Effect of Dietary Fatty Acids on Adipose Tissue Inflammation

膳食脂肪酸对脂肪组织炎症的影响

基本信息

  • 批准号:
    8903548
  • 负责人:
  • 金额:
    $ 43.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-12-01 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Adipose tissue inflammation is associated with insulin resistance and an increased risk of cardiovascular disease. Excess dietary saturated fatty acids (SFA) such as palmitate stimulate the production of reactive oxygen species (ROS) by a NOX4-dependent mitochondria-independent pathway, and increase the generation of monocyte chemotactic factors and inflammatory signals in adipocytes. Conversely, an isomer of conjugated linoleic acid (CLA) that is used as a weight loss supplement, decreases triglyceride accumulation and stimulates ROS production by mitochondria rather than NOX4. This too leads to adipocyte chemotactic factor generation and inflammation. On the basis of our preliminary data, we hypothesize that SFA such as palmitate stimulate adipose tissue inflammation by NOX4-dependent generation of ROS by adipocytes. This process involves transfer of key cellular proteins such as NOX4 to the plasma membrane, and can be blocked by removing cholesterol from plasma membranes by exposure to HDL. Conversely, we hypothesize that CLA stimulates adipose tissue inflammation by a distinct pathway that involves generation of ROS by mitochondria, is associated with reduced triglyceride accumulation in adipocytes, is not associated with translocation of proteins to the cell membrane, and is not blocked by HDL. To determine whether NOX expression by adipocytes is required for SFA-induced adipose tissue inflammation, we will specifically delete NOX4 in adipocytes. We also will determine mechanisms by which HDL and its major apolipoprotein, apoA-I, exert anti-inflammatory effects on adipocytes and adipose tissue in vitro and in vivo. Our in vivo studies will focus on the role o the cholesterol transporter, ABCG1, which we have shown in preliminary data to be a likely candidate for the removal of cholesterol from plasma membranes. Since ABCG1 is likely to be produced by adipose tissue macrophages rather than adipocytes, we will transplant either wild type or ABCG1-deficient bone marrow into apoA-I transgenic mice, in which SFA-mediated adipose tissue inflammation is blunted. We will identify differences in how adipocytes metabolize CLA versus palmitate, and determine why CLA leads to triglyceride reduction and fatty acid utilization by mitochondria rather than storage of triglycerides as occurs with other SFA. We also will investigate how this metabolic switch is linked to the generation of mitochondrial ROS, chemotactic factors and inflammatory molecules. Findings from this grant have important implications for preventing diet-induced adipose tissue inflammation and the accompanying insulin resistance and cardiovascular disease risk.
描述(申请人提供):脂肪组织炎症与胰岛素抵抗和心血管疾病风险增加有关。过量的膳食饱和脂肪酸(SFA),如棕榈酸,通过依赖于NOX4的线粒体非依赖性途径刺激活性氧(ROS)的产生,并增加脂肪细胞单核细胞趋化因子和炎症信号的产生。相反,共轭亚油酸(CLA)的异构体被用作减肥补充剂,减少甘油三酯的积累,并通过线粒体而不是NOX4刺激ROS的产生。这也会导致脂肪细胞产生趋化因子和炎症。根据我们的初步数据,我们假设棕榈酸酯等SFA通过脂肪细胞依赖NOX4产生ROS来刺激脂肪组织炎症。这一过程涉及到将关键的细胞蛋白如NOX4转移到质膜上,并可以通过接触高密度脂蛋白从质膜上去除胆固醇而被阻断。相反,我们假设CLA通过一种独特的途径刺激脂肪组织炎症,该途径涉及线粒体产生ROS,与脂肪细胞中甘油三酯的减少积累有关,与蛋白质向细胞膜的转运无关,也不被高密度脂蛋白阻断。为了确定脂肪细胞表达NOX是否是SFA诱导的脂肪组织炎症所必需的,我们将专门删除脂肪细胞中的NOX4。我们还将在体外和体内确定高密度脂蛋白及其主要载脂蛋白apoA-I对脂肪细胞和脂肪组织发挥抗炎作用的机制。我们的体内研究将集中在胆固醇转运蛋白Abcg1的作用上,我们在初步数据中表明,它可能是从质膜中去除胆固醇的候选分子。由于Abcg1很可能是由脂肪组织巨噬细胞而不是脂肪细胞产生的,我们将把野生型或Abcg1缺陷的骨髓移植到apoA-I转基因小鼠中,在其中SFA介导的脂肪组织炎症是钝化的。我们将确定脂肪细胞如何代谢共轭亚油酸与棕榈酸的差异,并确定为什么共轭亚油酸导致甘油三酯减少和线粒体对脂肪酸的利用,而不是像其他SFA那样导致甘油三酯的储存。我们还将研究这种代谢开关如何与线粒体ROS、趋化因子和炎症分子的产生有关。这项拨款的发现对于预防饮食诱导的脂肪组织炎症以及伴随的胰岛素抵抗和心血管疾病风险具有重要意义。

项目成果

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ALAN CHAIT其他文献

ALAN CHAIT的其他文献

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{{ truncateString('ALAN CHAIT', 18)}}的其他基金

Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue
营养因素对脂肪组织中巨噬细胞积累的影响
  • 批准号:
    7899952
  • 财政年份:
    2009
  • 资助金额:
    $ 43.5万
  • 项目类别:
Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue
营养因素对脂肪组织中巨噬细胞积累的影响
  • 批准号:
    8277088
  • 财政年份:
    2009
  • 资助金额:
    $ 43.5万
  • 项目类别:
Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue
营养因素对脂肪组织中巨噬细胞积累的影响
  • 批准号:
    8088162
  • 财政年份:
    2009
  • 资助金额:
    $ 43.5万
  • 项目类别:
Effect of Nutritional Factors on Macrophage Accumulation in Adipose Tissue
营养因素对脂肪组织中巨噬细胞积累的影响
  • 批准号:
    7729549
  • 财政年份:
    2009
  • 资助金额:
    $ 43.5万
  • 项目类别:
Role of Serum Amyloid A in Diabetic Vascular Disease
血清淀粉样蛋白 A 在糖尿病血管疾病中的作用
  • 批准号:
    7548830
  • 财政年份:
    2008
  • 资助金额:
    $ 43.5万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    7548837
  • 财政年份:
    2008
  • 资助金额:
    $ 43.5万
  • 项目类别:
Clinical Nutrition Research Unit
临床营养研究室
  • 批准号:
    7333085
  • 财政年份:
    2007
  • 资助金额:
    $ 43.5万
  • 项目类别:
Clinical Nutrition Research Unit
临床营养研究室
  • 批准号:
    7333080
  • 财政年份:
    2007
  • 资助金额:
    $ 43.5万
  • 项目类别:
BLOOD DONATIONS FOR ATHEROSCLEROSIS STUDIES
用于动脉粥样硬化研究的献血
  • 批准号:
    7603424
  • 财政年份:
    2007
  • 资助金额:
    $ 43.5万
  • 项目类别:
Clinical Nutrition Research Unit
临床营养研究室
  • 批准号:
    7333087
  • 财政年份:
    2007
  • 资助金额:
    $ 43.5万
  • 项目类别:

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成纤维细胞生长因子 8b 将棕色脂肪细胞募集到内脏白色脂肪组织中
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LOUISIANA COBRE: P1: INDUCE THERMOGENIC BROWN ADIPOCYTES IN WHITE ADIPOSE TISSUE
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