The circadian system of mammals is composed of a hierarchy of oscillators that function at the cellular, tissue, and systems levels. A common molecular mechanism underlies the cell-autonomous circadian oscillator throughout the body, yet this clock system is adapted to different functional contexts. In the central suprachiasmatic nucleus (SCN) of the hypothalamus, a coupled population of neuronal circadian oscillators acts as a master pacemaker for the organism to drive rhythms in activity and rest, feeding, body temperature, and hormones. Coupling within the SCN network confers robustness to the SCN pacemaker, which in turn provides stability to the overall temporal architecture of the organism. Throughout the majority of the cells in the body, cell-autonomous circadian clocks are intimately enmeshed within metabolic pathways. Thus, an emerging view for the adaptive significance of circadian clocks is their fundamental role in orchestrating metabolism.

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Central and Peripheral Circadian Clocks in Mammals

To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional “rush hours” preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.

https://www.pnas.org/content/pnas/111/45/16219.full.pdf

A circadian gene expression atlas in mammals: Implications for biology and medicine

Circadian clocks align behavioral and biochemical processes with the day/night cycle. Nearly all vertebrate cells possess self-sustained clocks that couple endogenous rhythms with changes in cellular environment. Genetic disruption of clock genes in mice perturbs metabolic functions of specific tissues at distinct phases of the sleep/wake cycle. Circadian desynchrony, a characteristic of shift work and sleep disruption in humans, also leads to metabolic pathologies. Here, we review advances in understanding the interrelationship among circadian disruption, sleep deprivation, obesity, and diabetes and implications for rational therapeutics for these conditions.

https://science.sciencemag.org/content/sci/330/6009/1349.full.pdf

Circadian Integration of Metabolism and Energetics

Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet

https://pure.rug.nl/ws/files/6779045/2012CurrBiolRoennebergErr.pdf

Social Jetlag and Obesity

During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis — a rhythmic process that is disturbed in people with diabetes. Experiments in mice now show that the pancreatic islets contain their own biological clock, which orchestrates insulin secretion during the sleep–wake cycle. The transcription factors CLOCK and BMAL1 are vital for this process, and mice with defective copies of the genes Clock and Bmal1 develop hypoinsulinaemia and diabetes. By demonstrating that a local tissue clock integrates circadian and metabolic signals in pancreatic β-cells, this work suggests that circadian analyses are crucial for deeper understanding of metabolic phenotypes, as well as for the treatment of metabolic diseases such as type 2 diabetes. Circadian rhythms control many physiological functions. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis — a rhythmic process that is disturbed in people with diabetes. These authors show that pancreatic islets contain their own clock: they have self-sustained circadian oscillations of CLOCK and BMAL1 genes and proteins, which are vital for the regulation of circadian rhythms. Without this clock, a cascade of cellular failure and pathology initiates the onset of diabetes mellitus. The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night1,2,3. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes4, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock5,6 and Bmal17 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective β-cell function at the very latest stage of stimulus–secretion coupling. These results demonstrate a role for the β-cell clock in coordinating insulin secretion with the sleep–wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.

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Shelley Mo

Papers

Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes