性的产生， 氧种类或其他炎症刺激将激活NF κ B依赖性趋化途径， 脂肪细胞，导致趋化因子的产生，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）评估机制， 营养素对脂肪细胞单核细胞趋化因子表达的调节作用;（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的作用。 （TLR 4），n-3多不饱和脂肪酸，一种称为FLAP的蛋白质（它产生强大的脂质趋化性 因子）和SAA 3对体内内脏脂肪组织中巨噬细胞积聚的影响;以及（3）评估 膳食胆固醇和膳食氧化固醇导致巨噬细胞蓄积的潜在机制 脂肪组织总的来说，这些研究将提供关于营养素作用的关键信息， 营养过剩的巨噬细胞积累在脂肪组织，并将导致治疗的见解，如何 减少脂肪组织炎症及其下游后果。