Low-Dose Bisphenol-A Impairs Adipogenesis and Generates Dysfunctional 3T3-L1 Adipocytes.
Low-Dose Bisphenol-A Impairs Adipogenesis and Generates Dysfunctional 3T3-L1 Adipocytes.
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DOI：
10.1371/journal.pone.0150762
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Valentino R
中科院分区：
文献类型：
--
作者：
Ariemma F;D'Esposito V;Liguoro D;Oriente F;Cabaro S;Liotti A;Cimmino I;Longo M;Beguinot F;Formisano P;Valentino R
环境内分泌干扰物（EDCs），包括双酚A（BPA），最近已参与肥胖和糖尿病的失调脂肪组织功能。我们的目的是研究长期暴露于低剂量BPA是否会影响脂肪生成和脂肪细胞代谢功能。因此，将3 T3-L1前脂肪细胞与BPA 1 nM一起培养三周以模拟人类环境暴露。我们评估BPA对细胞增殖、分化、基因表达和脂肪细胞代谢功能的影响。BPA显著增加前脂肪细胞增殖（p<0.01）。在BPA存在下分化的3 T3-L1脂肪细胞中，过氧化物酶体增殖物激活受体γ（PPARγ）、脂肪酸结合蛋白4/脂肪细胞蛋白2（FABP 4/AP 2）和CCAAT/增强子结合蛋白（C/EBPα）的表达分别增加3.5、1.5和3倍。成熟脂肪细胞也显示出脂质积累的显著增加（p<0.05）和胰岛素作用的改变，胰岛素刺激的葡萄糖利用显著减少（p<0.001）。在成熟脂肪细胞中，瘦素、白细胞介素6（IL 6）和γ干扰素（IFNγ）的mRNA水平显著升高（p<0.05）。总之，BPA长期暴露在低剂量下，与环境中发现的一致，可能会影响脂肪细胞分化程序，增强前脂肪细胞增殖，并预测参与脂质/葡萄糖代谢的主基因的表达。所得脂肪细胞是肥大的，具有受损的胰岛素信号传导、降低的葡萄糖利用和增加的促炎细胞因子表达。因此，这些数据支持了以下假设：在脂肪组织发育的关键阶段，BPA暴露可能导致脂肪细胞代谢功能障碍和炎症，从而增加患肥胖相关疾病的风险。
Environmental endocrine disruptors (EDCs), including bisphenol-A (BPA), have been recently involved in obesity and diabetes by dysregulating adipose tissue function. Our aim was to examine whether prolonged exposure to low doses of BPA could affect adipogenesis and adipocyte metabolic functions. Therefore, 3T3-L1 pre-adipocytes were cultured for three weeks with BPA 1nM to mimic human environmental exposure. We evaluated BPA effect on cell proliferation, differentiation, gene expression and adipocyte metabolic function. BPA significantly increased pre-adipocyte proliferation (p<0.01). In 3T3-L1 adipocytes differentiated in the presence of BPA, the expression of Peroxisome proliferator-activated receptor gamma (PPARγ), Fatty Acid Binding Protein 4/Adipocyte Protein 2 (FABP4/AP2) and CCAAT/enhancer binding protein (C/EBPα) was increased by 3.5, 1.5 and 3 folds, respectively. Mature adipocytes also showed a significant increase in lipid accumulation (p<0.05) and alterations of insulin action, with significant reduction in insulin-stimulated glucose utilization (p<0.001). Moreover, in mature adipocytes, mRNA levels of Leptin, interleukin-6 (IL6) and interferon-γ (IFNγ) were significantly increased (p<0.05). In conclusion, BPA prolonged exposure at low doses, consistent with those found in the environment, may affect adipocyte differentiation program, enhancing pre-adipocyte proliferation and anticipating the expression of the master genes involved in lipid/glucose metabolism. The resulting adipocytes are hypertrophic, with impaired insulin signaling, reduced glucose utilization and increased pro-inflammatory cytokine expression. Thus, these data supported the hypothesis that BPA exposure, during critical stages of adipose tissue development, may cause adipocyte metabolic dysfunction and inflammation, thereby increasing the risk of developing obesity-related diseases.