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Review
. 2015 Jan 9;290(2):755-61.
doi: 10.1074/jbc.R114.619957. Epub 2014 Dec 1.

Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) β

Liang Guo  1 , Xi Li  1 , Qi-Qun Tang  2
Affiliations
Review

Transcriptional regulation of adipocyte differentiation: a central role for CCAAT/enhancer-binding protein (C/EBP) β

Liang Guo et al. J Biol Chem. .

Abstract

A detailed understanding of the processes controlling adipogenesis is instrumental in the fight against the obesity epidemic. Adipogenesis is controlled by a transcriptional cascade composed of a large number of transcriptional factors, among which CCAAT/enhancer-binding protein (C/EBP) β plays an essential role. During 3T3-L1 adipocyte differentiation, C/EBPβ is induced early to transactivate the expression of C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ), two master transcription factors for terminal adipocyte differentiation. Studies in recent years have revealed many new target genes of C/EBPβ, implicating its participation in many other processes during adipogenesis, such as mitotic clonal expansion, epigenetic regulation, unfolded protein response, and autophagy. Moreover, the function of C/EBPβ is highly regulated by post-translational modifications, which are crucial for the proper activation of the adipogenic program. Advances toward elucidation of the function and roles of the post-translational modification of C/EBPβ during adipogenesis will greatly improve our understanding of the molecular mechanisms governing adipogenesis.

Keywords: Autophagy; CCAAT-Enhancer-binding Protein (C/EBP); Cell Proliferation; Epigenetics; Post-translational Modification (PTM); Unfolded Protein Response (UPR); adipogenesis.

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Figures

FIGURE 1.
FIGURE 1.
Multiple roles of C/EBPβ during adipogenesis. Besides its well known function in the direct transactivation of C/EBPα and PPARγ, many new roles of C/EBPβ during adipogenesis have been revealed in the past decade. At the early stage of 3T3-L1 adipocyte differentiation, C/EBPβ transactivates the expression of multiple cell cycle-related genes to facilitate MCE, a required step for terminal adipocyte differentiation. A novel feed forward mechanism involving C/EBPβ and Kdm4b in the regulation of MCE is illustrated. Moreover, C/EBPβ transiently transactivates the expression of G9a, which delays the expression of C/EBPα and PPARγ, two anti-proliferation factors, so as to ensure MCE. The transactivation of Kdm4b (a histone demethylase) and G9a (a histone methyltransferase) by C/EBPβ provides evidence for the epigenetic control of MCE by C/EBPβ. At the late stage of 3T3-L1 adipocyte differentiation, C/EBPβ is involved in the activation of UPR and autophagy, through the transactivation of Xbp1 and Atg4b, respectively. In addition, C/EBPβ activates the expression of some other transcriptional factors and inhibits the expression of Wnt10b, an anti-adipogenic factor. Together, these effects ultimately lead to the activation or up-regulation of C/EBPα and PPARγ, thereby promoting terminal adipocyte differentiation. Black solid lines with arrowheads or blunt ends indicate transcriptional regulation of gene expression. Black dashed lines with arrowheads indicate promotion of activity. A black dashed line with a blunt end indicates inhibition of protein stability. Blue dashed lines with arrowheads indicate promotion of biological processes.
FIGURE 2.
FIGURE 2.
The PTMs of C/EBPβ during adipogenesis. A, phosphorylation. C/EBPβ is phosphorylated on Thr-188 by MAPK (2–12 h after adipogenic induction) and by CDK2 (12–24 h after adipogenic induction), followed by GSK3β-mediated phosphorylation on Ser-184 or Thr-179. This dual phosphorylation induces conformational changes in C/EBPβ, which activates its DNA binding and facilitates adipogenesis. B, O-GlcNAcylation. The modification of O-GlcNAc on Ser-180 and Ser-181 of C/EBPβ prevents its phosphorylation on Thr-188, Ser-184, and Thr-179, thus suppressing its DNA binding activity. OGA, β-N-acetylglucosaminidase; OGT, β-N-acetylglucosaminyltransferase. C, acetylation. In general, acetylation of C/EBPβ increases its transcriptional activity to promote adipogenesis. D, methylation. PRMT4/CARM1 dimethylates C/EBPβ on Arg-3, which interferes with the interaction between C/EBPβ and SWI/SNF and inhibits adipogenesis. MAPK/CDK2-mediated phosphorylation on Thr-188 could block PRMT4/CARM1-mediated dimethylation of C/EBPβ on Arg-3. E, SUMOlation and ubiquitination. PIAS1-mediated SUMOlation of C/EBPβ on Lys-133 promotes its ubiquitination and proteasomal degradation, thereby suppressing adipogenesis. SUMO-specific protease SENP2 reverses the SUMOlation of C/EBPβ to promote adipogenesis. The cross-talks between different types of PTMs are indicated by red solid lines with arrowheads or blunt ends. The black solid lines with arrowheads at both ends indicate protein interaction.
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