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。美国正处于肥胖症的流行之中，由于其相关的条件：高血压，2型糖尿病和某些癌症，肥胖症正在导致大量的死亡率和发病率。这也给我们的医疗保健系统带来了巨大的压力。目前，还没有普遍有效的肥胖药物治疗方法可以加强对公众进行饮食和运动疗法教育的持续努力。该提案旨在基于棕色脂肪生物学的调节来推动人类肥胖症的治疗。在过去的几年里，棕色脂肪科学取得了突破性进展，棕色脂肪是一种在控制代谢率和对抗肥胖方面发挥关键作用的细胞类型。已在正常健康人中鉴定出棕色脂肪的显著沉积物，并且已鉴定出棕色脂肪的主要转录调节因子PRDM 16。该提案的重点是基于控制棕色脂肪的形成和功能，开发人类肥胖的科学和治疗方法。我们的第一个目标是通过转基因操作PRDM 16来研究全身能量稳态的调节，PRDM 16是我们在2007年发现的一种转录辅助调节因子，是棕色脂肪细胞决定的主要调节因子。第二个目标是分离和表征第二种棕色脂肪细胞，该细胞可以存在于白色脂肪组织中，并具有相当大的产热能力。我们的第三个目标将推动我们新获得的关于核受体PPAR 3在棕色脂肪和产热中的作用的知识直接转化为治疗方法。我们将结合联合收割机的化学筛选和化合物优化的结构为基础的方法，这一新的生化信息，开发PPAR 3配体，有一个优先的棕色脂肪的发展和功能的影响。我们将开发具有经典PPAR 3激动剂的最小特性的化合物，但保留调节某些白色脂肪细胞的“布朗宁”和刺激体内棕色脂肪介导的能量消耗的能力。还将研究新化合物在动物模型中治疗肥胖的能力。在我们的最终目标，我们将利用我们的广泛的数据，棕色脂肪基因表达的研究在产热过程中调节棕色脂肪的分泌蛋白。我们已经鉴定了几种这样的分子，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色脂肪中的产热基因程序。 公共卫生相关性：美国肥胖症的上升趋势对美国公众的健康构成了巨大的威胁，通过其相关的疾病：高血压，糖尿病和心血管疾病。这项建议的核心是针对棕色脂肪的治疗，这是身体天然防御肥胖的关键部分。我们调节由棕色脂肪介导的能量消耗途径的能力的提高有望减轻美国人口的疾病负担，并降低美国的医疗保健成本。

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.