Fibroblast Growth Factor and Energy Metabolism

 描述(申请人提供)：肥胖在美国和世界范围内以流行病的速度发生，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，制定肥胖症及其并存的预防和治疗策略对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，这是一种生理过程，在此过程中，能量被耗散，以应对环境变化，如寒冷的温度和饮食。虽然棕色脂肪曾经被认为只有婴儿才需要，但最近的研究提供了证据，与之前的看法相反，这种组织在成年人中存在并活跃。棕色脂肪调节能量消耗和产热的独特性质依赖于解偶联蛋白1(UCP1)的存在，解偶联蛋白1是一种线粒体离子载体，在棕色脂肪中唯一表达，允许质子通过线粒体内膜转运，从而将呼吸与ATP合成解偶联，促进脂肪酸氧化和能量消耗。因此，识别促进UCP1表达和功能的药物将为开发新的减肥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家族的成员可以强烈地诱导UCP1的表达，并增加线粒体的功能。在这些初步数据的基础上，我们假设旁分泌成纤维细胞生长因子通过诱导UCP1表达和促进燃料利用而作为线粒体活动和产热的新调节器发挥作用。我们建议使用体外和体内系统，通过确定细胞和分子机制来直接检验这一假说，这些细胞和分子机制介导了成纤维细胞生长因子对UCP1表达和线粒体功能的影响。拟议研究的成功不仅将启动能量调节的新范式，还将创造潜在的治疗方法来治疗肥胖症及其许多相关疾病。

 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.