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

Abstract

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

Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis

“…First, consistent with the earlier study [72], it was observed that Ror˛ was induced during the differentiation of 3T3-L1 mouse adipocytes, but unusually, the time course of induction was delayed in comparison with other early markers of adipogenesis [77,78]. Using either siRNA knockdown of Ror˛ in 3T3-L1 cells [78] or ex vivo mouse embryonic fibroblasts (MEF) derived from sg/sg mice [77], both groups demonstrated improved adipogenesis upon differentiation.…”

Rorα deficiency and decreased adiposity are associated with induction of thermogenic gene expression in subcutaneous white adipose and brown adipose tissue

“…Furthermore, sg/sg mice display reduced adiposity, increased metabolic rate, improved insulin sensitivity, resistance to diet-induced obesity, and hepatic steatosis (17,18). However, studies utilizing either 3T3-L1 cells or sg/sg MEF cells have indicated a contrary role whereby attenuation of Ror␣ enhanced adipogenesis (11,30). Therefore, we investigated overall body composition and adi-posity [by dual-energy X-ray absorptiometry (DEXA) and MRI] and then analyzed adipose tissue samples [by quantative PCR (qPCR) and Western blotting], comparing sg/sg mice with their wild-type (WT) counterparts.…”

Nonreceptor tyrosine phosphatase Shp2 promotes adipogenesis through inhibition of p38 MAP kinase

“…Peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding proteins (C/EBPs) are master transcription factors involved in adipogenesis and obesity development (6)(7)(8). Moreover, p300, a histone acetyltransferase (9), has been shown to promote adipogenesis through regulation of PPARγ and C/EBPβ expression (10,11). Despite a wealth of knowledge at the transcription level (5), intracellular signaling cascades underlying adipogenesis are not fully understood, with fragmented or controversial data in the literature (12)(13)(14).…”