Regional Differences in Preadipocyte Development

描述（由申请人提供）：即使在身体总脂肪含量相同的人群中，脂肪分布也有很大差异。中心脂肪增加与代谢综合征有关。为了确定细胞动力学和分子机制，我们建立了先进的方法来分离、克隆和分化人腹部皮下、肠系膜和网膜前脂肪细胞。我们发现，在其他细胞类型中，cAMP反应元件结合蛋白（CREB）、CITED2、FOXO1和某些同源盒（HOX）因子等发育因子存在明显的区域差异，这些因子相互作用以调节谱系进展、复制、凋亡和分化。它们的表达谱与前脂肪细胞复制、分化和凋亡的区域差异一致。我们发现了两种脂肪细胞前体亚型，一种能够更广泛的复制、分化和脂肪生成转录因子的表达，而在TNF α的反应中，细胞凋亡比另一种更少。前者在皮下脂肪细胞群中最丰富，在网膜前脂肪细胞群中最不丰富，这可能解释了复制、分化和凋亡能力的区域差异。我们的假设是，脂肪细胞前体亚型具有不同的细胞动态特征，由发育调节因子形成，有助于脂肪组织功能的区域差异。目的1是验证发育调节因子是前脂肪细胞功能区域差异的基础这一假设。调节活性将使用药理学和分子方法来测试来自一个储存库的前脂肪细胞的细胞动力学特征是否可以与其他储存库的细胞动力学特征相似。目的2是验证发育调节因子对两种前脂肪细胞亚型的不同细胞动态特性的影响。我们将确定每种亚型中发育调节因子的表达模式，并操纵发育因子的表达，以显示它们是否调节亚型细胞动力学或在亚型之间切换。目的3是检验前脂肪细胞亚型数量或质量的区域差异导致脂肪组织功能差异的假设。这些研究将阐明细胞动力学和发育机制，使来自不同脂肪库的前脂肪细胞获得不同的特征，从而导致区域肥胖和代谢综合征。

DESCRIPTION (provided by applicant): Fat distribution varies considerably, even among those with the same total body fat content. Increased central fat is associated with the metabolic syndrome. To define cell dynamic and molecular mechanisms that contribute, we established advanced methods to isolate, clone, and differentiate human abdominal subcutaneous, mesenteric, and omental preadipocytes. We found pronounced regional variation in the developmental factors, cAMP response element binding protein (CREB), CITED2, FOXO1, and certain homeobox (HOX) factors, that interact with each other to regulate lineage progression, replication, apoptosis, and differentiation in other cell types. Their expression profiles were consistent with regional variation in preadipocyte replication, differentiation, and apoptosis. We found two adipocyte precursor subtypes, one capable of more extensive replication, differentiation, and adipogenic transcription factor expression and less apoptosis in response to TNF alpha than the other. The former was most abundant in subcutaneous and least abundant in omental preadipocyte populations, potentially accounting for regional variation in capacities for replication, differentiation, and apoptosis. Our hypothesis is that adipocyte precursor subtypes, with distinct cell dynamic characteristics shaped by developmental regulators, contribute to regional differences in fat tissue function. Aim 1 is to test the hypothesis that developmental regulators underlie regional variation in preadipocyte function. Regulator activity will be manipulated using pharmacological and molecular approaches to test if cell dynamic features of preadipocytes from one depot can be made to resemble those of the others. Aim 2 is to test the hypothesis that developmental regulators contribute to the distinct cell dynamic characteristics of the two preadipocyte subtypes. We will determine expression patterns of developmental regulators in each subtype and manipulate expression of developmental factors to show if they regulate subtype cell dynamics or switching between subtypes. Aim 3 is to test the hypothesis that regional differences in preadipocyte subtype quantities or qualities cause differences in fat tissue function. These studies will elucidate cell dynamic and developmental mechanisms predisposing preadipocytes from different fat depots to acquire distinct characteristics responsible for regional obesity and the metabolic syndrome.