Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily, and is an important regulator of adipogenesis and adipocyte gene expression. PPARgamma exists as two isoforms, PPARgamma1 and PPARgamma2, that differ only in their N termini. Both isoforms are activated by ligands that include the antidiabetic thiazoladinedione drugs and 15-deoxy-Delta12, 14-prostaglandin J2, and potential differences in their function have yet to be described. We report that, in addition to a ligand-activated transcriptional activity, when studied under conditions of ligand depletion, intact PPARgamma has a ligand-independent activation domain. To identify the basis for this ligand-independent activation, we used GAL4-PPARgamma chimeric expression constructs and UAS-TK-LUC in CV1 cells and isolated rat adipocytes. In both cell systems, isolated PPARgamma1 and PPARgamma2 N termini have activation domains, and the activation function of PPARgamma2 is 5-6-fold greater than that of PPARgamma1. Insulin enhances the transcriptional effect mediated by both PPARgamma1 and PPARgamma2 N-terminal domains. These data demonstrate that 1) PPARgamma has an N-terminal (ligand-independent) activation domain; 2) PPARgamma1 and PPARgamma2 N termini have distinct activation capacities; and 3) insulin can potentiate the activity of the N-terminal domain of PPARgamma.
Werman
A
A
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Hollenberg
A
A
Solanes
G
G
Bjorbaek
C
C
Vidal-Puig
A J
AJ
Flier
J S
JS
D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D008024:Ligands; D008297:Male; D008830:Microbodies / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000378:metabolism; D011465:Prostaglandins, Synthetic / Q000378:metabolism; D011487:Protein Conformation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; C052130:GAL4 protein, S cerevisiae; D007328:Insulin; D008024:Ligands; D009687:Nuclear Proteins; D011465:Prostaglandins, Synthetic; D018160:Receptors, Cytoplasmic and Nuclear; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; C040810:9-deoxy-9,10-didehydro-12,13-didehydro-13,14-dihydroprostaglandin D2; D004247:DNA; D015230:Prostaglandin D2