Fibroblast Growth Factor and Energy Metabolism

成纤维细胞生长因子和能量代谢

基本信息

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
项目类别：
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

项目摘要

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呈流行趋势，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，正在开发预防和治疗方法。肥胖及其并发症的治疗策略对于医疗保健和科学研究界至关重要。棕色脂肪在适应性生热作用中发挥着关键作用，这是一种响应环境变化而消耗能量的生理过程。尽管棕色脂肪曾经被认为仅在婴儿中是必需的，但最近的研究提供的证据表明，与先前的看法相反，这种组织在成年人中存在并活跃，具有介导能量消耗和调节能量消耗的独特特性。产热依赖于解偶联蛋白 1 (UCP1) 的存在，UCP1 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易位，从而将呼吸与 ATP 合成解偶联并促进脂肪酸氧化因此，促进 UCP1 表达和功能的药物的鉴定将为开发新的抗肥胖疗法提供潜在途径，我们最近发现旁分泌成纤维细胞生长因子 (FGF) 家族的成员可以强有力地诱导 UCP1。基于这些初步数据，我们发现旁分泌 FGF 通过诱导 UCP1 表达和促进燃料利用来发挥线粒体活性和产热作用的新调节剂的作用。通过使用体外和体内系统确定 FGF 对 UCP1 表达和线粒体功能的影响的细胞和分子机制来直接检验这一假设。所提出的研究的成功不仅将推出一种新的能量调节范式，而且还将创造潜在的治疗方法。治疗肥胖及其许多相关疾病。