PPARs Integrate the Mammalian Clock and Energy Metabolism

Figure 1

Involvement of PPARs in the transcriptional feedback loops of the mammalian circadian clock. BMAL1:CLOCK/NPAS2 heterodimer activates transcription of PER, CRY, ROR, and REV-ERB via binding to E-box in their promoters. Upon accumulation, PER and CRY dimerize and translocate into the nucleus to repress BMAL1:CLOCK/NPAS2 activity and therefore their own transcription. ROR activates and REV-ERB represses RORE-mediated transcription. These interlocking loops also control numerous output genes in a circadian manner. In addition, PPARs are integrated in this system (shown in yellow). PPARα and PPARγ regulate the expression of BMAL1 and REV-ERB via binding to PPRE in their promoters. PPARα is also a direct target gene of BMAL1. PPARβ/δ is a target for miR-122 whose transcription is inhibited by REV-ERB. Besides, as the PPAR partner, RXR inhibits the transcriptional activity of BMAL1:CLOCK/NPAS2 complex via binding to CLOCK or NPAS2. All PPARs display circadian expression pattern in given tissues; however, it is still not known if γ or β/δ isoform is directly regulated by Bmal1 or if the integration of PPARs in circadian clock system forms a closed loop.