Cellular and molecular mechanisms of white adipose tissue mass regulation in deve

描述(申请人提供)：美国和其他工业化国家的肥胖症在过去30年里迅速增加，今天美国65%的成年人口超重，超过30%的人口符合肥胖标准。随着国民体重的增加，许多与肥胖相关的疾病的发病率也在增加，如糖尿病、动脉粥样硬化和某些类型的癌症。尽管白色脂肪组织(WAT)质量的增加是肥胖的定义特征，但我们对体内调节WAT质量的细胞和分子机制知之甚少。WAT由几个与肥胖研究相关的皮下和内脏储存库组成。在特定的仓库中过量水分的不同积累与患糖尿病和其他肥胖相关疾病的不同风险有关。然而，在不同的仓库中控制Wat质量的细胞和分子机制还不是很清楚。因此，确定在不同的Wat库中调节Wat质量的细胞和分子事件的差异将有助于更好地理解肥胖以及过量Wat如何导致继发性病理的发展。肥胖症中Wat的过度积聚是由于脂肪细胞大小(肥大)和数量(增生)的增加所致。由于成熟的脂肪细胞是有丝分裂后的，它们是由脂肪前体细胞的增殖和分化而产生的。我们最近在体内鉴定了脂肪细胞前体细胞和前体脂肪细胞，使我们能够确定体内脂肪细胞前体细胞对Wat质量的贡献的细胞和分子机制。我们假设，通过识别在特定仓库中调节组织对Wat质量的内在控制的起始信号，我们将能够确定将Wat与体内其他组织整合以调节新陈代谢和能量平衡的机制。为了解决这一假说，我们将研究两种不同的Wat质量积累模型：1)高脂饮食诱导肥胖开始期间Wat质量的过度积累；2)正常小鼠发育过程中Wat质量的建立。在每个模型中，我们将确定脂肪细胞前体增殖和分化为成熟脂肪细胞的激活时间，并确定成熟脂肪细胞的周转率。我们还将确定在发育过程中和饮食诱导的肥胖中调节Wat质量的分子机制，潜在地导致识别Wat质量调节的肥胖特定机制。识别调节Wat质量的分子机制将导致开发治疗肥胖症和肥胖症相关疾病的疗法，如糖尿病和心脏病。 与公共卫生相关：肥胖症被定义为脂肪过度积累，目前是主要的公共卫生挑战之一。肥胖是一个合法的公共卫生问题，原因有两个：1)其他几种疾病与肥胖有关，包括糖尿病、心血管疾病和癌症；2)在过去的40年里，肥胖率迅速上升，目前美国近三分之一的成年人口被归类为肥胖。这项建议的目标是确定脂肪中调节脂肪质量的信号，这可能会导致开发治疗肥胖和肥胖相关病理的新疗法。

DESCRIPTION (provided by applicant): Obesity in the United States and other industrialized nations has increased rapidly over the last thirty years and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity- linked disorders, such as diabetes, atherosclerosis and certain types of cancer. Despite an increase in white adipose tissue (WAT) mass being the defining characteristic of obesity, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with different risks of developing diabetes and other obesity-associated pathologies. However, the cellular and molecular mechanisms that control WAT mass in distinct depots are not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. The excessive accumulation of WAT in obesity results from an increase of both adipocyte size (hypertrophy) and number (hyperplasia). Since mature adipocytes are post-mitotic, they are generated from the proliferation and differentiation of adipoctye precursor cells. We have recently identified adipocyte progenitors and preadipocytes in vivo, allowing us to determine the cellular and molecular mechanisms that control adipocyte progenitor contribution to WAT mass in vivo. We hypothesize that by identifying the initiating signals that regulate the tissue-intrinsic control of WAT mass in specific depots we will be able to determine the mechanisms that integrate WAT with other tissues in the body to regulate metabolism and energy balance. To address this hypothesis, we will study two different models of WAT mass accumulation: 1) the excessive accumulation of WAT mass during the onset of high fat diet-induced obesity and 2) the establishment of WAT mass during development in normal mice. In each of these models we will define the timing of the activation of adipocyte precursor proliferation and differentiation into mature adipocytes, and determine the turnover rates of mature adipocytes. We will also determine the molecular mechanisms that regulate WAT mass in development and in diet-induced obesity, potentially leading to the identification of obesity-specific mechanisms of WAT mass regulation. Identifying molecular mechanisms that regulate WAT mass will lead to the development of therapeutics for the treatment of obesity and obesity-associated pathologies, such as diabetes and heart disease. PUBLIC HEALTH RELEVANCE: Obesity, which is defined as an excessive accumulation of fat mass, is currently one of the leading public health challenges. Obesity is a legitimate public health concern for two reasons: 1) several other diseases are associated with obesity, including diabetes, cardiovascular disease and cancer, and 2) the rates of obesity have increased rapidly over the last forty years with almost one third of the adult population in the U.S. being classified as obese today. The goal of this proposal is to identify signals within fat that regulate fat mass, which may lead to the development of novel therapies for the treatment of obesity and obesity-related pathologies.