Developmental Genes and the Origin of Fat

发育基因和脂肪的起源

• 批准号: 8035917
• 负责人: C RONALD KAHN
• 金额: $ 56.9万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8035917
• 关键词: 2,4-thiazolidinedione; Address; Adipocytes; Adipose tissue; Apple; Body Weight; Body fat; Boxing; Brown Fat; Cell model; Cultured Cells; Development; Developmental Gene; Diabetes Mellitus; Diet; Disease; Eating; Energy Metabolism; Equilibrium; Fatty acid glycerol esters; Food Energy; Gene Expression; Genes; Genetically Engineered Mouse; Glucose; Glypican; Grant; Health; Heterogeneity; Homeostasis; Human; In Vitro; Insulin Resistance; Knock-out; Lead; Light; Lipids; Measures; Mesenchymal Stem Cells; Metabolic; Metabolic syndrome; MicroRNAs; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Pattern; Pear; Peripheral; Play; Process; Regulation; Relative (related person); Research; Risk; Role; Shapes; Site; Thiazolidinediones; Transcriptional Regulation; Visceral; Waist-Hip Ratio; embryonic stem cell; homologous recombination; in vivo; insight; research study; response; subcutaneous; trait

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.

描述（由申请人提供）：肥胖的发生部分取决于食物摄入和热量利用之间的平衡；还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，不同储存库中的白色脂肪在其代谢功能以及对整体葡萄糖和脂质稳态的影响方面是异质的。过多的内脏脂肪堆积（中央型或“苹果型”肥胖）与胰岛素抵抗以及2型糖尿病和代谢综合征的风险增加有关，而皮下脂肪的堆积（周围型或“梨型”肥胖）则没有这样的风险。肥胖和身体脂肪分布都是可遗传的特征，但人们对脂肪组织的发育起源知之甚少。棕色与白色前脂肪细胞定向的控制；控制不同库中白色脂肪细胞的相对数量和功能差异；不同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间体。最近，我们和其他人开始对早期脂肪的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部分的基因表达模式，我们确定了基本发育和模式基因在此过程中的潜在重要作用，包括许多 Hox 基因、Shox2、T-box-15 (Tbx15)、Engrailed-1、Glypican-4 等。对于其中三个基因（Tbx15、Glypican-4 和 HoxA5），人类中的表达水平与肥胖水平（通过 BMI 衡量）以及脂肪分布（通过腰臀比 (WHR) 衡量）高度相关，这表明发育和模式基因可能在脂肪质量和分布的确定中发挥重要作用。在这项资助中，我们建议直接解决脂肪组织起源的问题，以及发育和模式基因如何在确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，以及这些库中脂肪细胞的差异功能，从而导致它们与糖尿病和代谢综合征的不同关联。该资助的具体目的是：通过体外和体内的过表达和表达不足，包括通过小鼠同源重组进行条件敲除，确定发育和模式基因在内脏和皮下脂肪细胞的脂肪细胞测定、分化和差异功能中的作用。此外，我们将利用体内谱系追踪实验来确定不同仓库中脂肪细胞的真正发育起源。最后，我们将确定来自不同库的脂肪细胞和前脂肪细胞之间的 microRNA 表达有何不同，以及 microRNA 如何在不同库的脂肪细胞的发育、分化和功能中发挥作用。 公众健康相关性：内脏脂肪过多（中央型或“苹果型”肥胖）的积累与 2 型糖尿病和代谢综合征的风险增加相关，而皮下脂肪（周围型或“梨型”肥胖）的积累则没有这样的风险。最近，我们已经证明，基本的发育基因当然可能在这个过程中发挥作用。在本研究中，我们将通过研究在培养物中的前脂肪细胞和体内基因工程小鼠中过度表达或敲除这些基因的表达来确定这些基因在脂肪细胞测定中的作用以及来自内脏和皮下储存库的脂肪细胞的差异功能。