Environmental chemicals promote adipogenesis by targeting THY1

摘要 肥胖通常与不良的饮食/过量的卡路里摄入和缺乏足够的体力有关。 活动然而，最近发现，环境成分可能会产生重大影响， 肥胖症的流行。在工业化国家、发达国家和 即使是不发达国家，也不能严格归咎于饮食不良和缺乏身体活动。 环境中的化学物质，被称为“肥胖原”，是内分泌干扰物，可以触发脂肪生成（脂肪 细胞形成）。然而，其作用机制仍不清楚。四溴双酚A（TBBPA）和 三丁基锡（TBT）是已知的致肥胖化学品。我们假设TBBPA和TBT促进脂肪生成 通过降低THY 1（CD 90）的水平，THY 1是存在于前脂肪细胞、某些成纤维细胞和 干细胞（例如人间充质干细胞（hMSC））。我们的实验室以前发现成纤维细胞 THY 1表达是异质的，其中只有THY 1-/低成纤维细胞分化成脂肪细胞， 确定了THY 1在脂肪形成和细胞命运决定中的关键作用。用一只成熟的老鼠 前脂肪细胞系（3 T3-L1），我表明TBBPA减少THY 1 mRNA和蛋白质，并促进 脂肪生成然而，这是否发生在人类干细胞，如hMSCs和诱导多能干细胞中， 干细胞（iPSC）是未知的。肥胖和脂肪形成也受到表观遗传和后遗传的影响。 翻译的变化，包括整体DNA甲基化和特异性DNA甲基化丰度的增加。 调节性微RNA（miRNA）。我在hMSCs中的支持数据显示，肥胖剂增加了某些miRNAs， 预测结合THY 1 mRNA。基因表达也可以通过DNA甲基化来调节。我支持 数据显示TBBPA增加了hMSC中THY 1启动子上的甲基化。因此，我假设 肥胖原，如TBBPA，改变了THY 1的转录后调节， 表达，从而引发前体细胞成为脂肪细胞。因此，我将在体外确定 肥胖原对人干细胞THY 1表达的影响及其分子机制。（AIM 1）。我还将确定环境致肥胖剂对体内THY 1表达的影响（AIM 2）。结果 将有助于确定对干细胞功能的致肥胖作用，并将提供关于 翻译后变化如何改变干细胞的命运和谱系。环境致肥胖物的研究应 因此，必须将其作为优先事项，因为它们可能是导致全球肥胖流行病日益严重的主要原因。

Abstract Obesity has been classically linked to poor diet/excessive calorie intake and insufficient physical activity. However, it has recently been discovered that environmental components may contribute significantly to the widespread obesity epidemic. The rapidly increasing obese populations in industrialized, developed and even undeveloped countries cannot be strictly accounted for by poor diet and physical inactivity. Environmental chemicals, termed “obesogens” are endocrine disruptors, that can trigger adipogenesis (fat cell formation). However, their mechanism(s) of action remain unknown. Tetrabromobisphenol-A (TBBPA) and tributylin (TBT) are known obesogenic chemicals. We hypothesize that TBBPA and TBT promote adipogenesis by decreasing levels of THY1 (CD90), a cell surface protein present on pre-adipocytes, certain fibroblasts, and stem cells, (e.g. human mesenchymal stem cells (hMSCs)). Our lab previously discovered fibroblasts are heterogeneous for THY1 expression, where only THY1-/low fibroblasts differentiate into adipocytes, which identified THY1’s crucial role during adipogenesis and cell fate determination. Using a well-established mouse pre-adipocyte cell line (3T3-L1), I show that TBBPA reduces THY1 mRNA and protein and promotes adipogenesis. However, whether this occurs in human stem cells, such as hMSCs and induced pluripotent stem cells (iPSCs) is unknown. Obesity and adipogenesis are also subject to epigenetic and post- translational changes, which include increases in both global DNA methylation and the abundance of specific regulatory microRNAs (miRNA). My supporting data in hMSCs shows obesogens increase certain miRNAs that are predicted to bind THY1 mRNA. Gene expression can also be regulated by DNA methylation. My supporting data shows that TBBPA increases methylation on the THY1 promoter in hMSCs. Therefore, I hypothesize that obesogens, such as TBBPA, alter post-transcriptional regulation of THY1 to decrease its expression, thereby priming precursor cells to become adipocytes. Therefore, I will determine the in vitro effects and underlying molecular mechanisms of obesogens on THY1 expression in human stem cells. (AIM 1). I will also determine the environmental obesogen effects on THY1 expression in vivo (AIM 2). The results from this project will help determine the obesogenic effects on stem cell function and will offer insight on as to how post-translational changes alter stem cell fate and lineage. Studies of environmental obesogens should be made a priority, since they likely overwhelmingly contribute to the growing worldwide obesity epidemic.