Molecular Regulation of Brown Adipose Cell Fate in Somitic Stem Cells

描述(由申请人提供) 摘要：肥胖症是美国和世界上许多其他国家最重要的公共卫生问题。它是越来越多疾病的主要风险因素，包括2型糖尿病、心脏病、中风和许多癌症。肥胖是一种遗传性疾病，由能量平衡的潜在缺陷引起，即从食物中摄取的能量长期超过能量消耗。棕色脂肪组织(BAT)非常适合消耗化学能作为热量，因此可以抵消肥胖。最近在正常健康的成年人中发现了相当数量的这种组织，这增加了它的活动变化可能会影响体重增加的可能性。重要的是，操纵控制蝙蝠形成的发育途径可能会为减少肥胖提供新的治疗途径。我们最近将PRDM16定义为棕色脂肪细胞分化的主要转录调节因子。值得注意的是，PRDM16似乎在决定棕色脂肪细胞命运方面扮演着发育开关的角色，而棕色脂肪细胞是骨骼肌和棕色脂肪的共同前体。然而，这种细胞类型还没有在活体环境中被识别。在这项提案中，我们将描述产生棕色脂肪细胞谱系的干细胞/前体细胞群体的特征。为了做到这一点，我们开发和利用先进的遗传工具，使我们能够标记和分离小鼠胚胎中的棕色脂肪前体。利用小鼠遗传学与干细胞生物学方法相结合的力量，我们将识别控制棕色脂肪与骨骼肌细胞命运的世系承诺的基因和信号通路。这项工作对我们理解脂肪和骨骼肌生物学具有深远的意义。我们希望我们的发现可以转化为促进能量消耗和减少人类肥胖的疗法。 与公共健康相关：肥胖是美国和世界上许多其他国家面临的最重要的公共健康问题。我们必须更好地了解导致体重增加的遗传因素。在这个项目中，我们将识别和表征控制棕色脂肪组织发育的新基因和新途径，棕色脂肪组织是一种关键的能量消耗组织，可以对抗肥胖。

DESCRIPTION (Provided by the applicant) Abstract: Molecular Regulation of Brown Adipose Cell Fate in Somitic Stem Cells Obesity is now recognized as the most significant public health issue in the U.S. and in many other countries around the world. It is the predominant risk factor for a growing number of diseases including type 2 diabetes, heart disease, stroke and many cancers. Obesity is a genetic disease caused by an underlying defect in energy balance, where energy intake from food chronically exceeds energy expenditure. Brown adipose tissue (BAT) is highly adapted to expend chemical energy as heat and can therefore counteract obesity. A significant amount of this tissue has been recently identified in normal healthy adult humans raising the possibility that variation in its activity may influence propensity for weight gain. Importantly, manipulating the developmental pathways that control BAT formation may provide new therapeutic avenues to reduce obesity. We recently defined PRDM16 as a dominant transcriptional regulator of brown fat cell differentiation. Significantly, PRDM16 appears to act as a developmental switch in specifying brown fat cell fate from a common precursor for skeletal muscle and brown fat. This cell type, however, has not been identified in an in vivo context. In this proposal, we will characterize the stem/precursor cell population that gives rise to the brown fat cell lineage. To do this, we develop and utilize sophisticated genetic tools that enable us to mark and isolate brown adipose precursors from mouse embryos. Using the power of mouse genetics combined with stem cell biology approaches, we will identify genes and signaling pathways that control lineage commitment to the brown fat vs. skeletal muscle cell fate. This work has profound implications for our understanding of adipose and skeletal muscle biology. We hope that our findings can be translated into therapies that promote energy expenditure and reduce human obesity. Public Health Relevance: Obesity is the single most important public health issue that faces the U.S. and many other countries worldwide. It is imperative that we develop a better understanding of the genetic factors that drive weight gain. In this project, we will identify and characterize novel genes and pathways that control the development of brown adipose tissue, a key energy expending tissue that can counteract obesity.