Early inflammatory responses to high saturated fat diet

描述（由申请人提供）：肥胖已成为大多数发达国家的主要健康风险。最近对人类和动物模型的研究表明，脂肪组织对肥胖饮食表现出炎症反应，其特征是白细胞的浸润和炎症细胞因子和趋化因子的表达。这种反应似乎对肥胖的全身性炎症并发症（如动脉粥样硬化、代谢综合征和脂肪性肝炎）起关键作用。由于大多数数据来自于肥胖形成后收集的脂肪组织，因此关于高饱和脂肪饮食的直接变化的信息很少。在体外，饱和脂肪酸处理可以激活多种细胞类型，这种反应是通过TLR4和TLR2介导的。三天的HSF饮食导致小鼠脂肪组织的中性粒细胞浸润，一顿饭在人类中引起短暂的内毒素血症和白细胞活化。在HSF喂养后，驻留在脂肪组织和循环中的白细胞可能的作用和相互作用尚不清楚。这个项目的目标是分析对HSF喂养的非常容易的局部和全身反应以及引发这种反应的细胞。我推测，驻留在脂肪组织中的白细胞启动了现成的变化，tlr对它们的激活是必要的。为了验证这一假设，我将在高饱和脂肪喂养的小鼠模型中检查血液和腹腔内脂肪组织中的分子和细胞变化，并利用TLR4缺陷、TLR2-/-和白细胞耗尽的小鼠模型来直接解决我的目标。饮食和肥胖与患其他疾病的风险增加密切相关，肥胖人数，包括儿童，每年都在增加。有必要了解导致这种风险的不同因素，包括对高饱和脂肪饮食的直接反应。

DESCRIPTION (provided by applicant): Obesity has become a major health risk in most developed countries. Recent studies in humans and animal models have shown adipose tissue to exhibit an inflammatory response to obesigenic diets that is characterized by infiltration of leukocytes and expression of inflammatory cytokines and chemokines. This response appears to contribute critically to the systemic inflammatory complications of obesity such as atherosclerosis, metabolic syndrome and steatohepatitis. Since most of the data comes from adipose tissues collected after obesity is established, there is little information available on the eady changes as a result of high saturated fat (HSF) diet. In vitro a variety of cell types are activated by treatment with saturated fatty-acids and this response is mediated through TLR4 and TLR2. Three days of HSF diet results in neutrophil infiltration of murine adipose tissues, and a single meal induces transient endotoxemia and leukocyte activation in humans. The possible roles and interaction of leukocytes resident in adipose tissue and in circulation following HSF feeding are unclear. The goal of this project is to analyze the very eady local and systemic response to HSF feeding and the cells which initiate this response. I hypothesize that leukocytes resident in the adipose tissue initiate eady changes and TLRs are necessary for their activation. To test this hypothesis I will examine molecular and cellular changes in the blood and intra- abdominal adipose tissue in a murine model of high saturated fat feeding and utilize the TLR4 deficient, TLR2-/- and leukocyte depleted mouse models to directly address my aims. There is a high association of diet and obesity with increased risk for other diseases and the number of obese persons, including children grows larger every year. It is necessary to understand the different factors that contribute to this risk, including the immediate response to a high saturated fat diet.