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

开发中白色脂肪组织质量调节的细胞和分子机制

• 批准号: 8409832
• 负责人: Matthew S Rodeheffer
• 金额: $ 37.93万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8409832
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Atherosclerosis; Bromodeoxyuridine; Cardiovascular Diseases; Cell Culture Techniques; Cells; Characteristics; Coulter counter; Developed Countries; Development; Diabetes Mellitus; Diet; Disease; ETS1 gene; ETS2 gene; Event; Fatty acid glycerol esters; Flow Cytometry; Gene Expression; Goals; Heart Diseases; Human; Hyperplasia; Hypertrophy; In Vitro; Incidence; Lead; Life; Link; Malignant Neoplasms; Metabolism; Mitotic; Modeling; Molecular; Mus; Obesity; Overweight; Pathology; Physiologic pulse; Population; Proliferating; Public Health; Regulation; Risk; Role; Signal Transduction; Staging; Testing; Time; Tissues; United States; Visceral; Weight; adipocyte differentiation; cancer type; digital; energy balance; in vivo; lipid biosynthesis; mature animal; meetings; novel; obesity treatment; precursor cell; progenitor; public health relevance; research study; subcutaneous; therapeutic development

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.

描述（由申请人提供）：过去三十年来，美国和其他工业化国家的肥胖率迅速增加，如今美国 65% 的成年人口超重，其中超过 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随之增加，例如糖尿病、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决定性特征，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库组成。特定仓库中过量 WAT 的差异积累与患糖尿病和其他肥胖相关疾病的不同风险相关。然而，控制不同仓库中 WAT 质量的细胞和分子机制尚不清楚。因此，确定不同 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了解肥胖以及过量的 WAT 如何导致继发性病变的发展。 肥胖症中 WAT 的过度积累是由于脂肪细胞大小（肥大）和数量（增生）增加所致。由于成熟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产生的。我们最近在体内鉴定了脂肪细胞祖细胞和前脂肪细胞，使我们能够确定控制脂肪细胞祖细胞对体内 WAT 质量的贡献的细胞和分子机制。我们假设，通过识别调节特定库中 WAT 质量的组织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代谢和能量平衡的机制。 为了解决这一假设，我们将研究两种不同的 WAT 质量积累模型：1）在高脂肪饮食诱导的肥胖发作期间 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，我们将定义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和饮食引起的肥胖中调节 WAT 质量的分子机制，这可能导致确定肥胖特异性的 WAT 质量调节机制。确定调节 WAT 质量的分子机制将有助于开发治疗肥胖和肥胖相关疾病（例如糖尿病和心脏病）的疗法。