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

使用批准的药物建立棕色脂肪生成概念的体内证明

• 批准号: 9300917
• 负责人: Olivier Boss
• 金额: $ 96.93万
• 依托单位: ENERGESIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-20 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9300917
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Agonist; Animal Model; Animals; Area; Atrophic; Back; Biological Assay; Body Temperature; Body Weight; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cell Differentiation process; Cells; Clinical; Clinical Research; Collection; Data; Desire for food; Development; Diabetes Mellitus; Diet; Dose; Drug Combinations; Dyslipidemias; Energy Intake; Energy Metabolism; Epidemic; Exposure to; Fatty acid glycerol esters; Genetic; Glucose; Glucose tolerance test; Goals; Gold; Harvest; Human; In Vitro; Individual; Insulin; Insulin Resistance; Intention; Lead; Libraries; Life; Link; Maintenance; Masks; Mitochondria; Monitor; Mus; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Obese Mice; Obesity; PPAR gamma; Patients; Pharmaceutical Preparations; Phase; Play; Population; Positron-Emission Tomography; Prediabetes syndrome; Proteins; Records; Recruitment Activity; Resistance; Rodent; Rodent Model; Role; Safety; Science; Secondary to; Serum; Skeletal Muscle; Specificity; Stem cells; System; Temperature; Testing; Therapeutic; Thermogenesis; Thinness; Time; Tissues; Weight; Weight maintenance regimen; Weight-Loss Drugs; Work; base; cold temperature; energy balance; flexibility; glucose metabolism; human data; human subject; in vitro testing; in vivo; lipid biosynthesis; metabolic rate; mitochondrial uncoupling protein; mouse model; obesity treatment; patient population; progenitor; public health relevance; reduced food intake; response; rosiglitazone; screening; success; tool; uncoupling protein 1

 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.

 描述（由申请人提供）：肥胖在美国已达到流行病的比例，并在2型糖尿病、血脂异常和心血管疾病的发展中起主要作用。仍然非常需要更好的非手术治疗。虽然大多数减肥药依赖于抑制食欲来减少热量摄入，但可以安全地提高能量消耗的策略有可能有效地治疗肥胖。棕色脂肪组织（BAT）是一种独特表达线粒体解偶联蛋白-1（UCP 1）的产热组织。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。它在暴露于低温时增加，并在维持啮齿动物的体温和能量平衡中起重要作用。BAT也是一种柔性组织，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，BAT质量的增加已经令人信服地显示出导致体重减轻和糖尿病抵抗。虽然BAT直到最近才被认为在成年人中实际上不存在，但过去几年通过PET成像获得的数据表明，成年人实际上具有显著的BAT，并且该组织具有功能。 其他数据表明，个体中活性BAT的量与瘦度密切相关，并且与一般肥胖最紧密相关的遗传基因座导致新棕色脂肪细胞的招募缺陷。直到最近还没有发现棕色脂肪干细胞。我们发现了一群人类骨骼肌驻留的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UCP 1和非常高的代谢率。使用祖细胞，我们开发了一种用于鉴定招募新的成熟棕色脂肪细胞的化合物的测定法。然后，我们用它来筛选一系列批准的药物，并发现了几种有效招募棕色脂肪细胞的药物。通过剂量反应试验验证了这些命中。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剂的潜在用途。我们将首先在体外评估其开发的适用性，然后在肥胖和胰岛素抵抗的高度预测性动物模型中进行研究。如果这项工作取得成功，我们计划迅速推进到一个概念验证的临床研究与潜在的棕色脂肪招募产品候选人治疗肥胖和糖尿病。