Off the Clock: From Circadian Disruption to Metabolic Disease.

Eleonore Maury

doi:10.3390/ijms20071597

Abstract

Circadian timekeeping allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment. Evidence from animal genetic models and from humans under circadian misalignment (such as shift work or jet lag) shows that disruption of circadian rhythms contributes to the development of obesity and metabolic disease. Inappropriate timing of food intake and high-fat feeding also lead to disruptions of the temporal coordination of metabolism and physiology and subsequently promote its pathogenesis. This review illustrates the impact of genetically or environmentally induced molecular clock disruption (at the level of the brain and peripheral tissues) and the interplay between the circadian system and metabolic processes. Here, we discuss some mechanisms responsible for diet-induced circadian desynchrony and consider the impact of nutritional cues in inter-organ communication, with a particular focus on the communication between peripheral organs and brain. Finally, we discuss the relay of environmental information by signal-dependent transcription factors to adjust the timing of gene oscillations. Collectively, a better knowledge of the mechanisms by which the circadian clock function can be compromised will lead to novel preventive and therapeutic strategies for obesity and other metabolic disorders arising from circadian desynchrony.

Highlights

The Mammalian Molecular Clockwork: A Short StoryCircadian timekeeping is a ubiquitous feature of most organisms that allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment [1]
Circadian timekeeping allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment
CRY1 itself is able to bind to the transactivation domain (TAD) of BMAL1 at sites that overlap with the binding sites of the coactivator, histone acetyltransferase CREB-binding protein (CBP), and its homolog p300, to switch off transcriptional activation by CLOCK/BMAL1 [4]

Summary

The Mammalian Molecular Clockwork: A Short Story

Circadian timekeeping is a ubiquitous feature of most organisms that allows appropriate temporal regulation of an organism’s internal metabolism to anticipate and respond to recurrent daily changes in the environment [1]. The impact of HFD feeding is tissue-specific, and a surprising observation from this study is the induction of ~100 de novo oscillating lipids to the SCN, while by comparison, another brain region (the medial prefrontal cortex) lost oscillating lipids [182] Whether such lipid changes impact CLOCK and BMAL1 binding at the chromatin level either in pacemaker neurons or in astrocytes, as well as the induction of surrogate transcriptional regulatory pathways in these cells, needs to be further explored. A recent study completed these observations by showing that REV-ERBα rhythmically binds to O-GlcNAc transferase to regulate ten-of-eleven translocation (TET) enzymes and DNA hydroxymethylated cytosine (5hmC) levels in the vicinity of REV-ERBα genomic binding sites, reciprocally [217] In addition to these metabolic sensors, oxygen, via hypoxia-inducible factor 1α (HIF1α) activation, is a resetting cue for circadian clocks [23,218,219,220]. Because IKK/NF-κB is an important physiological contributor to the hypoxic response, linking it to innate immunity and inflammation by playing a key role in HIF1α accumulation under hypoxic conditions [221], it would be relevant to further examine the link between these pathways in the regulation of circadian behavior

The Emerging Field of Chrono-Pharmacology

Findings

Conclusions