Peroxisome proliferator-activated receptor δ (PPhRδ)-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling

The peroxisome proliferator-activated receiptor gamma (PPAR gamma) is a key regulator of terminal adipocyte differentiation. PPAR delta 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 PPAR delta in adipocyte differentiation. We demonstrate that treatment of NIH-3T3 fibroblasts overexpressing PPAR delta with standard adipogenic inducers led to induction of PPAR gamma2 expression and terminal adipocyte differentiation in a manner that was strictly dependent on simultaneous administration of a PPAR delta ligand and methylisobutylxanthine (MM) or other cAMP elevating agents. We further show that ligands and MM synergistically stimulated PPAR delta -mediated transactivation. In 3T3-L1 preadipocytes, simultaneous administration of a PPAR delta -selective ligand and MM significantly enhanced the early expression of PPAR gamma and ALBP/aP2, but only modestly promoted terminal differentiation as determined by lipid accumulation. Finally, we provide evidence that synergistic activation of PPAR delta promotes mitotic clonal expansion in 3T3-L1 cells with or without forced expression of PPAR delta. In conclusion, our results suggest that PPAR delta may play a role in the proliferation of adipocyte precursor cells, whereas activation of endogenous PPAR delta in 3T3-L1 cells appears to have only minor impact on the processes leading to terminal adipocyte differentiation.