The Nuclear Receptor Rev-erbα Regulates Adipose Tissue-specific FGF21 Signaling

FGF21 is an atypical member of the FGF family that functions as a hormone to regulate carbohydrate and lipid metabolism. Here we demonstrate that the actions of FGF21 in mouse adipose tissue, but not in liver, are modulated by the nuclear receptor Rev-erb alpha, a potent transcriptional repressor. Interrogation of genes induced in the absence of Rev-erba for Rev-erb alpha-binding sites identified beta kappa lotho, an essential coreceptor for FGF21, as a direct target gene of Rev-erba in white adipose tissue but not liver. Rev-erba ablation led to the robust elevated expression of beta kappa lotho. Consequently, the effects of FGF21 were markedly enhanced in the white adipose tissue of mice lacking Rev-erb alpha. A major Rev-erb alpha-controlled enhancer at the Klb locus was also bound by the adipocytic transcription factor peroxisome proliferator-activated receptor (PPAR) gamma, which regulates its activity in the opposite direction. These findings establish Rev-erb alpha as a specific modulator of FGF21 signaling in adipose tissue.