Early inflammatory responses to high saturated fat diet

描述(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上的研究表明，脂肪组织对顺式饮食表现出炎症反应，其特征是白细胞的渗透和炎性细胞因子和趋化因子的表达。这种反应似乎对肥胖引起的全身炎性并发症如动脉粥样硬化、代谢综合征和脂肪性肝炎起到了至关重要的作用。由于大多数数据来自肥胖被证实后收集的脂肪组织，因此关于高饱和脂肪(HSF)饮食导致的EADY变化的信息很少。在体外，饱和脂肪酸可以激活多种类型的细胞，这种反应是通过TLR4和TLR2介导的。三天的HSF饮食会导致中性粒细胞在小鼠脂肪组织中的渗透，而一餐就会导致人类的一过性内毒素血症和白细胞激活。HSF喂养后，滞留在脂肪组织和循环中的白细胞的可能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系统反应，以及启动这种反应的细胞。我假设，脂肪组织中的白细胞启动了Eady变化，而TLRs是激活它们所必需的。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测血液和腹内脂肪组织的分子和细胞变化，并利用TLR4缺乏、TLR2-/-和白细胞耗尽的小鼠模型直接实现我的目标。饮食和肥胖与其他疾病风险的增加高度相关，肥胖者的数量，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即时反应。

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.