mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer.

TLDR

An adipocyte enhancer in the aP2 gene is regulated by the cell‑type restricted factor ARF6, which binds a DR‑1 motif recognized by RXR/PPAR heterodimers. The study cloned a novel peroxisome proliferator‑activated receptor, mPPARγ2, and demonstrated that it forms a functional ARF6 complex with RXRα. mPPARγ2, expressed early during adipocyte differentiation, heterodimerizes with RXRα to bind ARF6 sites and activate the aP2 enhancer, with activity potentiated by fatty acids, peroxisome proliferators, and 9‑cis retinoic acid. These results establish mPPARγ2 as the first adipocyte‑specific transcription factor and suggest that lipids such as fatty acids, peroxisome proliferators, and retinoic acid regulate adipocyte gene expression and differentiation.

Abstract

Previously, we have isolated and characterized an enhancer from the 5'-flanking region of the adipocyte P2 (aP2) gene that directs high-level adipocyte-specific gene expression in both cultured cells and transgenic mice. The key regulator of this enhancer is a cell type-restricted nuclear factor termed ARF6. Target sequences for ARF6 in the aP2 enhancer exhibit homology to a direct repeat of hormone response elements (HREs) spaced by one nucleotide; this motif (DR-1) has been demonstrated previously to be the preferred binding site for heterodimers of the retinoid X receptor (RXR) and the peroxisome proliferator-activated receptor (PPAR). We have cloned a novel member of the peroxisome proliferator-activated receptor family designated mPPAR gamma 2, and we demonstrate that a heterodimeric complex of mPPAR gamma 2 and RXR alpha constitute a functional ARF6 complex. Expression of mPPAR gamma 2 is induced very early during the differentiation of several cultured adipocyte cell lines and is strikingly adipose-specific in vivo. mPPAR gamma 2 and RXR alpha form heterodimers on ARF6-binding sites in vitro, and antiserum to RXR alpha specifically inhibits ARF6 activity in adipocyte nuclear extracts. Moreover, forced expression of mPPAR gamma 2 and RXR alpha activates the adipocyte-specific aP2 enhancer in cultured fibroblasts, and this activation is potentiated by peroxisome proliferators, fatty acids, and 9-cis retinoic acid. These results identify mPPAR gamma 2 as the first adipocyte-specific transcription factor and suggest mechanisms whereby fatty acids, peroxisome proliferators, 9-cis retinoic acid, and other lipids may regulate adipocyte gene expression and differentiation.