title: Nuclear factor erythroid-derived factor 2-related factor 2 regulates transcription of CCAAT/enhancer-binding protein β during adipogenesis.
abstract: Nuclear factor erythroid-derived factor 2-related factor 2 (Nrf2) is a cap-n-collar basic leucine zipper transcription factor that is involved in the cellular adaptive response to oxidative stress. Our previous study reported that targeted disruption of the Nrf2 gene in mice decreases adipose tissue mass and protects against obesity induced by a high-fat diet. Deficiency of Nrf2 in preadipocytes and mouse embryonic fibroblasts led to impaired adipogenesis. Consistent with these findings, the current study found that lack of Nrf2 in primary cultured mouse preadipocytes and 3T3-L1 cells hampered adipogenic differentiation induced by hormonal cocktails. Stable knockdown of Nrf2 in 3T3-L1 cells blocked the enhanced adipogenesis caused by deficiency of kelch-like ECH-associated protein 1 (Keap1), a Cul3-adapter protein that allows for Nrf2 to be ubiquinated and degraded by the 26S protesome complex. In addition, increased production of reactive oxygen species (ROS) and activation of Nrf2 occurred at the very early stage upon adipogenic hormonal challenge in 3T3-L1 cells, followed by an immediate induction of CCAAT/enhancer-binding protein β (C/EBPβ). Knockdown of Nrf2 led to reduced expression of C/EBPβ induced by adipogenic hormonal cocktails, chemical Nrf2 activators or Keap1 silencing. Cebpβ promoter-driven reporter assays and chromatin immunoprecipitation suggested that Nrf2 associates with a consensus antioxidant response element (ARE) binding site in the promoter of the Cebpβ gene during adipogenesis and upregulates its expression. These findings demonstrate a novel role of Nrf2 beyond xenobiotic detoxification and antioxidant response, and suggest that Nrf2 is one of the transcription factors that control the early events of adipogenesis by regulating expression of Cebpβ.
authors.affiliation: Institute for Chemical Safety Sciences, The Hamner Institutes for Health Sciences, Research Triangle Park, NC 27709, USA.
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.forename: Peng
authors.initials: P
authors.lastname: Xue
authors.forename: Yushi
authors.initials: Y
authors.lastname: Bai
authors.forename: Dianxin
authors.initials: D
authors.lastname: Liu
authors.forename: Courtney G
authors.initials: CG
authors.lastname: Woods
authors.forename: Kathy
authors.initials: K
authors.lastname: Yarborough
authors.forename: Jingqi
authors.initials: J
authors.lastname: Fu
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Guifan
authors.initials: G
authors.lastname: Sun
authors.forename: Sheila
authors.initials: S
authors.lastname: Collins
authors.forename: Jefferson Y
authors.initials: JY
authors.lastname: Chan
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Melvin E
authors.initials: ME
authors.lastname: Andersen
authors.forename: Jingbo
authors.initials: J
authors.lastname: Pi
mesh_terms: D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D041721:3T3-L1 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D050156:Adipogenesis; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics* / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D007328:Insulin / Q000494:pharmacology; D000072019:Kelch-Like ECH-Associated Protein 1; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D061251:Primary Cell Culture; D017382:Reactive Oxygen Species / Q000378:metabolism; D020218:Response Elements; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000975:Antioxidants; D022782:CCAAT-Enhancer-Binding Protein-beta; C545013:Cebpb protein, mouse; D003598:Cytoskeletal Proteins; D007328:Insulin; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D003907:Dexamethasone; D008156:Luciferases; D015056:1-Methyl-3-isobutylxanthine