The Role of Substrate Metabolism and Macrophage Activation in Obesity

底物代谢和巨噬细胞激活在肥胖中的作用

基本信息

  • 批准号:
    8453871
  • 负责人:
  • 金额:
    $ 4.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-08-06 至 2016-08-05
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The World Health Organization estimates 500 million adults and as many as 43 million children under the age of 5 are obese underscoring the fact that obesity and its related diseases, including insulin resistance and diabetes, remains a significant global public health problem. Research conducted over the past decade has increasingly linked obesity and inflammation; pro-inflammatory, classically activated M1 macrophage cells of the innate immune system infiltrate adipose tissue at the onset of weight gain contributing to the inflammatory state of fat, ultimately resulting in systemic insulin resistance, while alternatively activated, anti-inflammatory M2 macrophages safeguard insulin sensitivity in metabolic tissues. The mechanisms controlling macrophage subtype remain unclear and it is possible the type of energy substrates available to macrophages in the tissue microenvironment, or the ability of these cells to utilize specific substrates for fuel, may be one mechanism by which macrophage phenotype is modulated. Aim 1 of this proposal will explore how restricting fuel substrate availability affects macrophage subtype (i.e. pro- versus anti-inflammatory) through the use of a macrophage-specific glucose transporter 1 knockout mouse (Glut1 M¿-/-) and a high-fat feeding model of diet-induced obesity. Metabolic phenotyping, including body weight and composition, food intake and activity, systemic insulin sensitivity and glucose tolerance, and energy expenditure will be performed on lean and obese Glut1 M¿-/- and wildtype littermate controls. The degree of macrophage infiltration in epididymal white adipose tissue (eWAT), as well as macrophage subtype and modifications to the eWAT insulin signaling pathway, will be determined using a combination of histologic, gene and protein expression analyses. Lastly, the effect of macrophage phenotype on the eWAT microenvironment in total will be characterized through the use of genomic microarray analysis and metabolomic profiling. Obesity is considered an immune-suppressive state and the Centers for Disease Control and Prevention now recognize obesity as an independent risk factor for increased influenza morbidity and mortality. Aim 2 of this proposal will explore the relationship among obesity, macrophage phenotype and influenza infection and their joint influence over flu infection severity. The Glut1M¿-/- / diet-induced obesity model will be used as in Aim 1, with the addition o an influenza infection. Overall survival, lung pathology, viral clearance and immune cell population characterization will be completed. This project will afford an opportunity to work closely with, and be mentored by, a team of highly respected researchers in the public health fields of obesity and infectious disease. Completion of this research project will culminate in mastery of skills such as conducting controlled animal feeding studies, metabolic phenotyping, immune system characterization, and bioinformatic analyses of large genomic and metabolomics data sets, manuscript writing, data presentation, granstmanship and research project management.
描述(由申请人提供):世界卫生组织估计有5亿成年人和多达4 300万5岁以下儿童肥胖,这突出表明肥胖及其相关疾病,包括胰岛素抵抗和糖尿病,仍然是一个重大的全球公共卫生问题。过去十年进行的研究越来越多地将肥胖和炎症联系起来;在体重增加开始时,先天免疫系统的促炎、经典活化的M1巨噬细胞浸润脂肪组织,导致脂肪的炎症状态,最终导致全身胰岛素抵抗,而交替活化的抗炎M2巨噬细胞则保护代谢组织中的胰岛素敏感性。控制巨噬细胞亚型的机制尚不清楚,可能是组织微环境中巨噬细胞可用的能量底物类型,或者这些细胞利用特定底物作为燃料的能力

项目成果

期刊论文数量(0)
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Amy Johnson其他文献

Amy Johnson的其他文献

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{{ truncateString('Amy Johnson', 18)}}的其他基金

The Role of Substrate Metabolism and Macrophage Activation in Obesity
底物代谢和巨噬细胞激活在肥胖中的作用
  • 批准号:
    8733080
  • 财政年份:
    2013
  • 资助金额:
    $ 4.92万
  • 项目类别:
The Role of Substrate Metabolism and Macrophage Activation in Obesity
底物代谢和巨噬细胞激活在肥胖中的作用
  • 批准号:
    8893135
  • 财政年份:
    2013
  • 资助金额:
    $ 4.92万
  • 项目类别:

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