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

• Published in: The Journal of biological chemistry Vol. 276; no. 5; pp. 3175 - 3182
• Main Authors: Hansen, Jacob B., Zhang, Hongbin, Rasmussen, Thomas H., Petersen, Rasmus K., Flindt, Esben N., Kristiansen, Karsten
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.02.2001
• Subjects: 1-Methyl-3-isobutylxanthine - pharmacology; 3T3 Cells; Adipocytes - cytology; Adipocytes - physiology; Animals; Cell Differentiation - drug effects; Cell Division - physiology; Cyclic AMP - metabolism; Gene Expression; Mice; Mitosis - physiology; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Cytoplasmic and Nuclear - physiology; Signal Transduction - physiology; Transcription Factors - metabolism; Transcription Factors - physiology; Transcriptional Activation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M005567200

The peroxisome proliferator-activated receptor γ (PPARγ) 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.