Environmental chemicals promote adipogenesis by targeting THY1

摘要 传统上，肥胖与不良的饮食/过高的卡路里摄入量和身体不足有关 活动。然而，最近发现，环境因素可能起到很大作用 与广泛流行的肥胖有关。工业化、发达国家和发展中国家迅速增长的肥胖人口 即使是不发达的国家，也不能严格地归因于糟糕的饮食和缺乏体育活动。 环境化学物质，称为“肥胖源”，是一种内分泌干扰物，可引发脂肪生成 细胞形成)。然而，他们的作用机制(S)仍不清楚。四溴双酚A(TBBPA)和 三丁基(TBT)是已知的致肥胖化学物质。我们假设TBBPA和TBT促进脂肪生成 通过降低THY1(CD90)的水平，一种存在于前脂肪细胞、某些成纤维细胞和 干细胞(例如人骨髓间充质干细胞)。我们实验室之前发现成纤维细胞是 THY1表达的异质性，其中只有THY1-/低成纤维细胞分化为脂肪细胞，这 发现THY1‘S在脂肪形成和细胞命运决定中起关键作用。使用一只成熟的小鼠 在前脂肪细胞系(3T3-L1)中，我发现TBBPA降低THY1的mRNA和蛋白并促进 成脂作用。然而，这是否发生在人类干细胞，如hMSCs和诱导的多能性 干细胞(IPSCs)是未知的。肥胖和脂肪生成也受到表观遗传和后遗传因素的影响 翻译变化，包括全球DNA甲基化和特定基因丰度的增加 调控microRNAs(MiRNA)。我在hMSCs中的支持数据显示，致肥者增加了某些miRNA， 被预测与THY1mRNA结合。基因表达也可以通过DNA甲基化来调节。我的支持 数据显示，TBBPA增加了hMSCs中THY1启动子的甲基化。因此，我假设 致肥者，如TBBPA，改变THY1的转录后调节以减少其 表达，从而启动前体细胞成为脂肪细胞。因此，我将在体外测定 致癌物质对人干细胞THY1表达的影响及其分子机制。(目标 1)。我还将确定环境肥胖原对体内THY1表达的影响(AIM 2)。结果是 将有助于确定肥胖对干细胞功能的影响，并将为以下方面提供洞察力 翻译后的变化如何改变干细胞的命运和血统。对环境致肥者的研究应该 被列为优先事项，因为它们可能是日益严重的全球肥胖症流行的压倒性因素。

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.