Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue

饮食因素在产生可导致巨噬细胞的炎症信号方面起着重要作用 脂肪组织中的堆积。他们通过刺激单核细胞中脂肪细胞的表达来做到这一点。 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，一定程度的饱和 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， 鱼油似乎有相反的作用，可能会防止巨噬细胞在内脏脂肪中堆积。 在这项拨款中，我们计划测试导致产生反应性的营养因素的总体假设 氧物种或其他炎性刺激将激活依赖于NF？B的趋化通路 脂肪细胞，导致趋化因子的产生，巨噬细胞聚集，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 营养素对脂肪细胞单核细胞趋化因子表达的调节；(2)探讨 几种可能解释这些效应的潜在机制，包括Toll样受体4的作用 (TLR4)，n-3多不饱和脂肪酸，一种名为Flap的蛋白质(它产生一种强大的脂质趋化作用 因子)和SAA3对体内内脏脂肪组织中巨噬细胞聚集的影响；以及(3)评估 膳食胆固醇和膳食氧化甾醇导致巨噬细胞聚集的潜在机制 脂肪组织。总而言之，这些研究将提供有关营养素和 脂肪组织中巨噬细胞积累的营养过剩，并将导致对如何治疗的洞察 减少脂肪组织炎症及其下游后果。

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.