The cAMP-phosphodiesterase PDE4B2 controls peroxisome proliferator-activated receptor γ (PPARγ) expression and the initiation of adipogenesis in 3T3-L1 cells.

The cAMP-phosphodiesterase 4 (PDE4) family comprises four genes that together are expressed as ~25 protein variants. Non-selective PAN-PDE4 inhibition exerts various metabolic benefits, including reduced body weight and adiposity in humans and animals, but the role of individual PDE4s in mediating these effects remains ill-defined. We noticed that the hormonal induction of adipogenesis in 3T3-L1 pre-adipocytes increased the mRNA and protein expression of a single PDE4 variant, PDE4B2. Conversely, its siRNA-mediated knockdown markedly suppressed adipogenic differentiation and lipid accumulation, suggesting a critical role for PDE4B2 in adipogenesis. The onset of adipogenesis is well understood and involves the consecutive upregulation of pro-adipogenic transcription factors CCAAT-enhancer-binding proteins (C/EBPs) C/EBPδ, C/EBPβ, and C/EBPα, which ultimately induce peroxisome proliferator-activated receptor gamma (PPARγ) as the master regulator of adipogenesis. PDE4B knockdown potently suppressed the upregulation of C/EBPα and PPARγ expression, thereby curbing the early steps in adipogenic differentiation. Mirroring its anti-adipogenic effects in 3T3-L1 cells, PDE4B ablation in mice produces a lean phenotype characterized by reduced adipose tissue weight and reduced expression of C/EBPα and PPARγ. Although PPARγ agonists promote weight gain, they are also effective insulin sensitizers and are used therapeutically to treat type 2 diabetes. Conversely, despite reducing PPARγ expression and adiposity, PDE4B knockout mice exhibit slightly improved glucose homeostasis. Taken together, we show that a PDE4B-dependent regulation of C/EBPα and PPARγ expression is conserved between cell- and animal models. To what extent this mechanism contributes to the overall metabolic phenotypes of targeting PDE4B or PPARγ in vivo remains to be elucidated.