Peroxisome Proliferator-activated Receptor δ (PPARδ)-mediated Regulation of Preadipocyte Proliferation and Gene Expression Is Dependent on cAMP Signaling

Abstract

The peroxisome proliferator-activated receptor γ (PPAR-γ) is a key regulator of terminal adipocyte differentiation. PPARδ is expressed in preadipocytes, but the importance of this PPAR subtype in adipogenesis has been a matter of debate. Here we present a critical evaluation of the role of PPARδ in adipocyte differentiation. We demonstrate that treatment of NIH-3T3 fibroblasts overexpressing PPARδ with standard adipogenic inducers led to induction of PPARγ2 expression and terminal adipocyte differentiation in a manner that was strictly dependent on simultaneous administration of a PPARδ ligand and methylisobutylxanthine (MIX) or other cAMP elevating agents. We further show that ligands and MIX synergistically stimulated PPARδ-mediated transactivation. In 3T3-L1 preadipocytes, simultaneous administration of a PPARδ-selective ligand and MIX significantly enhanced the early expression of PPARγ and ALBP/aP2, but only modestly promoted terminal differentiation as determined by lipid accumulation. Finally, we provide evidence that synergistic activation of PPARδ promotes mitotic clonal expansion in 3T3-L1 cells with or without forced expression of PPARδ. In conclusion, our results suggest that PPARδ may play a role in the proliferation of adipocyte precursor cells, whereas activation of endogenous PPARδ in 3T3-L1 cells appears to have only minor impact on the processes leading to terminal adipocyte differentiation.