Developmental Genes and the Origin of Fat

描述(申请人提供)：肥胖的发展部分取决于食物摄入量和卡路里利用之间的平衡；但也取决于白色脂肪组织和棕色脂肪组织之间的平衡，白色脂肪组织是能量储存的主要部位，棕色脂肪组织专门用于能量消耗。此外，不同仓库中的白色脂肪在其代谢功能和对总体糖脂动态平衡的影响方面是不同的。过多的内脏脂肪堆积(中心型或“苹果型”肥胖)与胰岛素抵抗、2型糖尿病和代谢综合征风险增加有关，而皮下脂肪堆积(外周型或“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；棕色和白色前体脂肪细胞的定位控制；不同储存库中白色脂肪细胞之间的相对数量和功能差异的控制；不同储存库中白色脂肪细胞的异质性和内在差异；以及胚胎干细胞、中胚层/间充质干细胞、前脂肪细胞(或前脂肪细胞)和成熟脂肪细胞之间的确切途径和中介知之甚少。最近，我们和其他人已经开始对早期脂肪的发育和模式有了一些见解。通过比较来自不同储存库的脂肪细胞和含有前脂肪细胞的间质血管部分的基因表达谱，我们确定了基础发育和模式基因在这一过程中的潜在重要作用，包括一些Hox基因，Shox2，T-box-15(Tbx15)，Engrailed-1，Glypcan-4等。其中三个基因(Tbx15、Glypcan-4和HoxA5)在人类中的表达水平与BMI测量的肥胖水平和腰臀比(WHR)测量的脂肪分布高度相关，这表明发育和模式基因可能在决定脂肪质量和分布方面发挥重要作用。在这项资助中，我们建议直接解决脂肪组织的起源问题，以及发育和模式基因如何在决定不同脂肪储存库中脂肪细胞的数量和分布以及这些脂肪细胞在这些储存库中的不同功能，从而导致它们与糖尿病和代谢综合征的不同联系方面发挥重要作用。这项资助的具体目标是：通过体外和体内高表达和低表达，包括小鼠同源重组的条件性敲除，确定发育和模式基因在脂肪细胞决定、内脏和皮下脂肪细胞分化和分化功能中的作用。此外，我们将通过体内的谱系追踪实验来鉴定不同储存库中脂肪细胞的真实发育来源。最后，我们将确定microRNA在不同储存库的脂肪细胞和前脂肪细胞中的表达差异，以及microRNA如何在不同储存库的脂肪细胞的发育、分化和功能中发挥作用。公共卫生相关性：内脏脂肪过多(中心型或苹果型肥胖)的积累与2型糖尿病和代谢综合征风险的增加有关，而皮下脂肪(外周型或梨型肥胖)的积累则没有这种风险。最近，我们已经证明，基本的发育基因可能在这一过程中发挥作用。在这项研究中，我们将通过在培养的前脂肪细胞和体内基因工程小鼠中过表达或敲除它们的表达，来确定这些基因在脂肪细胞决定和内脏和皮下脂肪细胞分化功能中的作用。

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. PUBLIC HEALTH RELEVANCE: Accumulation of excess visceral fat (central or "apple-shaped" obesity) is associated with 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. Recently, we have demonstrated that certainly fundamental developmental genes may play a role in this process. In this study we will determine the role of these genes in adipocyte determination and differential function of adipocytes from visceral and subcutaneous depots through studies over-expressing or knocking out there expression in preadipocytes in culture and in genetically engineered mice in vivo.