title: RARγ-C-Fos-PPARγ2 signaling rather than ROS generation is critical for all-trans retinoic acid-inhibited adipocyte differentiation.
abstract: Obesity has become a worldwide public health problem, which is mainly determined by excess energy intake and adipose tissue expansion. Adipose tissue expansion can occur through hyperplasia (adipocyte differentiation) or hypertrophy. Retinoic acid was shown to inhibit adipocyte differentiation. However, the molecular mechanism is unclear. In the study, we found that all-trans-retinoic acid (ATRA) inhibited 3T3-L1 adipocyte differentiation. We did not observe significant apoptosis in differentiated adipocytes treated by ATRA. ATRA increased ROS generation and disturbed redox balance. However, antioxidant treatment did not ameliorate the reduction of lipid accumulation induced by ATRA, indicating that ROS generation was not involved in ATRA-inhibited adipocyte differentiation. ATRA reduced C/EBPα, PPARγ and its target gene expression. In the presence of ATRA, retinoic acid receptor (RAR) α/γ expression was increased. Inhibition of RARγ, but not RARα, blocked ATRA-induced reduction of PPARγ2 expression. ATRA induced a profound interaction between RARγ and C-Fos protein, reflected by Co-IP results. C-Fos was found to exhibit a differentiation-dependent DNA binding activity to PPARγ2 promoter. RARγ inhibitor significantly suppressed ATRA-inhibited DNA binding activity of C-Fos to PPARγ2 promoter, indicating that downregulation of C-Fos activity mediated activation of RARγ-exerted reduction of PPARγ2 expression and thus inhibition of adipocyte differentiation induced by ATRA. Taken together, these data demonstrates that RARγ-C-Fos-PPARγ2 signaling rather than ROS generation is critical for ATRA-inhibited adipocyte differentiation.
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China. Electronic address: xinwang@fmmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Health Statistics, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jiangzheng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Weihua
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Han
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Toxicology, Shaanxi Key Lab of Free Radical Biology and Medicine, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Xi'an 710032, China. Electronic address: cx-hai@fmmu.edu.cn.
authors.forename: Chunxu
authors.initials: C
authors.lastname: Hai
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001391:Azo Compounds / Q000737:chemistry; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D008055:Lipids / Q000032:analysis / Q000737:chemistry; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014212:Tretinoin / Q000494:pharmacology*; D000097768:Retinoic Acid Receptor gamma
chemical_list: D000970:Antineoplastic Agents; D001391:Azo Compounds; D008055:Lipids; D047495:PPAR gamma; D016760:Proto-Oncogene Proteins c-fos; D017382:Reactive Oxygen Species; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D000097768:Retinoic Acid Receptor gamma; C011049:oil red O
keywords: Adipocyte differentiation; All-trans retinoic acid; C-Fos; Peroxisome proliferator-activated receptors γ; Retinoic acid receptor