Regulation of Brown Fat: Toward New Therapy for Human Obesity

描述（由申请人提供）：本提案与研究主题“将基础科学发现转化为新的更好的治疗方法”密切相关。美国正处于肥胖的流行之中，由于高血压、2型糖尿病和某些癌症等相关疾病，肥胖导致了大量的死亡率和发病率。它也给我们的医疗保健系统带来了巨大的压力。目前，还没有普遍有效的治疗肥胖的药物，可以加强正在进行的教育公众关于饮食和运动养生的努力。这一建议旨在推动治疗人类肥胖向前发展，基于棕色脂肪生物学的调节。过去几年，棕色脂肪科学取得了突破，这种细胞类型在控制代谢率和对抗肥胖方面起着关键作用。在正常的健康人群中发现了大量的棕色脂肪沉积，并且发现了一种主要的棕色脂肪转录调节因子PRDM16。本提案的重点是发展科学和治疗方法，以控制棕色脂肪的形成和功能为基础的人类肥胖。我们的第一个目标是通过转基因操作PRDM16来研究全身能量稳态的调节，PRDM16是我们在2007年发现的一种转录共调节因子，是棕色脂肪细胞决定的主要调节因子。第二个目标将分离和表征第二种棕色脂肪细胞，它可以驻留在白色脂肪组织中，并具有大量的产热能力。我们的第三个目标是将我们新获得的关于核受体PPAR3在棕色脂肪和产热作用中的作用的知识直接转化为治疗方法。我们将结合基于结构的化学筛选和化合物优化方法，结合这些新的生化信息，开发对棕色脂肪发育和功能有优先作用的PPAR3配体。我们将开发具有经典PPAR3激动剂最小特性的化合物，但保留调节某些白色脂肪细胞“褐变”的能力，并刺激体内棕色脂肪介导的能量消耗。这种新化合物在动物模型中治疗肥胖的能力也将被研究。在我们的最终目标中，我们将利用我们关于棕色脂肪基因表达的广泛数据来研究在产热过程中调节的棕色脂肪分泌蛋白。我们已经确定了几个这样的分子，并将研究它们控制/影响棕色脂肪细胞分化的能力，以及棕色脂肪和皮下白色脂肪中的产热基因程序。

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.