The Orphan Nuclear Receptor Rev-Erbα Is a Peroxisome Proliferator-activated Receptor (PPAR) γ Target Gene and Promotes PPARγ-induced Adipocyte Differentiation

Abstract

Rev-Erb␣ (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor ␣ gene. Rev-Erb␣ mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor ␥ (PPAR␥) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erb␣ expression is induced by PPAR␥ activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Adipocyte differentiation is a complex biological process, which is reflected at the molecular level by the transcriptional activation of a number of adipocyte-specific genes and by the acquisition of the ability to accumulate cytoplasmic lipid droplets (1-3). The nuclear receptor peroxisome proliferator-activated receptor ␥ (PPAR␥, 1 NR1C3) (4, 5) and members of the CCAAT enhancer-binding protein (C/EBP) family (6 -12) play key roles in this adipogenic process. In addition, the adipocyte differentiation and determination factor-1 (SREBP-1/ADD1) appears to promote adipocyte differentiation by activating the expression of PPAR␥ and increasing the synthesis of endogenous PPAR␥ ligands (13-15). Members of the PPAR family bind as heterodimers with the retinoid X receptors (RXR) to specific response elements termed peroxisome proliferator response elements (PPRE) (for review see Ref. 16). These PPREs usually consist of a direct repeat of the PuGGTCA motif spaced by one nucleotide (DR1). The transcriptional activity of the PPARs is activated by a number of different fatty acid metabolites, most notably products of the cycloxygenase and lipoxygenase pathways. In addition, a large number of synthetic compounds are known to be potent and subtype specific PPAR ligands. For example, thiazolidinedione compounds used as insulin sensitizers in the treatment of type II diabetes are high affinity PPAR␥ ligands (17).Rev-Erb␣ (NR1D1) is another nuclear receptor, the expression of which is induced during adipocyte differentiation (18). Rev-Erb␣ is highly expressed in adipose tissue but also in skeletal muscle, liver and brain (18 -21). Since no ligand has been identified so far, Rev-Erb␣ is considered as an orphan member of the nuclear receptor superfamily. Rev-Erb␣ has been shown to act as a negative regulator of transcription (22) binding either as monomer on nuclear receptor half-site motifs flanked 5Ј by an A/T rich sequence (A/T PuGGTCA), or as a homodimer to a direct repeat of the PuGGTCA motif spaced by two nucleotides (DR2).We have previously shown that PPAR␣ activates the expression of Rev-Erb␣ through an atypical PPRE, a DR-2 element, in the Rev-Erb␣ promoter (23). Transcriptional activation by PPAR␥ through a DR-2 element has so far not been reported. However, since Rev-Erb␣ is induced during the course of adipocyte differentiation, we decided to investigate whether PPAR␥ could be involved in transcriptional induction of RevErb␣ expression in adipocytes. Furth...

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

“…mé~ê~ expression is phase shifted in response to a RF schedule and mé~ê~ âåçÅâJ çìí mice show altered phase shifts in brown adipose tissue and heart after RF, implying that this NR might be one of the molecular mediators of food entrainment (Goh=et alK, 2007). Similar functions as for PPARA have also been proposed for its close relative PPARG (Fontaine et al, 2003). A known PPARinteracting factor is PGC-1α (PPARGC1A), a transcriptional coactivator that plays a critical role in the maintenance of energy metabolism in a number of tissues.…”

PPARs Integrate the Mammalian Clock and Energy Metabolism

“…Notably, REV-ERB α , a target gene of PPAR γ [45], is one of the core clock components, although there has not been a direct evidence showing that PPAR γ exerts circadian function via REV-ERB α yet. PPAR γ coactivator 1 α (PGC-1 α ) is also identified as a circadian factor.…”

High Affinity Heme Binding to a Heme Regulatory Motif on the Nuclear Receptor Rev-erbβ Leads to Its Degradation and Indirectly Regulates Its Interaction with Nuclear Receptor Corepressor

“…Although peroxisome proliferator-activated receptor ␥ induces the high levels of Rev-erb␣ necessary for the early stages of preadipocyte differentiation (93), repression of peroxisome proliferator-activated receptor ␥2 and proteasomal degradation of Rev-erb␣ are required for later differentiation stages (85). Heme levels increase throughout adipogenesis at a rate closely matching that of Rev-erb␣ degradation.…”