Saturated fatty acid-induced macrophage migration: role of toll-like receptor 4

描述（由申请人提供）：与高脂血症、炎症和胰岛素抵抗有关的肥胖症在世界范围内日益流行。肥胖和这些下游代谢效应的存在大大增加了患糖尿病和心血管疾病的风险。有许多不同的因素导致肥胖增加，饮食脂肪的数量和组成是造成这种流行病的主要原因。饱和脂肪酸（sfa）的摄入已被证明与动脉粥样硬化疾病和IR的风险增加有关，而富含多不饱和脂肪酸（pufa）的饮食可预防这些疾病。巨噬细胞，先天免疫系统的细胞，已经被证明可以渗透到肥胖啮齿动物和人类的白色脂肪组织（WAT）中。WAT中巨噬细胞积累的增加与局部和全身性炎症有关，它们的积累也被证明暂时先于IR的发展。因此，脂肪组织巨噬细胞（ATMs）是肥胖病理生理后果的关键介质。我们的初步数据与肥胖以及膳食脂肪酸组成可以影响巨噬细胞浸润到WAT、局部和全身炎症以及IR的观点一致。我们的数据也支持toll样受体4 （TLR4）在SFA诱导的单核细胞迁移中的作用。因此，本提案的总体工作假设是：sfa可以通过趋化因子依赖性和非依赖性机制启动巨噬细胞向WAT的募集，巨噬细胞TLR4表达介导这种sfa响应性迁移。这一假设的一个推论是，PUFAs可以抑制sfa诱导的巨噬细胞迁移。这一假设将在三个具体目标中得到验证：(1)确定膳食sfa是否通过增加脂肪细胞或ATM趋化因子表达来促进巨噬细胞浸润WAT；(2)确定sfa是否可以独立于趋化因子表达来促进巨噬细胞迁移；(3)区分tlr4依赖性和非依赖性影响单核细胞募集到WAT的过程。我们将利用体外方法来确定SFAs是否可以作为化学引诱剂，以及单核细胞暴露于SFAs是否会增加它们的迁移潜力。此外，我们将使用肥胖易感小鼠，在体内研究膳食脂肪酸、WAT中脂肪酸动员和巨噬细胞TLR4表达对ATM积累的影响。肥胖的临床后果，包括糖尿病和心血管疾病，给我们的医疗保健系统带来了巨大的负担。更好地了解巨噬细胞感知和响应膳食脂肪酸的机制，从而导致它们在WAT中的募集和激活，对于我们理解它们对肥胖相关综合征的贡献至关重要。

DESCRIPTION (provided by applicant): There is a growing world-wide obesity epidemic that is linked to hyperlipidemia, inflammation, and insulin resistance. The presence of obesity and these down-stream metabolic effects greatly increases the risk of development of diabetes and cardiovascular disease. There are many different factors leading to increased adiposity, with the quantity and composition of dietary fats contributing heavily to this epidemic. Consumption of saturated fatty acids (SFAs) has been shown to be associated with increased risk of atherosclerotic disease as well as IR, while diets rich in polyunsaturated fatty acids (PUFAs) are protective against these conditions. Macrophages, cells of the innate immune system, have been demonstrated to infiltrate white adipose tissue (WAT) in obese rodents and humans. Increased macrophages accumulation in WAT is associated with local and systemic inflammation, and their accumulation has also been shown to temporally precede the development of IR. Thus, adipose tissue macrophages (ATMs) are key mediators of the pathophysiological consequences of obesity. Our preliminary data are consistent with the idea that not only obesity, but also dietary fatty acid composition, can influence macrophage infiltration into WAT, local and systemic inflammation, and IR. Our data are also in support of a role for Toll-like receptor 4 (TLR4) in SFA- induced monocyte migration. Consequently, the overall working hypothesis of this proposal is: SFAs can initiate macrophage recruitment to WAT by both chemokine-dependent and -independent mechanisms and that macrophaqe TLR4 expression mediates this SFA-responsive migration. A corollary to this hypothesis is that PUFAs can blunt SFA-induced macrophage migration. This hypothesis will be tested in three specific aims: (1) To determine whether dietary SFAs promote macrophage infiltration of WAT via increasing adipocyte or ATM chemokine expression, (2) To determine whether SFAs can promote macrophage migration independently of chemokine expression, and (3) To distinguish between TLR4-dependent and -independent processes effecting monocyte recruitment to WAT. We will utilize in vitro methods to determine whether SFAs can act as chemoattractants and whether exposure of monocytes to SFAs increases their migratory potential. In addition, we will use obesity-prone mice to study, in vivo, the effects of dietary fatty acids, fatty acid mobilization in WAT, and macrophage TLR4 expression on ATM accumulation. The clinical consequences of obesity, including diabetes and cardiovascular disease are placing a tremendous burden on our health care system. A better knowledge of mechanisms by which macrophages sense and respond to dietary fatty acids, leading to their recruitment and activation in WAT is imperative for our understanding of their contribution to obesity-related syndromes.