Fibroblast Growth Factor and Energy Metabolism

成纤维细胞生长因子和能量代谢

• 批准号: 9280924
• 负责人: Yu-Hua Tseng
• 金额: $ 37.24万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-03 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9280924
• 关键词: ATP Synthesis Pathway; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Belief; Binding; Blood Glucose; Blood Vessels; Brown Fat; Cardiovascular Diseases; Cell Line; Cell Proliferation; Cell surface; Cells; Communities; Comorbidity; Complex; Consumption; Data; Development; Diabetes Mellitus; Diet; Disease; Employee Strikes; Energy Intake; Energy Metabolism; Enzymes; Epidemic; Exercise; Exhibits; FGF6 gene; Family; Fatty acid glycerol esters; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Gene Expression; Generations; Genetic Transcription; Healthcare; Heparan Sulfate Proteoglycan; Human; Hypertension; In Vitro; Infant; Injectable; Inner mitochondrial membrane; Investigation; Ions; Knockout Mice; Knowledge; Libraries; Link; Lipids; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Morbidity - disease rate; NRIP1 gene; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obese Mice; Obesity; Oxygen Consumption; PTGS2 gene; Pathway interactions; Pharmacology; Physiological; Physiological Processes; Play; Prevention strategy; Property; Prostaglandins; Proteins; Protons; Regulation; Research; Respiration; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Stress; System; Testing; Therapeutic; Therapeutic Agents; Thermogenesis; Tissue Differentiation; Tissues; Transgenic Mice; Triglyceride Metabolism; United States; United States National Institutes of Health; adipocyte differentiation; adipokines; base; cold temperature; combat; cyclooxygenase 2; environmental change; experimental study; extracellular; fatty acid oxidation; fibroblast growth factor 6; glucose metabolism; improved; in vivo; member; mouse model; muscle regeneration; novel; novel strategies; novel therapeutics; obesity treatment; outcome forecast; oxidation; paracrine; prevent; protein expression; public health priorities; public health relevance; response; screening; success; treatment strategy; uncoupling protein 1

 DESCRIPTION (provided by applicant): Obesity is occurring at epidemic rates in the United States and worldwide, impacting the risk and prognosis of many diseases, especially type 2 diabetes mellitus, cardiovascular disorders, hypertension, and certain cancers. Therefore, developing prevention and treatment strategies for obesity and its co-morbidities is of the utmost importance for the healthcare and scientific research communities. Brown fat plays a pivotal role in adaptive thermogenesis, a physiological process during which energy is dissipated in response to environmental changes, such as cold temperature and diet. Although brown fat was once considered only necessary in infants, recent studies have provided evidence that, contrary to prior belief, this tissue is present and active in adult humans. The unique property of brown fat to mediate energy expenditure and thermogenesis depends on the presence of uncoupling protein 1 (UCP1), a mitochondrial ion carrier that is uniquely expressed in brown fat and permits proton translocation through the mitochondrial inner membrane, thereby uncoupling respiration from ATP synthesis and facilitating fatty acid oxidation and dissipation of energy. Thus, identification of agents that promote UCP1 expression and function would provide potential avenues for the development of new anti-obesity therapies. We have recently discovered that members of the paracrine Fibroblast Growth Factor (FGF) family can robustly induce UCP1 expression and increase mitochondrial function. Building on these preliminary data, we hypothesize that the paracrine FGF functions as a new regulator of mitochondrial activity and thermogenesis by inducing UCP1 expression and promoting fuel utilization. We propose to directly test this hypothesis by determining the cellular and molecular mechanisms mediating FGF's effect on UCP1 expression and mitochondrial function using both in vitro and in vivo systems. Success of the proposed studies would not only launch a new paradigm of energy regulation but also create potential therapeutic approaches to treat obesity and its many related disorders.

 描述（由申请人提供）：肥胖在美国和世界范围内以流行率发生，影响许多疾病的风险和预后，特别是2型糖尿病、心血管疾病、高血压和某些癌症。因此，制定肥胖及其共病的预防和治疗策略对于医疗保健和科学研究界至关重要。棕色脂肪在适应性产热中起着关键作用，适应性产热是一种生理过程，在此过程中，能量因环境变化而耗散，如寒冷的温度和饮食。虽然棕色脂肪曾经被认为是婴儿所必需的，但最近的研究提供了证据，与先前的观点相反，这种组织在成年人中存在并活跃。棕色脂肪介导能量消耗和产热的独特性质取决于解偶联蛋白1（UCP1）的存在，解偶联蛋白1是一种线粒体离子载体，在棕色脂肪中独特表达，允许质子通过线粒体内膜转运，从而使呼吸与ATP合成解偶联，促进脂肪酸氧化和能量耗散。因此，鉴定促进UCP1表达和功能的药物将为开发新的抗肥胖疗法提供潜在的途径。我们最近发现，旁分泌成纤维细胞生长因子（FGF）家族的成员可以强烈诱导UCP1表达并增加线粒体功能。基于这些初步数据，我们假设旁分泌FGF通过诱导UCP1表达和促进燃料利用，作为线粒体活性和产热的新调节剂发挥作用。我们建议直接测试这一假设，通过确定细胞和分子机制介导的成纤维细胞生长因子对UCP1表达和线粒体功能的影响，在体外和体内系统。拟议研究的成功不仅将启动能量调节的新范式，还将为治疗肥胖及其许多相关疾病创造潜在的治疗方法。