INDUCTION OF REV-ERBA-ALPHA, AN ORPHAN RECEPTOR ENCODED ON THE OPPOSITE STRAND OF THE ALPHA-THYROID HORMONE-RECEPTOR GENE, DURING ADIPOCYTEDIFFERENTIATION

Rev-ErbAalpha (Rev-Erb) is a nuclear hormone receptor-related transcri ptional activator that is encoded on the noncoding strand of the alpha -thyroid hormone receptor (TR) gene. The similarities between Rev-Erb and receptors for differentiating agents, as well as the abundance of Rev-Erb mRNA in fat, led us to study Rev-Erb gene expression during ad ipogenesis. Remarkably, Rev-Erb mRNA levels increased dramatically dur ing the differentiation of 3T3-L1 cells into adipocytes. Rev-Erb was s imilarly induced in the related 3T3-F442A cell line but not in nondiff erentiating 3T3-C2 cells. The time course of Rev-Erb induction was sim ilar to that of C/EBPalpha, an important transcriptional regulator in adipocytes, and Rev-Erb mRNA was superinduced by cycloheximide. Nuclea r run-on assays indicated that an increased rate of Rev-Erb mRNA synth esis accounted for the increased steady state mRNA levels; the half-li fe of Rev-Erb mRNA was indistinguishable in preadipocytes and adipocyt es. Treatment of preadipocytes with retinoic acid inhibited adipocyte differentiation and also prevented Rev-Erb induction. Thus, there is a correlation between Rev-Erb gene expression and differentiation, and transcriptional regulation by Rev-Erb could play an important role in the generation and/or maintenance of the adipocyte phenotype. Interest ingly, and possibly related to the overlap between the Rev-Erb gene an d the exon specific for TRalpha2, the induction of Rev-Erb was also as sociated with a 3-fold increase in the ratio of TRalpha1 to TRalpha2 m RNA levels, indicating that Rev-Erb expression has the potential to mo dulate adipocyte gene expression by multiple mechanisms.