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

The cyclic adenosine monophosphate (cAMP)-phosphodiesterase 4 (PDE4) family comprises four genes that together are expressed as ∼25 protein variants. Nonselective 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 preadipocytes 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 proadipogenic transcription factors CCAAT-enhancer-binding proteins (C/EBPs) C/EBPδ, C/EBPβ, and C/EBPα, which ultimately induce peroxisome proliferator-activated receptor γ (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 antiadipogenic 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.