Xu Jialin, Shimpi Prajakta, Armstrong Laura, Salter Deanna, Slitt Angela L
Institute of Biochemistry and Molecular Biology, College of Life and Health Sciences, Northeastern University, Shenyang 110819, PR China; Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States.
Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States.
Toxicol Appl Pharmacol. 2016 Jan 1;290:21-30. doi: 10.1016/j.taap.2015.11.002. Epub 2015 Nov 5.
PFOS is a chemical of nearly ubiquitous exposure in humans. Recent studies have associated PFOS exposure to adipose tissue-related effects. The present study was to determine whether PFOS alters the process of adipogenesis and regulates insulin-stimulated glucose uptake in mouse and human preadipocytes. In murine-derived 3T3-L1 preadipocytes, PFOS enhanced hormone-induced differentiation to adipocytes and adipogenic gene expression, increased insulin-stimulated glucose uptake at concentrations ranging from 10 to 100μM, and enhanced Glucose transporter type 4 and Insulin receptor substrate-1 expression. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), NAD(P)H dehydrogenase, quinone 1 and Glutamate-cysteine ligase, catalytic subunit were significantly induced in 3T3-L1 cells treated with PFOS, along with a robust induction of Antioxidant Response Element (ARE) reporter in mouse embryonic fibroblasts isolated from ARE-hPAP transgenic mice by PFOS treatment. Chromatin immunoprecipitation assays further illustrated that PFOS increased Nrf2 binding to ARE sites in mouse Nqo1 promoter, suggesting that PFOS activated Nrf2 signaling in murine-derived preadipocytes. Additionally, PFOS administration in mice (100μg/kg/day) induced adipogenic gene expression and activated Nrf2 signaling in epididymal white adipose tissue. Moreover, the treatment on human visceral preadipocytes illustrated that PFOS (5 and 50μM) promoted adipogenesis and increased cellular lipid accumulation. It was observed that PFOS increased Nrf2 binding to ARE sites in association with Nrf2 signaling activation, induction of Peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein α expression, and increased adipogenesis. This study points to a potential role of PFOS in dysregulation of adipose tissue expandability, and warrants further investigations on the adverse effects of persistent pollutants on human health.
全氟辛烷磺酸是一种人类几乎普遍接触的化学物质。最近的研究将全氟辛烷磺酸暴露与脂肪组织相关效应联系起来。本研究旨在确定全氟辛烷磺酸是否会改变脂肪生成过程，并调节小鼠和人类前脂肪细胞中胰岛素刺激的葡萄糖摄取。在小鼠来源的3T3-L1前脂肪细胞中，全氟辛烷磺酸增强了激素诱导的向脂肪细胞的分化和脂肪生成基因表达，在10至100μM的浓度范围内增加了胰岛素刺激的葡萄糖摄取，并增强了4型葡萄糖转运蛋白和胰岛素受体底物-1的表达。在用全氟辛烷磺酸处理的3T3-L1细胞中，核因子（红细胞衍生2）样2（Nrf2）、NAD（P）H脱氢酶醌1和谷氨酸-半胱氨酸连接酶催化亚基被显著诱导，同时在用全氟辛烷磺酸处理从ARE-hPAP转基因小鼠分离的小鼠胚胎成纤维细胞时，抗氧化反应元件（ARE）报告基因也被强烈诱导。染色质免疫沉淀分析进一步表明，全氟辛烷磺酸增加了Nrf2与小鼠Nqo1启动子中ARE位点的结合，表明全氟辛烷磺酸在小鼠来源的前脂肪细胞中激活了Nrf2信号通路。此外，给小鼠注射全氟辛烷磺酸（100μg/kg/天）可诱导附睾白色脂肪组织中的脂肪生成基因表达并激活Nrf2信号通路。此外，对人类内脏前脂肪细胞的处理表明，全氟辛烷磺酸（5和50μM）促进了脂肪生成并增加了细胞内脂质积累。据观察，全氟辛烷磺酸增加了Nrf2与ARE位点的结合，伴随着Nrf2信号通路的激活、过氧化物酶体增殖物激活受体γ和CCAAT/增强子结合蛋白α表达的诱导以及脂肪生成的增加。本研究指出了全氟辛烷磺酸在脂肪组织扩张能力失调中的潜在作用，并值得进一步研究持久性污染物对人类健康的不利影响。
