title: PFOS induces adipogenesis and glucose uptake in association with activation of Nrf2 signaling pathway.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jialin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States.
authors.forename: Prajakta
authors.initials: P
authors.lastname: Shimpi
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Armstrong
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States.
authors.forename: Deanna
authors.initials: D
authors.lastname: Salter
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Kingston, RI 02881, United States. Electronic address: aslitt@uri.edu.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Slitt
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects; D050156:Adipogenesis / Q000187:drug effects*; D052436:Adipose Tissue, White / Q000378:metabolism; D017738:Alkanesulfonic Acids / Q000633:toxicity*; D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D050260:Carbohydrate Metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005466:Fluorocarbons / Q000633:toxicity*; D005786:Gene Expression Regulation; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D023382:Toxicity Tests, Acute
chemical_list: D017738:Alkanesulfonic Acids; D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D005466:Fluorocarbons; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D047495:PPAR gamma; D012333:RNA, Messenger; C495693:Slc2a4 protein, mouse; C076994:perfluorooctane sulfonic acid; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D005721:Glutamate-Cysteine Ligase
keywords: ARE; Adipogenesis; Glucose uptake; Nrf2; PFOS; Pparγ