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
• 负责人: Amy Johnson
• 金额: $ 5.33万
• 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/8733080
• 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（由申请人提供）：世界卫生组织估计有5亿成年人和多达4300万5岁以下儿童肥胖，这强调了肥胖及其相关疾病（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;先天免疫系统的促炎、经典活化的M1巨噬细胞在体重增加时浸润脂肪组织，导致脂肪的炎症状态，最终导致全身胰岛素抵抗，而替代活化的抗炎M2巨噬细胞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仍不清楚，可能是组织微环境中巨噬细胞可用的能量底物类型，或这些细胞利用特定底物作为燃料的能力，可能是其中之一 调节巨噬细胞表型的机制。本提案的目的1将通过使用巨噬细胞特异性葡萄糖转运蛋白1敲除小鼠（Glut 1 M <$-/-）和饮食诱导肥胖的高脂喂养模型，探索限制燃料底物可用性如何影响巨噬细胞亚型（即促炎与抗炎）。将对瘦型和肥胖型Glut 1 M <$-/-和野生型同窝对照进行代谢表型分析，包括体重和组成、摄食量和活动、全身胰岛素敏感性和葡萄糖耐量以及能量消耗。将使用组织学、基因和蛋白质表达分析的组合来确定附睾白色脂肪组织（eWAT）中巨噬细胞浸润的程度以及巨噬细胞亚型和eWAT胰岛素信号传导途径的修饰。最后，巨噬细胞表型对eWAT微环境的总体影响将通过使用基因组微阵列分析和代谢组学分析来表征。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认为肥胖是增加流感发病率和死亡率的独立危险因素。目的二探讨肥胖、巨噬细胞表型与流感感染的关系，以及它们对流感感染严重程度的联合影响。如目的1所述，使用Glut 1 M-/- /饮食诱导的肥胖模型，并添加流感感染。将完成总生存期、肺病理学、病毒清除和免疫细胞群表征。这个项目将提供一个机会，与一个在肥胖和传染病公共卫生领域备受尊敬的研究人员团队密切合作，并得到他们的指导。该研究项目的完成将最终掌握技能，如进行控制动物饲养研究，代谢表型，免疫系统表征，大型基因组和代谢组学数据集的生物信息学分析，手稿写作，数据展示，granstmanship和研究项目管理。