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Inhibition of Adipogenesis by a COOH-Terminally Truncated Mutant of PPARγ2 in 3T3-L1 Cells☆

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Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ2 in thiazolidinedione-induced adipogenesis has now been investigated by expression of a mutant protein (PPARγ2-ΔC) that lacks the COOH-terminal 16 amino acids of full-length PPARγ2. 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 PPARγ2-ΔC inhibited the thiazolidinedione-induced increase in trans-activation activity of endogenous PPARγ in CV-1 cells. Furthermore, the mutant protein prevented thiazolidinedione-induced adipogenesis in 3T3-L1 cells, whereas expression of recombinant wild-type PPARγ2 promoted adipogenesis. These data show not only that the COOH-terminal region of PPARγ2 is indispensable for thiazolidinedione-induced adipogenesis mediated by this protein in 3T3-L1 cells, but also that the PPARγ2-ΔC mutant acts in a dominant negative manner by interfering with the access of endogenous PPARγ to the peroxisome proliferator response element of target genes.

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    Abbreviations used: PPAR, peroxisome proliferator-activated receptor; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; HA, hemagglutinin; GST, glutathione S-transferase; PCR, polymerase chain reaction; RXR retinoid X receptor; RAR, retinoic acid receptor; PPRE, peroxisome proliferator response element; TR, thyroid hormone receptor

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