title: Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α.
abstract: Brown adipose tissue is important for maintaining energy homeostasis and adaptive thermogenesis in rodents and humans. As disorders arising from dysregulated energy metabolism, such as obesity and metabolic diseases, have increased, so has interest in the molecular mechanisms of adipocyte biology. Using a functional screen, we identified cyclin C (CycC), a conserved subunit of the Mediator complex, as a novel regulator for brown adipocyte formation. siRNA-mediated CycC knockdown (KD) in brown preadipocytes impaired the early transcriptional program of differentiation, and genetic KO of CycC completely blocked the differentiation process. RNA sequencing analyses of CycC-KD revealed a critical role of CycC in activating genes co-regulated by peroxisome proliferator activated receptor γ (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα). Overexpression of PPARγ2 or addition of the PPARγ ligand rosiglitazone rescued the defects in CycC-KO brown preadipocytes and efficiently activated the PPARγ-responsive promoters in both WT and CycC-KO cells, suggesting that CycC is not essential for PPARγ transcriptional activity. In contrast, CycC-KO significantly reduced C/EBPα-dependent gene expression. Unlike for PPARγ, overexpression of C/EBPα could not induce C/EBPα target gene expression in CycC-KO cells or rescue the CycC-KO defects in brown adipogenesis, suggesting that CycC is essential for C/EBPα-mediated gene activation. CycC physically interacted with C/EBPα, and this interaction was required for C/EBPα transactivation domain activity. Consistent with the role of C/EBPα in white adipogenesis, CycC-KD also inhibited differentiation of 3T3-L1 cells into white adipocytes. Together, these data indicate that CycC activates adipogenesis in part by stimulating the transcriptional activity of C/EBPα.
authors.affiliation: From the Laboratory of Animal Fat Deposition and Muscle Development, Department of Animal Sciences, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.|the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and.
authors.forename: Ziyi
authors.initials: Z
authors.lastname: Song
authors.affiliation: the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and.|Departments of Developmental and Molecular Biology.
authors.forename: Alus M
authors.initials: AM
authors.lastname: Xiaoli
authors.affiliation: Genetics, and.
authors.forename: Quanwei
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and.|Departments of Developmental and Molecular Biology.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and.|Departments of Developmental and Molecular Biology.
authors.forename: Ellen S T
authors.initials: EST
authors.lastname: Yang
authors.affiliation: the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Sven
authors.initials: S
authors.lastname: Wang
authors.affiliation: the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
authors.forename: Rui
authors.initials: R
authors.lastname: Chang
authors.affiliation: Genetics, and.
authors.forename: Zhengdong D
authors.initials: ZD
authors.lastname: Zhang
authors.affiliation: From the Laboratory of Animal Fat Deposition and Muscle Development, Department of Animal Sciences, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China, gsyang999@hotmail.com.
authors.forename: Gongshe
authors.initials: G
authors.lastname: Yang
authors.affiliation: the Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey 08055.
authors.forename: Randy
authors.initials: R
authors.lastname: Strich
authors.affiliation: the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and.|Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Pessin
authors.affiliation: the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and fajun.yang@einstein.yu.edu.|Departments of Developmental and Molecular Biology.
authors.forename: Fajun
authors.initials: F
authors.lastname: Yang
mesh_terms: D041721:3T3-L1 Cells; D052437:Adipocytes, Brown / Q000378:metabolism*; D050156:Adipogenesis; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D056745:Cyclin C / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; C503675:Ccnc protein, mouse; D056745:Cyclin C; D047495:PPAR gamma
keywords: C/EBPα; Mediator complex; PPARγ; adipocyte; adipogenesis; brown adipocyte; cell differentiation; cyclin C; gene expression; transcription coregulator