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Review
. 2019 Mar 30;20(7):1597.
doi: 10.3390/ijms20071597.

Off the Clock: From Circadian Disruption to Metabolic Disease

Eleonore Maury  1
Affiliations
Review

Off the Clock: From Circadian Disruption to Metabolic Disease

Eleonore Maury. Int J Mol Sci. .

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.

Keywords: adipose tissue; circadian rhythm; high-fat diet; metabolism; molecular clock; nutrients; obesity; suprachiasmatic nucleus.

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Conflict of interest statement

The author declares no conflicts of interests.

Figures

Figure 1
Figure 1
(A) Core molecular clock network. The mammalian circadian clock consists of transcription/ translation feedback loops in which the positive limb (CLOCK or NPAS2 and BMAL1) heterodimerizes and activates the transcription of downstream genes, including Per, Cry, Rorα and Rev-erbα. The negative limb proteins (PERs and CRYs) multimerize and inhibit CLOCK/BMAL1. The phosphorylation of the repressors mediated by Casein Kinases 1 (CK1ε and CK1δ) and AMPK directs these proteins to ubiquitin-mediated proteasomal degradation (which, for CRY1, is regulated by FBXL protein ratios). In a secondary loop, Bmal1 is regulated by the repressor REV-ERBα and its opposing nuclear receptor RORα, which bind competitively to the shared element RORE, thus repressing or activating the transcription of the Bmal1 gene, respectively (reviewed in [5]). An additional level of circadian regulation exists with CRYs and PERs, which have been reported to bind independently of other core-clock factors to genomic sites enriched with Nuclear Receptor (NR) recognition motifs (response element, RE) [6,7,8,9]. Post-translational modifications of core-clock factors can also regulate transcription (e.g., deacetylation of BMAL1 or PER2 by SIRT1 [10,11]). (B) Regulation of clock-controlled genes. Cell-type and tissue-specific transcription factors bind to specific enhancers and/or respond to specific environmental signals and to chromatin accessibility (regulated by covalent modifications of DNA and histone tails, including histone acetyltransferases such as CBP [12,13], histone deacetylases such as SIRT6 [14], the histone lysine demethylase JARID1a [15], and the histone methyltransferase MLL3 [16], which activate transcription). Transcription factors can compete for CLOCK/BMAL1 binding (e.g., bHLH-ZIP factor USF1 [17], inflammatory factor NF-κB [18], nuclear receptor HNF4A [19], MYC oncogenic factor [20] or through chromatin remodeling (for example the recruitment of the HDAC3 co-repressor by REV-ERBα to regulate BMAL1 binding [21]) or through cooperative effects (lineage-determining transcription factors such as PDX1 [22] or hypoxia-induced HIF1α act synergistically with BMAL1 [23]), thus potentiating or inhibiting the metabolic outputs.
Figure 2
Figure 2
Anatomy of the suprachiasmatic nucleus. A schematic of a coronal slice of the mouse brain showing the location of the suprachiasmatic nucleus (SCN) in the hypothalamus above the optical chiasma (OC). The detailed portion shows the distinct anatomical sections of the SCN. The dorsal and ventral SCN are in pink and blue respectively. Subsets of SCN neurons are shown on the right: GABA+ (yellow), VIP+ (green), AVP+ (red), SAAS+ (gold) and GRP+ (purple) are expressed in the dorsal SCN. DRD1a+ (most SCN cells) and NMS+ neurons (~40%) are not shown. HC- Hippocampus, 3V- third ventricle.
Figure 3
Figure 3
From circadian synchrony in physiological processes to circadian disruption in metabolic diseases. In mammals, circadian clocks are found in all major organ and tissues. The mammalian circadian pacemaker is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN coordinates all of the cell autonomous oscillations in the peripheral tissues to maintain robustly rhythmic behavioral and physiological phenotypes. The coordination between behavioral (i.e., sleep–wake, feeding–fasting) and metabolic responses with the light/dark cycle involves the autonomic innervation and/or endocrine signals. During circadian misalignment induced by chronic jet lag, irregular eating times, high-fat feeding, abnormal sleep patterns, the peripheral tissues and the brain fail to receive the appropriate signals at the optimal time of the day, thereby potentiating the development of metabolic diseases. The main references (studies in mice and/or humans) are indicated.
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