Establishing In Vivo Proof of Concept of Brown Adipogenesis Using Approved Drugs

 描述(申请人提供)：肥胖症在美国已经达到流行的程度，并在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的需求仍然非常大。虽然大多数减肥剂依赖于抑制食欲来减少卡路里摄入量，但能够安全地增加能量消耗的策略有可能有效地治疗肥胖症。棕色脂肪组织(BAT)是一种唯一表达线粒体解偶联蛋白1(UCP1)的生热组织。这种蛋白质以热的形式驱散棕色脂肪细胞线粒体中的电化学梯度。当暴露在低温环境中时，它会增加，在维持啮齿类动物的体温和能量平衡方面发挥着重要作用。蝙蝠也是一种柔韧的组织，通常会随着时间的推移而扩大或萎缩，这取决于环境温度。在许多不同的啮齿动物模型中，蝙蝠质量的增加已被令人信服地证明可以导致体重减轻和糖尿病抵抗。尽管直到最近，人们还认为成年人中实际上不存在蝙蝠，但过去几年通过PET成像获得的数据显示，成年人实际上有大量的蝙蝠，而且这种组织是有功能的。 其他数据表明，个体中活跃的BAT数量与苗条程度密切相关，与普遍肥胖联系最紧密的基因位点会导致新棕色脂肪细胞的缺陷招募。直到最近，还没有发现棕色脂肪干细胞。我们发现了一组人类骨骼肌中的棕色脂肪细胞前体细胞，在适当的条件下，它们会变成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。利用前体细胞，我们开发了一种鉴定招募新的、成熟的棕色脂肪细胞的化合物的方法。然后，我们用这一点筛选了一系列批准的药物，发现了几种有效地招募棕色脂肪细胞的药物。这些命中通过剂量反应测试进行了验证。在拟议的工作中，我们的目标是进一步表征这些化合物作为抗肥胖治疗的潜在用途。我们将首先评估它们在体外发育的适合性，然后进行肥胖和胰岛素抵抗的高度预测动物模型的研究。如果这项工作成功，我们计划迅速进入概念验证临床研究，潜在的棕色脂肪招募产品候选用于治疗肥胖症和糖尿病。

 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 energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT) is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This protein dissipates the electrochemical gradient in the mitochondria of brown adipocytes as heat. It 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, data obtained in the past several years with PET imaging show that adults in fact have significant BAT, and that this tissue is functional. Other data demonstrate that the amount of active BAT in individuals is strongly correlated with leanness and that the genetic locus most tightly linked with general obesity causes defective recruitment of new brown adipocytes. 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. Using the progenitors we developed an assay for identifying compounds that recruit new, mature brown adipocytes. We then used this to screen a collection of approved drugs and found several that potently recruit brown adipocytes. These hits were validated with dose response testing. In the proposed work, we aim to further characterize these compounds for potential use as anti-obesity therapeutics. We will evaluate their suitability for development first in vitro, followed by studies in a highly predictive animal model of obesity and insulin resistance. If this work is successful, we plan to rapidly advance into a proof of concept clinical study with a potential brown fat recruiting product candidate for the treatment of obesity and diabetes.