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The Orphan Nuclear Receptor ROR Restrains Adipocyte Differentiation through a Reduction of C/EBPβ Activity and Perilipin Gene Expression

Department of Applied Biological Chemistry (N.O., S.K., Y.T., R.S.), Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan; Basic Research Activities for Innovative Biosciences (N.O., R.S.), Tokyo 105-0001, Japan; and Department of Molecular Health Sciences (H.H.), Graduate School of Pharmaceutical Sciences, Nagoya City University, Nagoya 467-8603, Japan

Address all correspondence and requests for reprints to: Ryuichiro Sato, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan. E-mail: aroysato{at}mail.ecc.u-tokyo.ac.jp.

The nuclear receptor-type transcription factor retinoic acid receptor-related orphan receptor (ROR) is a multifunctional molecule involved in tissue development and cellular function, such as inflammation, metabolism, and differentiation; however, the role of ROR during adipocyte differentiation has not yet been fully understood. Here we show that ROR inhibits the transcriptional activity of CCAAT/enhancer-binding protein β (C/EBPβ) without affecting its expression, thereby blocking the induction of both PPAR and C/EBP, resulting in the suppression of C/EBPβ-dependent adipogenesis. ROR interacted with C/EBPβ so as to repress both the C/EBPβ-p300 association and the C/EBPβ-dependent recruitment of p300 to chromatin. In addition to the inhibitory effect on C/EBPβ function, ROR also prevents the expression of the lipid droplet coating protein gene perilipin by peroxisome proliferators-activated receptor (PPAR), acting through the specific mechanism of its promoter. We identified a suppressive ROR-responsive element overlapping the PPAR-responsive element in the perilipin promoter and verified that ROR competitively antagonizes the binding of PPAR. ROR inhibits PPAR-dependent adipogenesis along with the repression of perilipin induction. These findings suggest that ROR is a novel negative regulator of adipocyte differentiation that acts through dual mechanisms.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARγ  |  REV-ERBα  |  RORα

Coregulators:   p300