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Review
.2009 Dec;107(6):1972-80.
doi: 10.1152/japplphysiol.00570.2009. Epub 2009 Aug 20.

Rev-erb-alpha: an integrator of circadian rhythms and metabolism

Affiliations
Review

Rev-erb-alpha: an integrator of circadian rhythms and metabolism

Hélène Duez et al. J Appl Physiol (1985).2009 Dec.

Abstract

The endogenous circadian clock ensures daily rhythms in diverse behavioral and physiological processes, including locomotor activity and sleep/wake cycles, but also food intake patterns. Circadian rhythms are generated by an internal clock system, which synchronizes these daily variations to the day/night alternance. In addition, circadian oscillations may be reset by the time of food availability in peripheral metabolic organs. Circadian rhythms are seen in many metabolic pathways (glucose and lipid metabolism, etc.) and endocrine secretions (insulin, etc.). As a consequence, misalignment of the internal timing system vs. environmental zeitgebers (light, for instance), as experienced during jetlag or shift work, may result in disruption of physiological cycles of fuel utilization or energy storage. A large body of evidence from both human and animal studies now points to a relationship between circadian disorders and altered metabolic response, suggesting that circadian and metabolic regulatory networks are tightly connected. After a review of the current understanding of the molecular circadian core clock, we will discuss the hypothesis that clock genes themselves link the core molecular clock and metabolic regulatory networks. We propose that the nuclear receptor and core clock component Rev-erb-alpha behaves as a gatekeeper to timely coordinate the circadian metabolic response.

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Figures

Figure 1
Figure 1
The ‘master’ clock residing in the suprachiasmatic nucleus (SCN) of the hypothalamus drives rhythmic behaviour (sleep/wake, locomotor activity, circadian feeding pattern) and synchronizes many peripheral clocks, which are thought to be important for local rhythmic activity, for instance of hepatic metabolism, cardiovascular function and the endocrine response. Food is also an important time cue for peripheral clocks. Transcriptome analysis in peripheral organs found 3–20% rhythmic genes (58), including genes involved in lipid and glucose metabolism and most of the transcription factors of the nuclear receptor family (86), suggesting a direct interaction between circadian behaviour and metabolic transcriptional networks.
Figure 2
Figure 2
Generation and maintenance of circadian rhythms require a complex interplay of transcriptional/translational feedback regulatory loops. The CLOCK/Bmal1 heterodimer activates transcription of thePer andCry genes via E boxes in their promoter. Per and Cry form a repressive complex which inhibits CLOCK/Bmal1 transcriptional activity, leading to their own repression. An interlocked regulatory loop is formed by Rev-erbα and RORα which compete for the binding to a RORE/RevRE and subsequent regulation (repression vs activation, respectively) ofBmal1. Rhythmic expression of Rev-erbα drives cyclic occupancy of this RORE. Post-translational modification (phosphorylation, ubiquitination, acetylation, and degradation by the proteasome) plays important role for the proper timing of the clock. Intracellular metabolism (through NAD+/SIRT1) and nutrients (through binding to nuclear receptors) impinge on the clock machinery. CK, Casein Kinase.
Figure 3
Figure 3
Rev-erbα binds to RORE/RevRE sites located in the promoter of its target genes. Rev-erbα is critical for the proper timing of the core clock machinery. Rev-erbα also regulates metabolic functions including lipid and bile acid metabolism, adipogenesis, gluconeogenesis, the inflammatory response and thrombosis. Rev-erbα ligands modify its transcriptional activity and suggest that Rev-erbα may constitute a promising target for the treatment of circadian alterations of metabolic pathways. * synthetic ligand: see Meng et al. BP, Blood pressure.
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