USF1 regulates sleep and circadian traits in humans
Hanna M. OllilaHarri LittowJillyn TurunenKaisa SilanderM. PerolaV. SalomaaJouko MiettunenMikko HärmäSampsa PuttonenJuha VeijolaVesa KiviniemiTarja Porkka‐HeiskanenT. Paunio
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Significance Disruption of the timing of the sleep–wake cycle and circadian rhythms, such as occurs during jet lag and shift work, leads to disordered physiological rhythms, but to what extent the molecular elements of circadian rhythm generation are affected is not known. Here, we show that delaying sleep by 4 h for 3 consecutive days leads to a sixfold reduction of circadian transcripts in the human blood transcriptome to just 1%, whereas, at the same time, the centrally driven circadian rhythm of melatonin is not affected. Genes and processes affected included those at the core of circadian rhythm generation and gene expression. The data have implications for understanding the negative health outcomes of disruption of the sleep–wake cycle.
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Circadian rhythms occur in almost all species and control vital aspects of our physiology, from sleeping and waking to neurotransmitter secretion and cellular metabolism. Epidemiological studies from recent decades have supported a unique role for circadian rhythm in metabolism. As evidenced by individuals working night or rotating shifts, but also by rodent models of circadian arrhythmia, disruption of the circadian cycle is strongly associated with metabolic imbalance. Some genetically engineered mouse models of circadian rhythmicity are obese and show hallmark signs of the metabolic syndrome. Whether these phenotypes are due to the loss of distinct circadian clock genes within a specific tissue versus the disruption of rhythmic physiological activities (such as eating and sleeping) remains a cynosure within the fields of chronobiology and metabolism. Becoming more apparent is that from metabolites to transcription factors, the circadian clock interfaces with metabolism in numerous ways that are essential for maintaining metabolic homeostasis.
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Most organisms display endogenously produced ∼24-hour fluctuations in physiology and behavior, termed circadian rhythms. Circadian rhythms are driven by a transcriptional-translational feedback loop that is hierarchically expressed throughout the brain and body, with the suprachiasmatic nucleus of the hypothalamus serving as the master circadian oscillator at the top of the hierarchy. Appropriate circadian regulation is important for many homeostatic functions including energy regulation. Multiple genes involved in nutrient metabolism display rhythmic oscillations, and metabolically related hormones such as glucagon, insulin, ghrelin, leptin, and corticosterone are released in a circadian fashion. Mice harboring mutations in circadian clock genes alter feeding behavior, endocrine signaling, and dietary fat absorption. Moreover, misalignment between behavioral and molecular circadian clocks can result in obesity in both rodents and humans. Importantly, circadian rhythms are most potently synchronized to the external environment by light information and exposure to light at night potentially disrupts circadian system function. Since the advent of electric lights around the turn of the 20th century, exposure to artificial and irregular light schedules has become commonplace. The increase in exposure to light at night parallels the global increase in the prevalence of obesity and metabolic disorders. In this review, we propose that exposure to light at night alters metabolic function through disruption of the circadian system. We first provide an introduction to the circadian system, with a specific emphasis on the effects of light on circadian rhythms. Next we address interactions between the circadian system and metabolism. Finally, we review current experimental and epidemiological work directly associating exposure to light at night and metabolism.
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The increasing prevalence of metabolic disease in modern society has accelerated our need to understand factors that may be contributing to its development. Both circadian disruption and sleep deprivation are associated with metabolic dysfunction. Thus, for my dissertation I sought to gain insight into this association by studying the genetic and neural basis of interactions between circadian rhythms, sleep and metabolism. The relative simplicity of fly neuroanatomy and physiology, vast array of available genetic tools, and conservation across many organisms, makes Drosophila melanogaster an ideal model to dissect complex interactions between physiological systems. Through our studies we identified a novel role for a molecule that regulates feeding behavior, Neuropeptide F (NPF), in the circadian system. We found that NPF drives circadian gene expression of the detoxification gene sex-specific enzyme 1 in a peripheral metabolic tissue, possibly to coordinate consumption of toxins with their removal. Our results support a role for NPF in synchronizing behavior and metabolism to ensure circadian coherence and promote survival. In addition, we studied the interaction between sleep and metabolism by evaluating whether alterations in sleep cause metabolic dysfunction or are the result of shared molecular pathways. The insect equivalent of norepinephrine, octopamine, promotes wake in flies by signaling through insulin-producing neurons. We determined that although sleep and metabolic neural circuitry intersect, the octopamine signaling pathway regulates sleep and metabolism independently. This dissertation highlights the great power of Drosophila as a model organism to investigate complex interactions between different biological systems. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor Amita Sehgal Second Advisor Tom Jongens
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Circadian and sleep-homeostatic processes both contribute to sleep timing and sleep structure. Elimination of circadian rhythms through lesions of the suprachiasmatic nuclei (SCN), the master circadian pacemaker, leads to fragmentation of wakefulness and sleep but does not eliminate the homeostatic response to sleep loss as indexed by the increase in EEG delta power. In humans, EEG delta power declines during sleep episodes nearly independently of circadian phase. Such observations have contributed to the prevailing notion that circadian and homeostatic processes are separate but recent data imply that this segregation may not extend to the molecular level. Here we summarize the criteria and evidence for a role for clock genes in sleep homeostasis. Studies in mice with targeted disruption for core circadian clock genes have revealed alterations in circadian rhythmicity as well as changes in sleep duration, sleep structure and EEG delta power. Clock-gene expression in brain areas outside the SCN, in particular the cerebral cortex, depends to a large extent on prior sleep-wake history. Evidence for effects of clock genes on sleep homeostasis has also been obtained in Drosophila and humans, pointing to a phylogenetically preserved pathway. These findings suggest that, while within the SCN clock genes are utilized to set internal time-of-day, in the forebrain the same feedback circuitry may be utilized to track time spent awake and asleep. The mechanisms by which clock-gene expression is coupled to the sleep-wake distribution could be through cellular energy charge whereby clock genes act as energy sensors. The data underscore the interrelationships between energy metabolism, circadian rhythmicity, and sleep regulation.
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The adaptation of organisms to a rhythmic environment is mediated by an internal timing system termed the circadian clock. In mammals, molecular clocks are found in all tissues and organs. This circadian clock network regulates the release of many hormones, which in turn influence some of the most vital behavioural functions. Sleep-wake cycles are under strict circadian control with strong influence of rhythmic hormones such as melatonin, cortisol and others. Food intake, in contrast, receives circadian modulation through hormones such as leptin, ghrelin, insulin and orexin. A third behavioural output covered in this review is mating and bonding behaviours, regulated through circadian rhythms in steroid hormones and oxytocin. Together, these data emphasize the pervasive influence of the circadian clock system on behavioural outputs and its mediation through endocrine networks.
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