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

基本信息

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
项目类别：
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

项目摘要

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程度，并且在 2 型糖尿病、血脂异常和心血管疾病的发展中发挥着重要作用，尽管大多数体重增加，但仍然非常需要更好的非手术治疗。棕色脂肪组织（BAT）是一种独特表达线粒体的产热组织，通过抑制食欲来减少热量摄入，安全地增加能量消耗的策略有可能有效治疗肥胖。解偶联蛋白-1 (UCP1)。这种蛋白在暴露于低温时会增加棕色脂肪细胞线粒体中的电化学梯度，在维持 BAT 的体温和能量平衡中发挥重要作用。 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，具体取决于环境温度。在许多不同的啮齿动物模型中，BAT 质量的增加已被令人信服地证明可以导致体重减轻和抵抗糖尿病。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着的 BAT，并且该组织具有功能性。其他数据表明，个体中活性 BAT 的数量与瘦削程度密切相关，并且与一般肥胖关系最密切的基因位点导致新棕色脂肪细胞的募集缺陷，直到最近我们才发现了一个群体。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，这些细胞具有高水平的 UCP1 和非常高的代谢率。然后，我们用它来筛选一系列已批准的药物，并发现了几种能有效招募棕色脂肪细胞的药物。在拟议的工作中，我们的目标是进一步表征这些化合物。我们将首先在体外对其进行开发，然后在肥胖和胰岛素抵抗的高度预测动物模型中进行研究，如果这项工作成功，我们计划迅速推进概念验证。潜在棕色脂肪的临床研究招募治疗肥胖和糖尿病的候选产品。