PPARs Integrate the Mammalian Clock and Energy Metabolism

Abstract

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of numerous target genes. PPARs play an essential role in various physiological and pathological processes, especially in energy metabolism. It has long been known that metabolism and circadian clocks are tightly intertwined. However, the mechanism of how they influence each other is not fully understood. Recently, all three PPAR isoforms were found to be rhythmically expressed in given mouse tissues. Among them, PPAR α and PPAR γ are direct regulators of core clock components, Bmal1 and Rev-erb α , and, conversely, PPAR α is also a direct Bmal1 target gene. More importantly, recent studies using knockout mice revealed that all PPARs exert given functions in a circadian manner. These findings demonstrated a novel role of PPARs as regulators in correlating circadian rhythm and metabolism. In this review, we summarize advances in our understanding of PPARs in circadian regulation.

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.