Adipocyte development: lineage analysis and molecular characterization

描述(申请人提供)：我们的总体目标是阐明控制脂肪组织形成的机制，并确定这些过程是否以及如何通过代谢性疾病的治疗而改变。现代生活提供了无与伦比的食物供应，助长了肥胖的全球流行和糖尿病、脂肪肝、心血管疾病甚至癌症等继发性负面健康后果。因此，迫切需要更好地了解控制脂肪细胞形成和脂肪组织扩张的机制和分子。脂肪组织是高度动态的，在各种动态平衡、药物和饮食刺激下膨胀和收缩。这种新的脂肪细胞在整个生命过程中形成，这表明可能存在一种造脂干细胞。我们最近通过设计、设计和研究在脂肪谱系中表达分子记者的小鼠来鉴定这样一种脂肪干细胞。这些工具使我们能够在体内可视化脂肪干细胞，并跟踪它们的后代分裂、迁移和发育为成熟脂肪细胞的过程。这项建议的中心焦点是使用这些工具来描绘我们新发现的成人脂肪干细胞的体内功能和分子特征。我们将定义脂肪干细胞的机制基础，并了解生理和药物刺激如何调节干细胞数量和脂肪组织的生长。这些研究旨在阐明脂肪生物学和代谢控制的新方面，强调那些与肥胖症和糖尿病的新疗法特别相关的方面。与公共健康相关：调节脂肪储存和新陈代谢的能力是基本过程。然而，肥胖和糖尿病的双重流行危及数百万人，并正在改变我们的医疗保健格局。这一危机可以通过识别控制脂肪组织形成和扩张的基因来解决。我们最近鉴定了脂肪干细胞，并发现它在脂肪组织的正常维持和对糖尿病治疗的反应中非常重要。我们的目标是揭开这些效应背后的发育、生理和分子机制，我们相信这将增强我们对脂肪细胞生物学的理解，并可能导致肥胖和糖尿病的新治疗靶点。

DESCRIPTION (provided by applicant): Our overall objective is to elucidate the mechanisms that control formation of adipose tissues and to determine whether and how these processes are altered by treatments for metabolic diseases. Modern life has provided unparalleled access to food supplies, contributing to a worldwide epidemic of obesity and secondary negative health consequences such as diabetes, fatty liver, cardiovascular disease, and even cancer. Thus there is an urgent need to better understand the mechanisms and molecules that control formation of adipocytes and the expansion of adipose tissue. Adipose tissue is highly dynamic, expanding and shrinking in response to various homeostatic, pharmacologic and dietary stimuli. That new adipocytes form throughout life indicates the presence of a putative adipogenic stem cell. We recently identified such an adipose stem cell by designing, engineering, and studying mice that express molecular reporters in the adipose lineage. These tools enable us to visualize adipose stem cells in vivo, as well as to follow their descendents as they divide, migrate and develop into mature adipocytes. The central focus of this proposal is to use these tools to delineate the in vivo functions and molecular characteristics of our newly discovered adult adipose stem cells. We will define the mechanistic underpinnings of the adipose stem cells and we will understand how physiological and pharmacological stimuli regulate the stem population and the growth of adipose tissue. These studies are designed to elucidate new aspects of adipose biology and metabolic control, highlighting those that are particularly relevant to new therapies for obesity and diabetes. PUBLIC HEALTH RELEVANCE: The ability to regulate fat storage and metabolism are fundamental processes. However, the dual epidemics of obesity and diabetes endanger millions and are altering our health care landscape. This crisis that could be addressed by identifying genes that control formation and expansion of adipose tissue. We recently identified the adipose stem cell and found that it is important in the normal maintenance of adipose tissue mass and the response to diabetes treatments. Our goal is to unravel the developmental, physiological and molecular mechanisms underlying these effects, which we believe will enhance our understanding of adipocyte biology and may lead to novel therapeutic targets for obesity and diabetes.