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J Biol Chem. 2017 May 26;292(21):8918-8932. doi: 10.1074/jbc.M117.776229. Epub 2017 Mar 28.

Cyclin C regulates adipogenesis by stimulating transcriptional activity of CCAAT/enhancer-binding protein α.

Author information

1
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.
2
the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and.
3
Departments of Developmental and Molecular Biology.
4
Genetics, and.
5
the Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, and.
6
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.
7
the Department of Molecular Biology, Rowan University School of Osteopathic Medicine, Stratford, New Jersey 08055.
8
Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461.
9
the Department of Medicine, Division of Endocrinology and Diabetes Research Center, and fajun.yang@einstein.yu.edu.

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.

KEYWORDS:

C/EBPα; Mediator complex; PPARγ; adipocyte; adipogenesis; brown adipocyte; cell differentiation; cyclin C; gene expression; transcription coregulator

PMID:
28351837
PMCID:
PMC5448125
DOI:
10.1074/jbc.M117.776229
[Indexed for MEDLINE]
Free PMC Article

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