Identifying Novel Targets for Recruitment of Brown Adipocytes

描述（由申请人提供）：肥胖在美国已经达到流行病的程度，在2型糖尿病、血脂异常和心血管疾病的发展中起着重要作用。对更好的非手术治疗仍有很大的需求。虽然大多数减肥药依赖于抑制食欲来减少热量摄入，但可以安全地提高代谢率的策略，这是一种以前未实现的减肥或维持体重的方法，有可能有效治疗肥胖。棕色脂肪细胞具有极高的代谢率，因为它们表达线粒体解偶联蛋白1 （UCP1）。这种蛋白质将棕色脂肪细胞线粒体中的电化学梯度作为热量消散。低温环境下褐脂肪组织（BAT）产热增加，在维持体温和能量平衡中起重要作用。BAT也是一种灵活的组织，通常会随着时间的推移而根据环境温度增大或萎缩。在许多不同的啮齿动物模型中，BAT质量的增强已令人信服地证明可导致体重减轻和糖尿病抵抗。虽然直到最近人们才认为BAT在成人中不存在，但最近通过PET成像获得的数据显示，成年人实际上有显著的BAT，并且该组织具有功能。其他数据表明，个体中活跃BAT的数量与瘦度密切相关。直到最近才发现棕色脂肪干细胞。我们发现了一群人类骨骼肌棕色脂肪细胞祖细胞，在适当的条件下成为功能齐全的棕色脂肪细胞。分化后，这些细胞具有高水平的UCP1和非常高的代谢率。这种独特的人类祖先群体现在可以用来识别参与人类棕色脂肪形成的分子因子。我们认为，现有药物和其他化合物的一些机制/靶点可能参与棕色脂肪的形成，我们的初步数据在小范围内证明了这一点。在这里，我们建议开发一种新的高含量检测系统，并将其用于筛选具有已知靶点和细胞作用机制的化合物库。在这样做的过程中，我们预计这种独特的分析系统可能会发现以前未被怀疑参与棕色脂肪细胞募集的目标。因此，这项工作可以为指导未来旨在增加人类棕色脂肪的药物开发提供重要的见解。如果这个一期项目成功，我们计划随后通过确定棕色脂肪形成的特异性和贡献来进一步表征具有进一步发展实际潜力的机制。然后，我们将根据这些发现确定更有效和特定的化合物，并在动物肥胖模型中测试最佳化合物。

DESCRIPTION (provided by applicant): Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2 diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non- surgical treatments. While most weight loss agents rely on suppressing appetite to reduce caloric intake, strategies that can safely enhance metabolic rate, a previously unrealized approach to weight loss or weight maintenance, have potential to effectively treat obesity. Brown adipocytes have an extremely high metabolic rate because they express mitochondrial uncoupling protein-1 (UCP1). This protein dissipates the electrochemical gradient in the mitochondria of brown adipocytes as heat. Brown adipose tissue (BAT) thermogenesis is increased upon exposure to low temperatures, and plays an important role in the maintenance of body temperature and energy balance in rodents. BAT is also a flexible tissue that normally enlarges or atrophies over time depending on environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be effectively nonexistent in adult humans, recent data obtained with PET imaging shows that adults in fact have significant BAT, and that this tissue is functional. Other data demonstrates that the amount of active BAT in individuals is strongly correlated with leanness. Until recently no brown adipocyte stem cell had been identified. We discovered a population of human skeletal muscle-resident brown adipocyte progenitors that under appropriate conditions become fully functional brown adipocytes. Following differentiation, these cells have high levels of UCP1 and a very high metabolic rate. This unique human progenitor population can now be utilized to identify molecular actors involved in human brown adipogenesis. We believe that some of the mechanisms/targets of existing drugs and other compounds may be involved in brown adipogenesis, and our preliminary data demonstrates this on a small scale. Here we propose to develop a novel high content assay system and deploy it to screen a library of compounds with known targets and cellular mechanisms of action. In doing so we anticipate that this unique assay system may uncover targets previously unsuspected of being involved in brown adipocyte recruitment. This work could therefore provide important insights for directing future drug development aimed at increasing brown fat in humans. If this Phase I project is successful, we plan subsequently to further characterize mechanisms with practical potential for further development by determining their specificity for and contributions o brown adipogenesis. We will then identify more potent and specific compounds based on these findings and test the best compounds in animal models of obesity.