Developmental Genes and the Origin of Fat

描述（由申请人提供）：肥胖的发展部分取决于食物摄入和热量利用之间的平衡;但也取决于白色脂肪组织（能量储存的主要部位）和棕色脂肪组织（专门用于能量消耗）之间的平衡。此外，不同贮库中的白色脂肪在其代谢功能和对总体葡萄糖和脂质稳态的影响方面是异质的。过多内脏脂肪的积累（中心或“苹果形”肥胖）与胰岛素抵抗和2型糖尿病和代谢综合征的风险增加有关，而皮下脂肪的积累（外周或“梨形”肥胖）则没有这种风险。肥胖和体脂分布都是可遗传的特征，但对脂肪组织的发育起源、棕色前脂肪细胞与白色前脂肪细胞定型的控制、不同贮库中白色脂肪细胞之间相对数量和功能差异的控制、不同贮库中白色脂肪细胞的异质性和内在差异、不同贮库中脂肪细胞的分化和分化等知之甚少。以及胚胎干细胞、中胚层/间充质干细胞、前脂肪细胞（或多个前脂肪细胞）和成熟脂肪细胞之间的确切途径和中间体。最近，我们和其他人已经开始对早期脂肪发育和模式有了一些了解。通过比较脂肪细胞和含有来自不同库的前脂肪细胞的基质血管组分的基因表达模式，我们确定了基本发育和图案化基因在此过程中的潜在重要作用，包括许多Hox基因、Shox 2、T-box-15（Tbx 15）、Engrailed-1、Glypican-4等。对于这些基因中的三个（Tbx 15、磷脂酰肌醇蛋白聚糖-4和HoxA 5），人中的表达水平与肥胖水平（如通过BMI测量的）和脂肪分布（如通过腰臀比（WHR）测量的）高度相关，表明发育和模式化基因可能在确定脂肪质量和分布中起重要作用。在这项资助中，我们建议直接解决脂肪组织起源的问题，以及发育和模式化基因如何在决定不同脂肪库中脂肪细胞的数量和分布方面发挥重要作用，以及这些脂肪库中脂肪细胞的差异功能，这导致它们与糖尿病和代谢综合征的差异关联。这项资助的具体目的是：通过体外和体内的过度表达和表达不足，包括小鼠同源重组的条件性敲除，确定发育和模式化基因在脂肪细胞决定、内脏和皮下脂肪细胞分化和差异功能中的作用。此外，我们将确定真正的发展起源的脂肪细胞在不同的仓库使用谱系示踪实验在体内。最后，我们将确定microRNA的表达如何不同的脂肪细胞和前脂肪细胞从不同的仓库，以及如何microRNA可能发挥作用的发育，分化和功能的脂肪细胞在不同的仓库。

DESCRIPTION (provided by applicant): The development of obesity depends in part on the balance between food intake and caloric utilization; but also on the balance between white adipose tissue, which is the primary site of energy storage, and brown adipose tissue, which is specialized for energy expenditure. In addition, white fat in different depots is heterogeneous with respect to its metabolic functions and impact on overall glucose and lipid homeostasis. Accumulation of excess visceral fat (central or "apple-shaped" obesity) is associated with insulin resistance and increased risk of type 2 diabetes and metabolic syndrome, whereas accumulation of subcutaneous adipose (peripheral or "pear-shaped" obesity) does not have such a risk. Both obesity and body fat distribution are heritable traits, however little is known about the developmental origins of adipose tissue; the control of brown versus white preadipocyte commitment; the control of relative amounts and functional differences between white fat cells in different depots; the heterogeneity and intrinsic differences of white fat cells in different depots; and the exact pathways and intermediates between the embryonic stem cell, the mesodermal/mesenchymal stem cell, the preadipocyte (or preadipocytes) and the mature fat cell. Recently, we and others have begun to gain some insights into early adipose development and patterning. By comparing gene expression patterns of adipocytes and stromovascular fraction containing preadipocytes from different depots, we identified a potentially important role for fundamental developmental and patterning genes in this process, including a number of Hox genes, Shox2, T-box-15 (Tbx15), Engrailed-1, Glypican-4, and others. For three of these genes (Tbx15, Glypican-4, and HoxA5), the level of expression in humans is highly correlated with the level of obesity, as measure by BMI, and the fat distribution as measured by waist- hip ratio (WHR), suggesting that developmental and patterning genes may play important roles in determination of adipose mass and distribution. In this grant, we propose to directly address the question of the origin of adipose tissue, as well as how developmental and patterning genes may play important roles in determining number and distribution of adipocytes in different fat depots, and the differential function of adipocytes in these depots, which leads to their differential association with diabetes and metabolic syndrome. The specific aims of this grant are to: Determine the role of developmental and patterning genes in adipocyte determination, differentiation and differential function of adipocytes from visceral and subcutaneous depots, through in vitro and in vivo over- and under-expression, including conditional knockout by homologous recombination in mice. In addition, we will identify the true developmental origins of adipocytes in different depots using lineage tracing experiments in vivo. Finally, we will determine how microRNA expression differs between adipocytes and preadipocytes from different depots, and how microRNAs might play a role in development, differentiation and function of adipocytes in different depots.