The REV-ERB Nuclear Receptors: Timekeepers for the Core Clock Period and Metabolism

Abstract

REV-ERB nuclear receptors are potent transcriptional repressors that play an important role in the core mammalian molecular clock and metabolism. Deletion of both REV-ERBα and its largely redundant isoform REV-ERBβ in a murine tissue-specific manner have shed light on their specific functions in clock mechanisms and circadian metabolism. This review highlights recent findings that establish REV-ERBs as crucial circadian timekeepers in a variety of tissues, regulating overlapping and distinct processes that maintain normal physiology and protect from metabolic dysfunction.

Keywords: REV-ERB; circadian rhythms; desynchrony; lipids; metabolism; molecular clocks; nuclear receptors.

Figure 1.

Hierarchical model of the circadian system and core clock machinery. Endogenous biological timekeeping is mediated by a clock mechanism involving transcriptional and translational feedback loops, in which REV-ERBs function as transcriptional repressors (upper right). Genes that are rhythmically expressed due to regulated by the highly circadian core clock transcription factors, either alone or in combination, are referred to as clock controlled genes (CGCs). The circadian system is hierarchically organized with a master clock located in the SCN (center) which integrates light/dark cycles and synchronizes peripheral clocks through the regulation of temporal activity as well as neuronal and hormonal signals.

Figure 2.

REV-ERB, timekeepers for the core clock period and metabolism. REV-ERBα and REV-ERBβ act as timekeepers for the circadian homeostasis at several levels. In the SCN master clock, REV-ERBs regulate the master clock period while REV-ERBs regulate diurnal feeding behaviors in the hypothalamus and circadian metabolism in peripheral organs. Altogether, considering the communication across central and peripheral clocks through endocrine, nervous, and behavioral signals, the timekeeper functions of REV-ERBs at both the central and peripheral level are essential to maintain overall circadian homeostasis.