Induction of Rev-ErbA alpha, an orphan receptor encoded on the opposite strand of the alpha-thyroid hormone receptor gene, during adipocyte differentiation.
Rev-ErbA alpha (Rev-Erb) is a nuclear hormone receptor-related transcriptional 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 adipogenesis. Remarkably, Rev-Erb mRNA levels increased dramatically during the differentiation of 3T3-L1 cells into adipocytes. Rev-Erb was similarly induced in the related 3T3-F442A cell line but not in nondifferentiating 3T3-C2 cells. The time course of Rev-Erb induction was similar to that of C/EBP alpha, an important transcriptional regulator in adipocytes, and Rev-Erb mRNA was superinduced by cycloheximide. Nuclear run-on assays indicated that an increased rate of Rev-Erb mRNA synthesis accounted for the increased steady state mRNA levels; the half-life of Rev-Erb mRNA was indistinguishable in preadipocytes and adipocytes. 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. Interestingly, and possibly related to the overlap between the Rev-Erb gene and the exon specific for TR alpha 2, the induction of Rev-Erb was also associated with a 3-fold increase in the ratio of TR alpha 1 to TR alpha 2 mRNA levels, indicating that Rev-Erb expression has the potential to modulate adipocyte gene expression by multiple mechanisms.
Chawla
A
A
Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Lazar
M A
MA
D016475:3T3 Cells; D000273:Adipose Tissue / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation; D002460:Cell Line; D003513:Cycloheximide / Q000494:pharmacology; D004268:DNA-Binding Proteins; D051379:Mice; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone / Q000235:genetics*; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology
D004268:DNA-Binding Proteins; C498262:Nr1d1 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D014212:Tretinoin; D003513:Cycloheximide