Immune determinants of adaptive thermogenesis

适应性产热的免疫决定因素

• 批准号: 8254514
• 负责人: Ajay Chawla
• 金额: $ 41.83万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-25 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254514
• 关键词: Adipocytes; Adipose tissue; Adrenergic Receptor; Adult; Alzheimer' s Disease; Animals; Applications Grants; Body mass index; Brain; Brown Fat; Calories; Cardiovascular Diseases; Catecholamines; Cells; Cessation of life; Cholelithiasis; Chronic; Chronic Disease; Coronary heart disease; Coupled; Data; Development; Diet; Disease; Dyslipidemias; Energy Intake; Energy Metabolism; Environment; Epidemic; Exposure to; Fatty Acids; Genes; Heating; Hematopoietic System; Human; IL4 gene; Immune; Immune system; Insulin Resistance; Intake; Knock-out; Life Expectancy; Lipolysis; Liver diseases; Macrophage Activation; Maintenance; Malignant Neoplasms; Mammals; Medical Care Costs; Metabolism; Mitochondria; Modeling; Molecular; Molecular Target; Mus; Myeloid Cells; Nature; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Obesity; Organism; Overweight; Pathway interactions; Physiological; Physiological Processes; Physiology; Process; Production; Respiration; Risk Factors; Rodent; Role; Shivering; Signal Pathway; Signal Transduction; Skeletal Muscle; Stimulus; Stroke; Sum; Sympathetic Nervous System; Temperature; Testing; Thermogenesis; Time; Tyrosine; United States; Work; base; cancer type; cell type; cellular targeting; combat; eosinophil; global health; hypertensive heart disease; macrophage; non-alcoholic fatty liver; novel; premature; residence; response; trafficking; uncoupling protein 1

DESCRIPTION (provided by applicant): Increased intake of calories coupled with decreased energy expenditure has fueled an epidemic of obesity, insulin resistance, and type 2 diabetes mellitus in the United States. In 2008, based on the body mass index (BMI), approximately 72.5 million adults in the United States were classified as being obese (BMI > 30). Obesity is an independent risk factor for development of various chronic diseases, including type 2 diabetes, coronary heart disease, hypertension, stroke, certain types of cancer, and premature death. In addition to its impact on disease and life expectancy, the medical care costs of obesity in the United States are staggering, exceeding $147 billion in 2008. Thus, to blunt the eventual impact of this epidemic, it is extremely important to understand the molecular and cellular determinants that control energy expenditure and obesity. Fundamentally, there are two major ways of combating obesity: to decrease energy intake or to increase energy expenditure. In this regard, careful studies in rodents have demonstrated that activation of nonshivering thermogenesis in brown adipose tissue increases energy expenditure and confers protection against obesity. Moreover, the recent discovery of brown adipose tissue in humans suggests that activation of brown fat might be useful in the treatment of human obesity. While significant progress has been made on the molecular pathways controlling the differentiation of brown adipocytes, little is known about extrinsic signaling pathways that regulate brown adipose tissue physiology and energy expenditure. Remarkably, we have discovered that cells of the innate immune system take residence in brown adipose tissue, raising the possibility that the innate immune system might coordinate nonshivering thermogenesis in animals, and perhaps, humans. We thus propose three specific aims to explore this hypothesis, which are: 1) Investigate the regulatory role of macrophages in nonshivering thermogenesis, 2) Investigate the mechanisms by which macrophages in brown adipose tissue regulate uncoupled respiration and energy expenditure, and 3) Investigate the trafficking and functions of other immune cells in cold- and diet-induced thermogenesis. PUBLIC HEALTH RELEVANCE: Obesity, which is now a global health problem, results when energy intake exceeds energy expenditure. In both mice and humans, activation of brown adipose tissue increases energy expenditure, resulting in protection from obesity. Thus, studies in this grant application will elucidate novel cellular circuits that control cold- and diet-induced thermogenesis in brown adipose tissue.

描述（由申请人提供）：加上卡路里的摄入量以及能量消耗的减少加剧了美国的肥胖症，胰岛素抵抗和2型糖尿病的流行病。 2008年，根据体重指数（BMI），美国约有7250万成年人被归类为肥胖（BMI> 30）。肥胖是发展各种慢性疾病的独立危险因素，包括2型糖尿病，冠心病，高血压，中风，某些类型的癌症和过早死亡。除了对疾病和预期寿命的影响外，美国肥胖的医疗费用令人惊叹，2008年超过1470亿美元。因此，为了掩盖这种流行病的最终影响，了解能够控制能量支出和肥胖的分子和细胞决定因素非常重要。从根本上讲，打击肥胖症有两种主要方法：减少能量摄入或增加能量支出。在这方面，对啮齿动物的仔细研究表明，棕色脂肪组织中非刺激的热发生的激活增加了能量消耗，并赋予了对肥胖症的保护。此外，最近在人类中发现棕色脂肪组织的发现表明，棕色脂肪的激活可能有助于治疗人类肥胖症。尽管在控制棕色脂肪细胞分化的分子途径上取得了重大进展，但对调节棕色脂肪组织生理和能量消耗的外在信号传导途径知之甚少。值得注意的是，我们发现先天免疫系统的细胞居住在棕色的脂肪组织中，从而提高了先天免疫系统可能协调动物中的非刺激性生成的可能性，也许是人类。因此，我们提出了三个特定的旨在探索这一假设的特定旨在：1）研究巨噬细胞在非屏蔽热生成中的调节作用，2）研究棕色脂肪组织中巨噬细胞调节未偶联的呼吸和能量的机制，以及3）调查其他免疫细胞在冷热和饮食中的作用。 公共卫生相关性：当能量摄入超过能源消耗时，肥胖症现在是一个全球健康问题。在小鼠和人类中，棕色脂肪组织的激活都会增加能量消耗，从而保护肥胖。因此，在此赠款应用中的研究将阐明控制棕色脂肪组织中冷和饮食诱导的热发生的新型细胞回路。