The nuclear hormone receptor, Rev-erb beta operates as a transcriptional silencer. We previously demonstrated that exogenous expression of Rev-erb beta Delta E in skeletal muscle cells increased Srebp-1c mRNA expression. We validated these in vitro observations by injection of an expression vector driving Rev-erb beta Delta E expression into mouse tibialis muscle that resulted in increased Srebp-1c mRNA expression. Paradoxically, Rev-erb beta siRNA expression in skeletal muscle cells repressed Srebp-1c expression, and indicated that Rev-erb beta expression was necessary for Srebp-1c expression. ChIP analysis demonstrated that Rev-erb beta was recruited to the Srebp-1c promoter. Moreover, Rev-erbb trans-activated the Srebp-1c promoter, in contrast, Rev-erb beta efficiently repressed the Rev-erb alpha promoter, a previously characterized target gene. Finally, treatment with the Rev-erb agonist ( hemin) (i) increased the trans-activation of the Srebp-1c promoter by Rev-erb beta; and (ii) increased Rev-erb beta and Srebp-1c mRNA expression. These data suggest that Rev-erb beta has the potential to activate gene expression, and is a positive regulator of Srebp-1c, a regulator of lipogenesis. (C) 2009 Published by Elsevier Inc.