Bifunctional role of Rev-erbα in adipocyte differentiation

The nuclear receptor Rev-erb alpha is a potent transcriptional repressor that regulates circadian rhythm and metabolism. Here we demonstrate a dissociation between Rev-erb alpha mRNA and protein levels that profoundly influences adipocyte differentiation. During adipogenesis, Rev-erb alpha gene expression initially declines and subsequently increases. Remarkably, Rev-erb alpha protein levels are nearly the opposite, increasing early in adipogenesis and then markedly decreasing in adipocytes. The Rev-erb alpha protein is necessary for the early mitotic events that are required for adipogenesis. The subsequent reduction in Rev-erb alpha protein, due to increased degradation via the 26S proteasome, is also required for adipocyte differentiation because Rev-erb alpha represses the expression of PPAR gamma 2, the master transcriptional regulator of adipogenesis. Thus, opposite to what might be predicted from Rev-erb alpha gene expression, Rev-erb alpha protein levels must rise and then fall for adipocyte differentiation to occur.