Regulation of Brown Fat: Toward New Therapy for Human Obesity

棕色脂肪的调节：人类肥胖的新疗法

• 批准号: 8045934
• 负责人: BRUCE M. SPIEGELMAN
• 金额: $ 420.75万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8045934
• 关键词: Adipocytes; Adipose tissue; Affect; Agonist; American; Animal Model; Animals; Area; Automobile Driving; Basic Science; Biochemical; Biology; Body part; Brown Fat; Cardiovascular Diseases; Cell Differentiation process; Cells; Chemicals; Computing Methodologies; Data; Deposition; Development; Diabetes Mellitus; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Gene Expression; Genes; Health; Health Care Costs; Healthcare Systems; Homeostasis; Human; Hypertension; Individual; Knowledge; Leukocytes; Ligands; Malignant Neoplasms; Mediating; Medical; Metabolic Control; Metabolic Diseases; Metabolism; Methods; Mining; Molecular Profiling; Morbidity - disease rate; Movement; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Pathway interactions; Phosphorylation; Phosphorylation Inhibition; Physiological; Physiology; Play; Population; Primary Cell Cultures; Process; Property; Proteins; Public Health; Reading; Regimen; Regulation; Relative (related person); Reporting; Research; Role; Science; Screening procedure; Structure; Therapeutic; Thermogenesis; Time; Tissues; Transgenic Organisms; Translating; Translations; Work; abstracting; base; burden of illness; cell determination; cell type; diet and exercise; fighting; gain of function; improved; in vivo; mortality; natural hypothermia; novel therapeutics; polypeptide; programs; subcutaneous; therapeutic target

DESCRIPTION (provided by applicant): This proposal is closely aligned with the Research Theme: "Translating Basic Science Discoveries into New and Better Treatments". The USA is in the midst of an epidemic of obesity that is causing a great deal of mortality and morbidity due to its associated conditions: hypertension, type 2 diabetes and certain cancers. It is also putting a great strain on our health care system. At the present time, there is no generally effective medical therapy for obesity that can augment ongoing efforts to educate the public about diet and exercise regimens. This proposal is aimed at driving therapeutics for human obesity forward, based on modulation of brown fat biology. The last several years have seen breakthroughs in the science of brown fat, a cell-type that plays a critical role in controlling metabolic rates and fighting obesity. Significant deposits of brown fat have been identified in normal healthy humans, and a major transcriptional regulator of brown fat, PRDM16, has been identified. This proposal is focused on developing the science and therapeutic approaches to human obesity, based on the control of brown fat formation and function. Our first Aim will investigate regulation of whole body energy homeostasis via transgenic manipulation of PRDM16, a transcriptional co-regulator that we discovered in 2007 as a dominant regulator of brown fat cell determination. A second Aim will isolate and characterize a second kind of brown fat cell that can reside in white adipose tissues and has substantial thermogenic capacity. Our third Aim will drive translation of our newly acquired knowledge about the role of the nuclear receptor PPAR3 in brown fat and thermogenesis directly into therapeutics. We will combine structure-based methods for chemical screening and compound optimization, with this new biochemical information, to develop PPAR3 ligands that have a preferential effect on brown fat development and function. We will develop compounds that have minimal properties of a classic PPAR3 agonist, but retain the ability to modulate the "browning" of certain white fat cells and stimulate brown fat-mediated energy expenditure in vivo. The ability to treat obesity in animal models will also be investigated with the new compounds. In our final Aim, we will utilize our extensive data concerning brown fat gene expression to investigate the secreted proteins of brown fat that are regulated during thermogenesis. We have already identified several such molecules and will examine their ability to control/affect brown fat cell differentiation and a thermogenic gene program in brown fat and subcutaneous white fat. PUBLIC HEALTH RELEVANCE: The rising tide of obesity in the USA presents a huge threat to the health of the American public, through its associated conditions: hypertension, diabetes and cardiovascular disease. This proposal is centered on therapeutic targeting of brown fat, a key part of the body's natural defense against obesity. Improvements in our ability to regulate pathways of energy expenditure mediated by brown fat promise to relieve the disease burden of the American population and lower healthcare costs in the USA.

描述（由申请人提供）：该建议与研究主题紧密一致：“将基础科学发现转化为新的，更好的治疗方法”。美国正处于肥胖症的流行中，由于其相关条件而引起了极大的死亡率和发病率：高血压，2型糖尿病和某些癌症。它还给我们的医疗保健系统带来了巨大压力。目前，尚无对肥胖症的一般有效的药物治疗，可以扩大持续的努力来教育公众饮食和运动方案。该建议旨在根据棕色脂肪生物学的调节来推动人类肥胖前进的治疗疗法。在过去的几年中，棕色脂肪科学的突破是棕色脂肪的突破，这种细胞类型在控制代谢率和抵抗肥胖症中起着至关重要的作用。在正常健康的人类中已经确定了棕色脂肪的大量沉积物，并且已经鉴定出棕色脂肪的主要转录调节剂PRDM16。该建议的重点是基于对棕色脂肪形成和功能的控制，开发了人类肥胖的科学和治疗方法。我们的第一个目标将通过转基因操纵PRDM16（一种转录共同调节剂，我们在2007年作为棕色脂肪细胞测定的主要调节剂发现）来调查全身能量稳态的调节。第二个目标将隔离并表征第二种可以驻留在白色脂肪组织中并具有实质性热能力的棕色脂肪细胞。我们的第三个目标将推动我们新获得的有关核受体PPAR3在棕色脂肪和热生成中的作用的知识，直接直接进入治疗剂。我们将结合基于结构的化学筛选和化合物优化的方法，以及这种新的生化信息，以开发对棕色脂肪发育和功能具有优先影响的PPAR3配体。我们将开发具有经典PPAR3激动剂的最小特性的化合物，但保留了调节某些白色脂肪细胞“褐变”并刺激体内棕色脂肪介导的能量消耗的能力。在动物模型中治疗肥胖症的能力也将使用新化合物进行研究。在我们的最终目标中，我们将利用有关棕色脂肪基因表达的广泛数据来研究在热发生过程中受调节的棕色脂肪的分泌蛋白。我们已经确定了几个这样的分子，并将检查它们控制/影响棕色脂肪细胞分化的能力以及棕色脂肪和皮下白脂肪中的热基因程序。 公共卫生相关性：美国肥胖的潮流通过其相关条件：高血压，糖尿病和心血管疾病对美国公众的健康构成了巨大威胁。该建议集中在棕色脂肪的治疗靶向上，棕色脂肪是人体防御肥胖症的重要部分。我们调节由棕色脂肪介导的能源消耗途径的能力的改善，有望减轻美国人口的疾病负担，并在美国降低医疗保健费用。