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: 8453871
• 负责人: Amy Johnson
• 金额: $ 4.92万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8453871
• 关键词: 5 year old; Address; Adipocytes; Adipose tissue; Adult; Affect; Age; Animal Feed; Anti-Inflammatory Agents; Anti-inflammatory; Bioinformatics; Biological Markers; Body Composition; Body Weight; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Communicable Diseases; Contracts; Control Animal; Data; Data Set; Dependence; Development; Diabetes Mellitus; Diet; Disease; Eating; Energy Metabolism; Energy-Generating Resources; Epidemic; Epidemiology; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Genomics; Glucose; Glucose Transporter; Goals; Hepatocyte; Histologic; Hyperlipidemia; Hypertension; Immune; Immune response; Immune system; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Influenza; Insulin Resistance; Insulin Signaling Pathway; Joints; Knockout Mice; Knowledge; Lead; Link; Lipolysis; Lung; Macrophage Activation; Maintenance; Manuscripts; Mediating; Mentors; Metabolic; Metabolic syndrome; Metabolism; Microarray Analysis; Modeling; Modification; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome; Pathogenesis; Pathology; Pathway interactions; Phenotype; Play; Population; Pre-Clinical Model; Predisposition; Prevalence; Public Health; Research; Research Personnel; Research Project Grants; Risk; Risk Factors; Role; SLC2A1 gene; Severities; Shapes; Structure of parenchyma of lung; Tissues; Viral; Weight Gain; Work; World Health Organization; Wound Healing; Writing; cytokine; design; disorder prevention; fatty acid oxidation; feeding; glucose metabolism; glucose tolerance; immune clearance; improved; in vivo; influenza outbreak; innovation; insight; insulin sensitivity; macrophage; metabolic abnormality assessment; metabolomics; mortality; mouse model; nutrient metabolism; pathogen; protein expression; public health relevance; response; skills; therapeutic target; tissue repair

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（由适用提供）：世界卫生组织估计有5亿成年人和多达4300万年龄的5岁以下儿童在5岁以下肥胖，因为肥胖及其相关疾病（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。在过去的十年中进行的研究已经增加了肥胖和感染。促炎的，经典激活的M1巨噬细胞在体重开始时先天免疫系统浸润脂肪组织浸润脂肪组织有助于脂肪的炎症状态，最终导致全身性胰岛素抵抗，而替代激活，抗炎的M2巨噬细胞抗炎M2-巨噬细胞中胰岛素胰岛素胰岛素抑制剂中的抗元素。控制巨噬细胞亚型的机制尚不清楚，并且有可能可用于组织微环境中巨噬细胞的能量底物的类型，或者这些细胞利用特定底物进行燃料的能力，可能是一种 调节巨噬细胞表型的机制。该提案的目标1将探讨限制燃料底物的可用性如何通过使用巨噬细胞特异性葡萄糖转运蛋白1基因敲除小鼠（Glut1 M€ - / - ）和饮食诱导的obes i诱导的高脂肪喂养模型，如何通过使用巨噬细胞特异性葡萄糖转运蛋白1敲除小鼠（Glut1 M¿代谢表型，包括体重和组成，食物摄入和活动，全身性胰岛素敏感性和葡萄糖耐受性以及能量消耗，将在瘦肉和肥胖的glut1 m€ - / - 以及野生型同型同层控制上进行。附睾白脂肪组织（EWAT）以及巨噬细胞亚型和对EWAT胰岛素信号途径的修饰的巨噬细胞浸润程度将使用组织学，基因和蛋白质表达分析的组合确定。最后，通过使用基因组微阵列分析和代谢组分析，将表征巨噬细胞表型对EWAT微环境的影响。肥胖被认为是一种免疫抑制状态，疾病控制和预防中心现在将肥胖症视为增加影响力的发病率和死亡率的独立危险因素。该提案的目标2将探讨肥胖，巨噬细胞表型和对流感感染的影响及其对流感感染严重程度的关节影响。 GLUT1M�- / - /饮食诱导的肥胖模型将与AIM 1一起使用，并产生影响。总体生存率，肺病理学，病毒清除和免疫细胞人群表征将完成。该项目将有机会与肥胖和传染病公共卫生领域的一支备受尊敬的研究人员保持紧密合作并考虑。该研究项目的完成将最终掌握诸如进行受控动物喂养研究，代谢表型，免疫系统表征以及对大型基因组和代谢组学数据集，手稿写作，数据表现，GranstMisship和Research Project Project Project Project Project项目的生物信息学分析。