Significance: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that coordinates the basal and stress-inducible activation of a vast array of cytoprotective genes. Unders...

Transcriptional Regulation by Nrf2

Glucose-6-phosphate dehydrogenase deficiency is a genetic disorder that occurs almost exclusively in males. This condition mainly affects red blood cells, which carry oxygen from the lungs to tissues throughout the body. In affected individuals, a defect in an enzyme called glucose-6-phosphate dehydrogenase causes red blood cells to break down prematurely. This destruction of red blood cells is called hemolysis.

Glucose-6-phosphate dehydrogenase deficiency.

A majority of mammalian genes exhibit daily fluctuations in expression levels, making circadian expression rhythms the largest known regulatory network in normal physiology. Cell-autonomous circadian clocks interact with daily light-dark and feeding-fasting cycles to generate approximately 24-hour oscillations in the function of thousands of genes. Circadian expression of secreted molecules and signaling components transmits timing information between cells and tissues. Such intra- and intercellular daily rhythms optimize physiology both by managing energy use and by temporally segregating incompatible processes. Experimental animal models and epidemiological data indicate that chronic circadian rhythm disruption increases the risk of metabolic diseases. Conversely, time-restricted feeding, which imposes daily cycles of feeding and fasting without caloric reduction, sustains robust diurnal rhythms and can alleviate metabolic diseases. These findings highlight an integrative role of circadian rhythms in physiology and offer a new perspective for treating chronic diseases in which metabolic disruption is a hallmark.

http://science.sciencemag.org/content/sci/354/6315/1008.full.pdf

Circadian physiology of metabolism.

Humans, like all mammals, partition their daily behaviour into activity (wakefulness) and rest (sleep) phases that differ largely in their metabolic requirements. The circadian clock evolved as an autonomous timekeeping system that aligns behavioural patterns with the solar day and supports the body functions by anticipating and coordinating the required metabolic programmes. The key component of this synchronization is a master clock in the brain, which responds to light–darkness cues from the environment. However, to achieve circadian control of the entire organism, each cell of the body is equipped with its own circadian oscillator that is controlled by the master clock and confers rhythmicity to individual cells and organs through the control of rate-limiting steps of metabolic programmes. Importantly, metabolic regulation is not a mere output function of the circadian system, but nutrient, energy and redox levels signal back to cellular clocks in order to reinforce circadian rhythmicity and to adapt physiology to temporal tissue-specific needs. Thus, multiple systemic and molecular mechanisms exist that connect the circadian clock with metabolism at all levels, from cellular organelles to the whole organism, and deregulation of this circadian–metabolic crosstalk can lead to various pathologies. Circadian rhythms align organismal functions with phases of rest and activity. Accordingly, circadian oscillations occur in many physiological processes, including various metabolic functions. In turn, metabolic cues are emerging as regulators of the circadian clock. This crosstalk between metabolism and circadian rhythms has important implications for human health.

Crosstalk between metabolism and circadian clocks

Dysfunction in 24-h circadian rhythms is a common occurrence in ageing adults; however, circadian rhythm disruptions are more severe in people with age-related neurodegenerative diseases, including Alzheimer's disease and related dementias, and Parkinson's disease. Manifestations of circadian rhythm disruptions differ according to the type and severity of neurodegenerative disease and, for some patients, occur before the onset of typical clinical symptoms of neurodegeneration. Evidence from preliminary studies suggest that circadian rhythm disruptions, in addition to being a symptom of neurodegeneration, might also be a potential risk factor for developing Alzheimer's disease and related dementias, and Parkinson's disease, although large, longitudinal studies are needed to confirm this relationship. The mechanistic link between circadian rhythms and neurodegeneration is still not fully understood, although proposed underlying pathways include alterations of protein homoeostasis and immune and inflammatory function. While preliminary clinical studies are promising, more studies of circadian rhythm disruptions and its mechanisms are required. Furthermore, clinical trials are needed to determine whether circadian interventions could prevent or delay the onset of neurodegenerative diseases.

Association between circadian rhythms and neurodegenerative diseases.

The Pentose Phosphate Pathway Regulates the Circadian Clock

Summary Circadian rhythms are present in all living organisms. They organise processes such as gene transcription, mitosis, feeding, and rest at different times of day and night. These rhythms are orchestrated by a network of core ‘clock genes’ that are organised into transcription–translation feedback loops (TTFLs), producing oscillations with a period of approximately 24 h. The modern understanding of circadian timekeeping has revolved around the TTFL paradigm. Recently, however, this has been challenged by new findings that redox reactions persist in the absence of gene transcription, and that cycles of oxidation and reduction are conserved across all domain of life. These results suggest that non-transcriptional processes such as metabolic state may interact and work in parallel with the canonical genetic mechanisms of keeping circadian time.

Lisa Wulund

Papers

The Pentose Phosphate Pathway Regulates the Circadian Clock

A brief history of circadian time: The emergence of redox oscillations as a novel component of biological rhythms