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

The nuclear receptor-type transcription factor retinoic acid receptor-related orphan receptor alpha (ROR alpha) is a multifunctional molecule involved in tissue development and cellular function, such as inflammation, metabolism, and differentiation; however, the role of ROR alpha during adipocyte differentiation has not yet been fully understood. Here we show that ROR alpha inhibits the transcriptional activity of CCAAT/enhancer-binding protein beta (C/EBP beta) without affecting its expression, thereby blocking the induction of both PPAR gamma and C/EBP alpha, resulting in the suppression of C/EBP beta-dependent adipogenesis. ROR alpha interacted with C/EBP alpha so as to repress both the C/EBP beta-p300 association and the C/EBP beta-dependent recruitment of p300 to chromatin. In addition to the inhibitory effect on C/EBP beta function, ROR alpha also prevents the expression of the lipid droplet coating protein gene perilipin by peroxisome proliferators-activated receptor gamma (PPAR gamma), 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 alpha competitively antagonizes the binding of PPAR gamma. ROR alpha inhibits PPAR gamma-dependent adipogenesis along with the repression of perilipin induction. These findings suggest that ROR alpha is a novel negative regulator of adipocyte differentiation that acts through dual mechanisms. (Molecular Endocrinology 23: 759-771, 2009)