The Orphan Nuclear Receptor Rev-Erbα Is a Peroxisome Proliferator-activated Receptor (PPAR) γ Target Gene and Promotes PPARγ-induced Adipocyte Differentiation*

Abstract

Rev-Erbα (NR1D1) is an orphan nuclear receptor encoded on the opposite strand of the thyroid receptor α gene. Rev-Erbα mRNA is induced during adipocyte differentiation of 3T3-L1 cells, and its expression is abundant in rat adipose tissue. Peroxisome proliferator-activated receptor γ (PPARγ) (NR1C3) is a nuclear receptor controlling adipocyte differentiation and insulin sensitivity. Here we show that Rev-Erbα expression is induced by PPARγ activation with rosiglitazone in rat epididymal and perirenal adipose tissues in vivo as well as in 3T3-L1 adipocytes in vitro. Furthermore, activated PPARγ induces Rev-Erbα promoter activity by binding to the direct repeat (DR)-2 response element Rev-DR2. Mutations of the 5′ or 3′ half-sites of the response element totally abrogated PPARγ binding and transcriptional activation, identifying this site as a novel type of functional PPARγ response element. Finally, ectopic expression of Rev-Erbα in 3T3-L1 preadipocytes potentiated adipocyte differentiation induced by the PPARγ ligand rosiglitazone. These results identify Rev-Erbα as a target gene of PPARγ in adipose tissue and demonstrate a role for this nuclear receptor as a promoter of adipocyte differentiation.