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Bifunctional Role of Rev-erb in Adipocyte Differentiation

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine and Department of Genetics, and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104

Received 31 August 2007/ Returned for modification 9 October 2007/ Accepted 20 January 2008

The nuclear receptor Rev-erb is a potent transcriptional repressor that regulates circadian rhythm and metabolism. Here we demonstrate a dissociation between Rev-erb mRNA and protein levels that profoundly influences adipocyte differentiation. During adipogenesis, Rev-erb gene expression initially declines and subsequently increases. Remarkably, Rev-erb protein levels are nearly the opposite, increasing early in adipogenesis and then markedly decreasing in adipocytes. The Rev-erb protein is necessary for the early mitotic events that are required for adipogenesis. The subsequent reduction in Rev-erb protein, due to increased degradation via the 26S proteasome, is also required for adipocyte differentiation because Rev-erb represses the expression of PPAR2, the master transcriptional regulator of adipogenesis. Thus, opposite to what might be predicted from Rev-erb gene expression, Rev-erb protein levels must rise and then fall for adipocyte differentiation to occur.

Published ahead of print on 28 January 2008.