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

TY - JOUR

T1 - Peroxisome proliferator-activated receptor delta (PPARdelta )-mediated regulation of preadipocyte proliferation and gene expression is dependent on cAMP signaling

AU - Hansen, Jacob B.

AU - Zhang, H

AU - Rasmussen, T H

AU - Petersen, R K

AU - Flindt, E N

AU - Kristiansen, K

N1 - Keywords: 1-Methyl-3-isobutylxanthine; 3T3 Cells; Adipocytes; Animals; Cell Differentiation; Cell Division; Cyclic AMP; Gene Expression; Mice; Mitosis; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Transcription Factors; Transcriptional Activation

PY - 2001

Y1 - 2001

N2 - The peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of terminal adipocyte differentiation. PPARdelta 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 PPARdelta in adipocyte differentiation. We demonstrate that treatment of NIH-3T3 fibroblasts overexpressing PPARdelta with standard adipogenic inducers led to induction of PPARgamma2 expression and terminal adipocyte differentiation in a manner that was strictly dependent on simultaneous administration of a PPARdelta ligand and methylisobutylxanthine (MIX) or other cAMP elevating agents. We further show that ligands and MIX synergistically stimulated PPARdelta-mediated transactivation. In 3T3-L1 preadipocytes, simultaneous administration of a PPARdelta-selective ligand and MIX significantly enhanced the early expression of PPARgamma and ALBP/aP2, but only modestly promoted terminal differentiation as determined by lipid accumulation. Finally, we provide evidence that synergistic activation of PPARdelta promotes mitotic clonal expansion in 3T3-L1 cells with or without forced expression of PPARdelta. In conclusion, our results suggest that PPARdelta may play a role in the proliferation of adipocyte precursor cells, whereas activation of endogenous PPARdelta in 3T3-L1 cells appears to have only minor impact on the processes leading to terminal adipocyte differentiation.

AB - The peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of terminal adipocyte differentiation. PPARdelta 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 PPARdelta in adipocyte differentiation. We demonstrate that treatment of NIH-3T3 fibroblasts overexpressing PPARdelta with standard adipogenic inducers led to induction of PPARgamma2 expression and terminal adipocyte differentiation in a manner that was strictly dependent on simultaneous administration of a PPARdelta ligand and methylisobutylxanthine (MIX) or other cAMP elevating agents. We further show that ligands and MIX synergistically stimulated PPARdelta-mediated transactivation. In 3T3-L1 preadipocytes, simultaneous administration of a PPARdelta-selective ligand and MIX significantly enhanced the early expression of PPARgamma and ALBP/aP2, but only modestly promoted terminal differentiation as determined by lipid accumulation. Finally, we provide evidence that synergistic activation of PPARdelta promotes mitotic clonal expansion in 3T3-L1 cells with or without forced expression of PPARdelta. In conclusion, our results suggest that PPARdelta may play a role in the proliferation of adipocyte precursor cells, whereas activation of endogenous PPARdelta in 3T3-L1 cells appears to have only minor impact on the processes leading to terminal adipocyte differentiation.

U2 - 10.1074/jbc.M005567200

DO - 10.1074/jbc.M005567200

M3 - Journal article

C2 - 11069900

SN - 0021-9258

VL - 276

SP - 3175

EP - 3182

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 5

ER -