Molecular regulation of adipose tissue development, homeostasis and expansion

项目摘要 儿童和成人肥胖及其相关的代谢并发症是一个公共卫生问题。在 仅在美国，超过67%的成年人和33%的儿童目前超重或肥胖， 会导致即时和长期的健康问题。如果这种流行病得不到纠正， 随之而来的代谢紊乱，如心脏病、糖尿病、动脉粥样硬化和癌症。脂肪或脂肪 组织似乎是肥胖危机的关键。然而，人们对这些细胞知之甚少， 监督脂肪细胞和脂肪组织的形成和扩张的分子机制。我们 最近使用遗传小鼠模型的研究结果表明，有两个祖先群体， 生成脂肪细胞：发育祖细胞，用于脂肪发育，和成体祖细胞，用于脂肪发育 体内平衡在已建立的成人脂肪库中，而不是发育中的脂肪库中，脂肪细胞命运图 从血管周围的祖细胞池中分离出来。与成人脂肪组织相反， 发育祖细胞的细胞起源和控制其细胞动力学的信号，包括 模式、扩散、迁移和形成。这项建议的核心重点是利用我们的遗传工具 确定与成人脂肪组织相比，对脂肪组织发育重要的新的调节机制， 组织稳态和扩张。以前的研究表明，血小板衍生生长因子 PDGFRα受体是发育中脂肪祖细胞的重要潜在来源。此外，委员会认为， PDGFRα+细胞有助于脂肪组织扩张，以响应高脂饮食喂养。但很少 研究已经检查了PDGFRα基因功能是否对脂肪组织发育或成人调节至关重要。 基于我们的初步数据，我假设PDGFRα信号是脂肪组织的中心调节因子， 通过建立脂肪谱系进行发育。因此，本研究的具体目标集中在：目标1： 确定PDGFRα是否是脂肪组织发育（器官发生）所必需的。目标2：确定 PDGFRα控制脂肪组织发育的机制。目的3：确定PDGFRα是否 成人脂肪组织致肥性扩张所必需的。根据初步数据，PDGFRα对于 PDGFRα调节脂肪组织的生长，而不是维持脂肪组织的生长。 促进脂肪组织器官形成的祖细胞命运。这些发现将对 三个原因：1）胚胎细胞如何采用脂肪组织细胞的命运，2）分子基础， 控制着这种发育细胞的命运，以及3）脂肪组织如何响应热量过剩而膨胀 与成人脂肪组织稳态相比。这些重要的发现可能会导致新的离散 儿童和成人肥胖症的治疗目标。

Project Summary Childhood and adult obesity and their associated metabolic complications is a public health problem. In the United States alone, more than 67% of adults and 33% of children are currently overweight or obese, which can cause both immediate and long-term health problems. If this epidemic is uncorrected it will lead to a range of ensuing metabolic disorders such as heart disease, diabetes, atherosclerosis, and cancer. Adipose or fat tissues appear to be at the nexus of the obesity crisis. However, very little is known about the cells and molecular mechanisms that oversee the formation and the expansion of adipocytes and adipose tissues. Our recent findings using genetic mouse models demonstrate that there are two progenitor populations that give rise to adipocytes: developmental progenitors, for adipose development, and adult progenitors, for adipose homeostasis. In established adult adipose depots, not developmental adipose depots, adipocytes fate-map from a perivascular residing progenitor cell pool. Contrary to adult adipose tissue, even less is known about the cellular origin of developmental progenitor cells and the signals that control their cellular dynamics including pattern, proliferation, migration and formation. The central focus of this proposal aims to use our genetic tools to identify novel regulatory mechanisms important for adipose tissue development compared to adult adipose tissue homeostasis and expansion. Previous studies have suggested that platelet derived growth factor receptor α (PDGFRα) is an important potential source of developmental adipose progenitor cells. Furthermore, PDGFRα+ cells contribute to adipose tissue expansion in respond to high fat diet feeding. However, few studies have examined if PDGFRα, gene function, is critical for adipose tissue development or adult regulation. Based on our preliminary data, I hypothesize that PDGFRα signaling is a central regulator of adipose tissue development by establishing the adipose lineage. Thus the specific aims of this study are focused on: Aim 1: Determine if PDGFRα is necessary for adipose tissue development (organogenesis). Aim 2: Determine the mechanisms by which PDGFRα controls adipose tissue development. Aim 3: Determine if PDGFRα is necessary for adult adipose tissue obesogenic expansion. Based on preliminary data, PDGFRα is critical for the development of adipose tissue but not for maintaining it. It appears that PDGFRα regulates adipose progenitor cell fate promoting adipose tissue organogenesis. These findings will be of great importance for three reasons: 1) how embryonic cells adopt an adipose tissue cell fate, 2) the molecular underpinning that govern this developmental cell fate, and 3) how adipose tissue expands in response to caloric excess compared to adult adipose tissue homeostasis. These important findings may lead to novel discrete therapeutic targets for childhood and adult obesity.