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

饱和脂肪酸诱导的巨噬细胞迁移：Toll 样受体 4 的作用

• 批准号: 7837069
• 负责人: Alyssa H Hasty
• 金额: $ 24.25万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7837069
• 关键词: Adhesions; Adipocytes; Adipose tissue; Affect; Cardiovascular Diseases; Cells; Chemotactic Factors; Chemotaxis; Clinical; Consumption; Data; Development; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Disease; Epidemic; Event; Fatty Acids; Fatty acid glycerol esters; Fish Oils; Healthcare Systems; Human; Hyperlipidemia; Immune system; In Vitro; Infiltration; Inflammation; Infusion procedures; Insulin Resistance; Knowledge; Lead; Link; Lipids; Marrow; Mediating; Mediator of activation protein; Metabolic; Metabolic syndrome; Methods; Mus; Obesity; Physiological; Polyunsaturated Fatty Acids; Process; Research Personnel; Risk; Rodent; Role; Saturated Fatty Acids; Stream; Syndrome; System; Testing; Transplantation; Work; cell motility; cell type; chemokine; feeding; in vivo; insulin sensitivity; macrophage; migration; monocyte; obesity risk; programs; receptor; response; toll-like receptor 4

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.

描述（由申请人提供）：世界范围内肥胖症的流行日益严重，与高脂血症、炎症和胰岛素抵抗有关。肥胖的存在和这些下游代谢影响大大增加了患糖尿病和心血管疾病的风险。导致肥胖增加的因素有很多，其中膳食脂肪的数量和成分是造成这种流行病的主要原因。饱和脂肪酸 (SFAs) 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) 的饮食可以预防这些疾病。巨噬细胞是先天免疫系统的细胞，已被证明可以渗透肥胖啮齿动物和人类的白色脂肪组织 (WAT)。 WAT 中巨噬细胞积累的增加与局部和全身炎症相关，并且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（ATM）是肥胖病理生理后果的关键介质。我们的初步数据与以下观点一致：不仅肥胖，膳食脂肪酸组成也会影响巨噬细胞浸润 WAT、局部和全身炎症以及 IR。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，该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招募至 WAT，并且巨噬细胞 TLR4 表达介导这种 SFA 响应性迁移。这一假设的推论是 PUFA 可以抑制 SFA 诱导的巨噬细胞迁移。该假设将在三个具体目标中进行测试：（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促进巨噬细胞迁移，以及（3）区分影响单核细胞募集到 WAT 的 TLR4 依赖和独立过程。我们将利用体外方法来确定 SFA 是否可以充当化学引诱剂以及单核细胞暴露于 SFA 是否会增加其迁移潜力。此外，我们将使用肥胖倾向的小鼠在体内研究膳食脂肪酸、WAT 中的脂肪酸动员以及巨噬细胞 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，从而导致巨噬细胞在 WAT 中招募和激活，对于我们了解巨噬细胞对肥胖相关综合征的影响至关重要。