Environmental obesogens reduce Thy1 expression and promote obesity

描述（由申请人提供）：肥胖在过去30年中急剧上升。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症的流行率。肥胖通过过度的脂肪生成（脂肪细胞的形成）或通过既定脂肪细胞大小的增加而发生。环境中的有毒物质称为致肥剂，会破坏内分泌系统，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）会增加肥胖症。外源性肥胖素破坏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）锚定的膜蛋白，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Thy1的表达是异质的，只有Thy1+成纤维细胞可以分化为瘢痕形成肌成纤维细胞，只有Thy1-/低成纤维细胞可以分化为脂肪细胞。在这个R21应用中，我们假设Thy1在阻止脂肪形成中有直接作用。我们的支持性数据显示Thy1的缺失增加脂肪形成，而Thy1的过度表达损害脂肪形成。这些数据支持Thy1不仅仅是一个标记物，Thy1可以起到改变细胞命运的作用。我们还发现，Thy1的表达减少后，暴露于TBBPA，BADGE和TBT的人和小鼠多能基质细胞（MSC）。重要的是，肥胖原可能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学。Thy1基因座含有多个CpG岛，这些CpG岛可以被表观遗传学控制，并且可能是肥胖原的关键靶点。发育暴露于致肥胖剂可能会重新编程Thy1表达水平，并在暴露后很长时间内改变生理学。因此，我们假设环境致肥胖物改变Thy1表达以增加脂肪形成和肥胖。为了研究这一假设，我们提出了以下目标。目的1：检验环境致肥胖物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。目的2：测试发育暴露于致肥胖剂降低Thy1表达并增加体内脂肪形成和肥胖的假设。这些研究的结果将首次表明，Thy1的表达被环境致胖剂降低，这种降低是致胖剂增加脂肪形成和肥胖的机制的关键。

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.