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）：肥胖症在过去30年中急剧上升。仅在美国，有6000万人被定义为临床上的肥胖。特别是关于儿童肥胖的流行率。肥胖是通过过度的脂肪生成（形成脂肪细胞的形成）或通过已建立的脂肪细胞大小的增加而发生的。环境有毒物质称为肥胖症，破坏了内分泌系统，并可能增加脂肪形成。据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，据报道，二苯酚-A二甘油甲苯（徽章）和四抗溴苯酚A（TBBPA）会增加肥胖。异种生物性肥胖剂功能破坏内分泌系统并提高肥胖速率的机制需要进行积极的研究。我们的工作着重于表面糖蛋白Thy1（CD90）。 Thy1是一种糖磷脂酰肌醇（GPI）锚定的膜蛋白，该膜蛋白在神经元，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在Thy1的表达中是异质的，并且只有Thy1+成纤维细胞才能区分成疤痕形成的肌纤维细胞，并且只有THY1-/低成纤维细胞才能区分int脂肪细胞。在此R21应用中，我们假设Thy1在预防脂肪形成中具有直接的作用。我们的支持数据表明，Thy1的耗竭会增加脂肪形成，而Thy1的过度表达会损害脂肪形成。这些数据支持以下概念：Thy1不仅仅是标记，并且Thy1可以起作用以修改细胞命运。我们还发现，暴露于TBBPA，徽章和TBT后，人和小鼠多能基质细胞（MSC）降低了THY1的表达。重要的是，一种可能作用的一种机制是重新编程MSC的表观遗传代码以改变生理学。 Thy1基因座包含多个可以表观遗传控制的CpG岛，并且可能是肥胖症的关键靶标。暴露于肥胖症的发育暴露可能会在暴露后长时间重新编程THY1表达水平并修饰生理学。因此，我们假设环境性肥胖症改变了Thy1的表达以增加脂肪生成和肥胖。为了研究这一假设，我们已经开发了以下目标。目标1：检验以下假设：环境性肥胖者在多能基质细胞中降低Thy1的表达和活性以增加脂肪形成。目标2：检验以下假设：发育性暴露于肥胖症会降低Thy1的表达并增加体内的脂肪形成和肥胖。这些研究的结果将首次表明THY1表达通过环境性肥胖剂降低，而这种减少是一种机制的关键，该机制可以使您的脂肪形成和肥胖。