Inhibition of adipogenesis by a COOH-terminally truncated mutant of PPARgamma2 in 3T3-L1 cells.
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor that is thought to be an important regulator of adipocyte differentiation. This ligand-dependent transcription factor is also activated by thiazolidinediones, a new class of synthetic antidiabetic drugs, resulting in a marked adipogenic response in cultured cells and enhanced insulin sensitivity in vivo. The importance of the COOH-terminal region of PPARgamma2 in thiazolidinedione-induced adipogenesis has now been investigated by expression of a mutant protein (PPARgamma2-DeltaC) that lacks the COOH-terminal 16 amino acids of full-length PPARgamma2. The mutant protein failed to bind a thiazolidinedione ligand, but its ability to bind the peroxisome proliferator response element was similar to that of the wild-type protein. Expression of PPARgamma2-DeltaC inhibited the thiazolidinedione-induced increase in trans-activation activity of endogenous PPARgamma in CV-1 cells. Furthermore, the mutant protein prevented thiazolidinedione-induced adipogenesis in 3T3-L1 cells, whereas expression of recombinant wild-type PPARgamma2 promoted adipogenesis. These data show not only that the COOH-terminal region of PPARgamma2 is indispensable for thiazolidinedione-induced adipogenesis mediated by this protein in 3T3-L1 cells, but also that the PPARgamma2-DeltaC mutant acts in a dominant negative manner by interfering with the access of endogenous PPARgamma to the peroxisome proliferator response element of target genes.
Masugi
J
J
Second Department of Internal Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
Tamori
Y
Y
Kasuga
M
M
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D017353:Gene Deletion; D051379:Mice; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects
D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C089946:2,4-thiazolidinedione