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.
Copyright 1999 Academic Press.