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。最近在人类和动物模型中的研究表明，脂肪组织表现出对肥胖饮食的炎症反应，其特征在于白细胞的浸润和炎性细胞因子和趋化因子的表达。这种反应似乎对肥胖症的全身炎症并发症如动脉粥样硬化、代谢综合征和脂肪性肝炎有重要作用。由于大多数数据来自于肥胖建立后收集的脂肪组织，因此关于高饱和脂肪（HSF）饮食导致的快速变化的信息很少。在体外，各种细胞类型通过饱和脂肪酸处理而被激活，并且这种反应通过TLR 4和TLR 2介导。三天的HSF饮食导致中性粒细胞浸润的小鼠脂肪组织，和一个单一的膳食诱导短暂的内毒素血症和白细胞活化的人。HSF喂养后，脂肪组织和循环中白细胞的可能作用和相互作用尚不清楚。本项目的目标是分析非常容易的地方和系统的反应，以HSF喂养和细胞启动这种反应。我推测，白细胞驻留在脂肪组织启动迅速的变化和TLR是必要的激活。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内脂肪组织中的分子和细胞变化，并利用TLR 4缺陷、TLR 2-/-和白细胞耗尽的小鼠模型来直接解决我的目标。饮食和肥胖与其他疾病风险增加密切相关，包括儿童在内的肥胖人数每年都在增加。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.