Bifunctional role of Rev-erbalpha in adipocyte differentiation

The nuclear receptor Rev-erbalpha is a potent transcriptional repressor that regulates circadian rhythm and metabolism. Here we demonstrate a dissociation between Rev-erbalpha mRNA and protein levels that profoundly influences adipocyte differentiation. During adipogenesis, Rev-erbalpha gene expression initially declines and subsequently increases. Remarkably, Rev-erbalpha protein levels are nearly the opposite, increasing early in adipogenesis and then markedly decreasing in adipocytes. The Rev-erbalpha protein is necessary for the early mitotic events that are required for adipogenesis. The subsequent reduction in Rev-erbalpha protein, due to increased degradation via the 26S proteasome, is also required for adipocyte differentiation because Rev-erbalpha represses the expression of PPARgamma2, the master transcriptional regulator of adipogenesis. Thus, opposite to what might be predicted from Rev-erbalpha gene expression, Rev-erbalpha protein levels must rise and then fall for adipocyte differentiation to occur.