Environmental obesogens reduce Thy1 expression and promote obesity

环境致肥胖因素降低Thy1表达并促进肥胖

• 批准号: 8723204
• 负责人: RICHARD P. PHIPPS
• 金额: $ 22.79万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-19 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8723204
• 关键词: Address; Adipocytes; Affect; Biological Markers; Blood Glucose; Cell Surface Proteins; Cells; Chondrocytes; Cicatrix; Code; CpG Islands; Data; Development; Dichlorodiphenyl Dichloroethylene; Diet; Effector Cell; Endocrine system; Epidemic; Epigenetic Process; Ethers; Exposure to; Fatty acid glycerol esters; Fibroblasts; Flow Cytometry; Gene Expression; Genomics; Goals; Growth; Human; In Vitro; Inherited; Investigation; Knockout Mice; Life; Lipids; Measures; Mediating; Membrane Glycoproteins; Membrane Proteins; Mesenchymal Stem Cells; Methylation; Modification; Mus; Myofibroblast; Neonatal; Neurons; Obesity; Osteocytes; Physiology; Production; Property; Reporting; Role; Staining method; Stains; Stem cells; Stromal Cells; Testing; Time; Toxic Environmental Substances; Weight; Western Blotting; Whole Organism; Work; Xenobiotics; bisphenol A; blood glucose regulation; cell type; chromatin immunoprecipitation; environmental agent; environmental chemical; in utero; in vivo; lipid biosynthesis; obesity in children; obesogen; offspring; oil red O; prevent; public health relevance; repaired; tetrabromobisphenol A; tributyltin

DESCRIPTION (provided by applicant): Obesity has risen dramatically over the last 30 years. In the U.S. alone, 60 million people are defined as clinically obese. Especially concerning is the nearly epidemic rate of childhood obesity. Obesity occurs through excessive adipogenesis (formation of adipocytes) or through increases in established adipocyte size. Environmental toxicants termed obesogens disrupt the endocrine system and can increase adipogenesis. Tributyltin (TBT), dichlorodiphenyl-dichloroethylene (DDE), bisphenol-A diglycidyl ether (BADGE), and tetrabromobisphenol-A (TBBPA), have been reported to increase obesity. The mechanism(s) by which xenobiotic obesogens function to disrupt the endocrine system and increase rates of obesity requires active investigation. Our work focuses on the surface glycoprotein, Thy1 (CD90). Thy1 is an glycophosphatidylinositol (GPI)-anchored membrane protein expressed on subsets of neurons, stem cells and other cell types. We discovered that fibroblasts are heterogeneous for expression of Thy1 and that only Thy1+ fibroblasts can differentiate into scar-forming myofibroblasts and only Thy1-/low fibroblasts can differentiate int adipocytes. In this R21 application, we hypothesize that there is a direct role for Thy1 in preventing adipogenesis. Our supporting data show that depletion of Thy1 increases adipogenesis while over- expression of Thy1 impairs adipogenesis. These data support the concept that Thy1 is more than a marker and that Thy1 can function to modify cell fate. We also discovered that Thy1 expression is reduced in both human and mouse multipotent stromal cells (MSCs) after exposure to TBBPA, BADGE and TBT. Importantly, one mechanism by which obesogens may function is to reprogram the epigenetic code of MSCs to alter physiology. The Thy1 locus contains multiple CpG islands that can be controlled epigenetically and may be key targets of obesogens. Developmental exposure to obesogens may reprogram Thy1 expression levels and modify physiology long after exposure. Therefore, we hypothesize that environmental obesogens alter Thy1 expression to increase adipogenesis and obesity. To investigate this hypothesis we have developed the following aims. Aim 1: Test the hypothesis that environmental obesogens diminish Thy1 expression and activity in multipotent stromal cells to increase adipogenesis. Aim 2: Test the hypothesis that developmental exposure to obesogens reduces Thy1 expression and increases adipogenesis and obesity in vivo. The results of these studies will show for the first time that Thy1 expression is reduced by environmental obesogens and this reduction is key to the mechanism whereby obesogens increase adipogenesis and obesity.

描述（由申请人提供）：过去 30 年来，肥胖率急剧上升。仅在美国就有 6000 万人被定义为临床肥胖。尤其令人担忧的是儿童肥胖率近乎流行。肥胖是由于过度的脂肪生成（脂肪细胞的形成）或通过已建立的脂肪细胞大小的增加而发生的。被称为肥胖源的环境毒物会破坏内分泌系统，并可能增加脂肪生成。据报道，三丁基锡 (TBT)、二氯二苯基二氯乙烯 (DDE)、双酚 A 二缩水甘油醚 (BADGE) 和四溴双酚 A (TBBPA) 会增加肥胖。外源致肥胖物质扰乱内分泌系统和增加肥胖率的机制需要积极研究。我们的工作重点是表面糖蛋白 Thy1 (CD90)。 Thy1 是一种糖磷脂酰肌醇 (GPI) 锚定膜蛋白，在神经元、干细胞和其他细胞类型的亚群上表达。我们发现成纤维细胞的 Thy1 表达具有异质性，并且只有 Thy1+ 成纤维细胞可以分化为疤痕形成肌成纤维细胞，而只有 Thy1-/低成纤维细胞可以分化为脂肪细胞。在此 R21 应用中，我们假设 Thy1 在预防脂肪生成中具有直接作用。我们的支持数据表明，Thy1 的消耗会增加脂肪生成，而 Thy1 的过度表达则会损害脂肪生成。这些数据支持这样的概念：Thy1 不仅仅是一个标记，而且 Thy1 可以发挥作用来改变细胞命运。我们还发现，暴露于 TBBPA、BADGE 和 TBT 后，人类和小鼠多能基质细胞 (MSC) 中的 Thy1 表达都会降低。重要的是，肥胖因子发挥作用的一种机制是重新编程 MSC 的表观遗传密码以改变生理机能。 Thy1 基因座包含多个可通过表观遗传学控制的 CpG 岛，可能是致肥胖的关键靶标。发育过程中接触肥胖物质可能会重新编程 Thy1 表达水平，并在接触后很长时间内改变生理机能。因此，我们假设环境致肥胖因素改变 Thy1 表达以增加脂肪生成和肥胖。为了研究这一假设，我们制定了以下目标。目标 1：检验环境致肥胖物质会降低多能基质细胞中 Thy1 表达和活性以增加脂肪生成的假设。目标 2：检验以下假设：发育过程中暴露于致肥胖物质会降低 Thy1 表达并增加体内脂肪生成和肥胖。这些研究的结果将首次表明 Thy1 表达会被环境致肥胖物质减少，而这种减少是致肥胖物质增加脂肪生成和肥胖机制的关键。