Ajuba functions as a co-activator of C/EBPβ to induce expression of PPARγ and C/EBPα during adipogenesis

Abstract

Adipogenesis is regulated by a complicated network of transcription factors among which PPARγ and C/EBP family members are the major regulators. During adipogenesis, C/EBPβ is induced early and then transactivates PPARγ and C/EBPα, which cooperatively induce genes whose expressions give rise to the mature adipocyte phenotype. Identifying the factors that influence the expression and activity of C/EBPβ should provide additional insight into the mechanisms regulating adipogenesis. Here, we demonstrate that depletion of Ajuba in 3T3-L1 cells significantly decreases mRNA and protein levels of PPARγ and C/EBPα and impairs adipocyte differentiation, while overexpression increases expression of these genes and promotes adipocyte differentiation. Moreover, restoration of C/EBPα or PPARγ expression in Ajuba-deficient 3T3-L1 cells improves the impaired lipid accumulation. Mechanistically, Ajuba interacts with C/EBPβ and recruits CBP to facilitate the binding of C/EBPβ to the promoter of PPARγ and C/EBPα, resulting in increased H3 histone acetylation and target gene expression. Collectively, these data indicate that Ajuba functions as a co-activator of C/EBPβ, and may be an important therapeutic target for combating obesity-related diseases.

Keywords: Adipogenesis; Ajuba; C/EBPα; C/EBPβ; PPARγ.