The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by ...which intermittent fasting might lead to improved health outcomes. A MEDLINE search was performed using PubMed and the terms "intermittent fasting," "fasting," "time-restricted feeding," and "food timing." Modified fasting regimens appear to promote weight loss and may improve metabolic health. Several lines of evidence also support the hypothesis that eating patterns that reduce or eliminate nighttime eating and prolong nightly fasting intervals may result in sustained improvements in human health. Intermittent fasting regimens are hypothesized to influence metabolic regulation via effects on (
a
) circadian biology, (
b
) the gut microbiome, and (
c
) modifiable lifestyle behaviors, such as sleep. If proven to be efficacious, these eating regimens offer promising nonpharmacological approaches to improving health at the population level, with multiple public health benefits.
Circadian rhythms drive our daily behaviors to coincide with the earth’s rotation on an approximate 24-h cycle. The circadian clock mechanism present in nearly every cell is responsible for our ...circadian rhythms and is comprised of a transcriptional-translational feedback loop in mammals. The central clock resides in the hypothalamus responding to external light cues, whereas peripheral clocks receive signals from the central clock and are also sensitive to cues from feeding and activity. Of the peripheral clocks, the skeletal muscle clock is particularly sensitive to exercise which has shown to be an important time-cue with the ability to influence and adjust the muscle clock phase in response to exercise timing. Since the skeletal muscle clock is also involved in the expression of tissue-specific gene expression—including glucoregulatory genes—this might suggest a role for exercise timing as a therapeutic strategy in metabolic diseases, like type 2 diabetes. Notably, those with type 2 diabetes have accompanied disruptions in their skeletal muscle clock mechanism which may also be related to the increased risk of type 2 diabetes seen among shift workers. Therefore, the direct influence of exercise on the skeletal muscle clock might support the use of exercise timing to provide disease-mitigating effects. Here, we highlight the potential use of time-of-day exercise as a chronotherapeutic tool within circadian medicine to improve the metabolic profile of type 2 diabetes and support long-term glycemic control, potentially working through the skeletal muscle clock and circadian physiology.
Melatonin in mood disorders Srinivasan, Venkataramanujan; Smits, Marcel; Spence, Warren ...
The world journal of biological psychiatry,
01/2006, Letnik:
7, Številka:
3
Journal Article
Recenzirano
The cyclic nature of depressive illness, the diurnal variations in its symptomatology and the existence of disturbed sleep-wake and core body temperature rhythms, all suggest that dysfunction of the ...circadian time keeping system may underlie the pathophysiology of depression. As a rhythm-regulating factor, the study of melatonin in various depressive illnesses has gained attention. Melatonin can be both a 'state marker' and a 'trait marker' of mood disorders. Measurement of melatonin either in saliva or plasma, or of its main metabolite 6-sulfatoxymelatonin in urine, have documented significant alterations in melatonin secretion in depressive patients during the acute phase of illness. Not only the levels but also the timing of melatonin secretion is altered in bipolar affective disorder and in patients with seasonal affective disorder (SAD). A phase delay of melatonin secretion takes place in SAD, as well as changes in the onset, duration and offset of melatonin secretion. Bright light treatment, that suppresses melatonin production, is effective in treating bipolar affective disorder and SAD, winter type. This review discusses the role of melatonin in the pathophysiology of bipolar disorder and SAD.
Summary Frequently disrupted and restricted sleep is a common problem for many people in our modern around-the-clock society. In this context, it is an important question how sleep loss affects the ...stress systems in our bodies since these systems enable us to deal with everyday challenges. Altered activity and reactivity of these systems following insufficient sleep might have serious repercussions for health and well-being. Studies on both humans and rodents have shown that sleep deprivation and sleep restriction are conditions often associated with mild, temporary increases in the activity of the major neuroendocrine stress systems, i.e., the autonomic sympatho-adrenal system and the hypothalamic-pituitary-adrenal axis. Sleep deprivation may not only have a direct activating effect by itself but, in the long run, it may also affect the reactivity of these systems to other stressors and challenges. Although the first signs of alterations in the way people deal with challenges under conditions of restricted sleep appear to be on the level of emotional perception, chronic sleep restriction may ultimately change the fundamental properties of neuroendocrine stress systems as well. Understandably, few controlled studies in humans have been devoted to this topic. Yet, experimental studies in rodents show that chronic sleep restriction may gradually alter neuroendocrine stress responses as well as the central mechanisms involved in the regulation of these responses. Importantly, the available data from studies in laboratory animals suggest that sleep restriction may gradually change certain brain systems and neuroendocrine systems in a manner that is similar to what is seen in stress-related disorders such as depression (e.g., reduced serotonin receptor sensitivity and altered regulation of the hypothalamic-pituitary-adrenal axis). Such data support the view that insufficient sleep, by acting on stress systems, may sensitize individuals to stress-related disorders. Indeed, epidemiological studies suggest that sleep complaints and sleep restriction may be important risk factors for a variety of diseases that are often linked to stress, including cardiovascular diseases and mood disorders.
MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA's acute cardiotoxicity includes tachycardia and arrhythmia which are associated with ...cardiomyopathy. MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. To identify permanent MDMA-induced pathogenetic changes, mice received daily 10- or 35-day MDMA, or daily 10-day MDMA followed by 25-day saline washout (10 + 25 days). MDMA treatment caused differential gene expression (p < .05, fold change >1.5) in 752 genes following 10 days, 558 genes following 35 days, and 113 genes following 10-day MDMA + 25-day saline washout. Changes in MAPK and circadian rhythm gene expression were identified as early as 10 days. After 35 days, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) persisted to be differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was found to be 71% at 10 days, 68% at 35 days, and 91% at 10 + 25 days washout. Differential gene expression paralleled DNA methylation in 22% of genes at 10-day treatment, 17% at 35 days, and 48% at 10 + 25 days washout. We show here that MDMA induced cardiac epigenetic changes in DNA methylation where hypermethylation predominated. Moreover, MDMA induced gene expression of key elements of circadian rhythm regulatory genes. This suggests a fundamental organism-level event to explain some of the etiologies of MDMA dysfunction in the heart.
Alzheimer's disease (AD) patients exhibit sleep and circadian disturbances prior to the onset of cognitive decline, and these disruptions worsen with disease severity. However, the molecular ...mechanisms behind sleep and circadian disruptions in AD patients are poorly understood. In this study, we investigated sleep pattern and circadian rhythms in Presenilin-1/2 conditional knockout (DKO) mice. Assessment of EEG and EMG recordings showed that DKO mice displayed increased NREM sleep time but not REM sleep during the dark phase compared to WT mice at the age of two months; at the age of six months, the DKO mice showed increased wakefulness periods and decreased total time spent in both NREM and REM sleep. WT exhibited time-of-day dependent modulation of contextual and cued memory. Compared with WT mice, 4-month-old DKO mice exhibited the deficiency regardless trained and tested in the same light/night phase or not. Particularly interesting was that DKO showed circadian modulation deficiency when trained in the resting period but not in the active period. Long noncoding RNAs (lncRNAs) are typically defined as transcripts longer than 200 nucleotides, and they have rhythmic expression in mammals. To date no study has investigated rhythmic lncRNA expression in Alzheimer's disease. We applied RNA-seq technology to profile hippocampus expression of lncRNAs in DKO mice during the light (/resting) and dark (/active) phases and performed gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses of the cis lncRNA targets. Expression alteration of lncRNAs associated with immune response and metallodipeptidase activity may contribute to the circadian disruptions of DKO mice. Especially we identified some LncRNAs which expression change oppositely between day and light in DKO mice compared to WT mice and are worthy to be studied further. Our results exhibited the circadian rhythm sleep disorders and a noteworthy time-of-day-dependent memory deficiency in AD model mice and provide a useful resource for studying the expression and function of lncRNAs during circadian disruptions in Alzheimer's disease.
•Loss of presenilin function altered sleep-wake pattern and circadian rhythms of mice.•Loss of presenilin function impaired time-of-day-dependent fear memory in mice.•lncRNAs associated with immune response and metallodipeptidase activity expression alteration in presenilin knockout mice.
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•Hh signaling shows diurnal oscillations in liver and hepatocytes in vitro and in vivo.•Hh signaling feeds-back on the liver clock via GLI transcription factors.•The amplitude of the ...oscillations of the liver clock is decreased in hepatocytes from Smo-knockout mice.•Rhythmicity of many metabolic pathways, including hepatic lipid metabolism, is affected by oscillating Hh signaling.•Diurnal timing of starvation affects the clock-hedgehog module differently.
The mammalian circadian clock controls various aspects of liver metabolism and integrates nutritional signals. Recently, we described Hedgehog (Hh) signaling as a novel regulator of liver lipid metabolism. Herein, we investigated crosstalk between hepatic Hh signaling and circadian rhythm.
Diurnal rhythms of Hh signaling were investigated in liver and hepatocytes from mice with ablation of Smoothened (SAC-KO) and crossbreeds with PER2::LUC reporter mice. By using genome-wide screening, qPCR, immunostaining, ELISA and RNAi experiments in vitro we identified relevant transcriptional regulatory steps. Shotgun lipidomics and metabolic cages were used for analysis of metabolic alterations and behavior.
Hh signaling showed diurnal oscillations in liver and hepatocytes in vitro. Correspondingly, the level of Indian Hh, oscillated in serum. Depletion of the clock gene Bmal1 in hepatocytes resulted in significant alterations in the expression of Hh genes. Conversely, SAC-KO mice showed altered expression of clock genes, confirmed by RNAi against Gli1 and Gli3. Genome-wide screening revealed that SAC-KO hepatocytes showed time-dependent alterations in various genes, particularly those associated with lipid metabolism. The clock/hedgehog module further plays a role in rhythmicity of steatosis, and in the response of the liver to a high-fat diet or to differently timed starvation.
For the first time, Hh signaling in hepatocytes was found to be time-of-day dependent and to feed back on the circadian clock. Our findings suggest an integrative role of Hh signaling, mediated mainly by GLI factors, in maintaining homeostasis of hepatic lipid metabolism by balancing the circadian clock.
The results of our investigation show for the first time that the Hh signaling in hepatocytes is time-of-day dependent, leading to differences not only in transcript levels but also in the amount of Hh ligands in peripheral blood. Conversely, Hh signaling is able to feed back to the circadian clock.
Highlights • Animals use changes in photoperiod as a calendar. • In mammals, nocturnal melatonin secretion provides photoperiodic information. • In birds, light is perceived by deep brain ...photoreceptors to regulate the seasonality. • The pars tuberalis thyrotropin is the key hormone regulating seasonal reproduction. • Hypothalamic thyroid hormone activation regulates seasonal GnRH secretion.
Styrene increased lung tumors in mice at chronic inhalation exposures of 20ppm and greater. MIEs, KEs and MFs were examined using gene expression in three strains of male mice (the parental C57BL/6 ...strain, a CYP2F2(−/−) knock out and a CYP2F2(−/−) transgenic containing human CYP2F1, 2A13 and 2B6). Exposures were for 1-day and 1, 4 and 26weeks. After 1-day exposures at 1, 5, 10, 20, 40 and 120ppm significant increases in differentially expressed genes (DEGs) occurred only in parental strain lungs where there was already an increase in DEGs at 5ppm and then many thousands of DEGs by 120ppm. Enrichment for 1-day and 1-week exposures included cell cycle, mitotic M-M/G1 phases, DNA-synthesis and metabolism of lipids and lipoproteins pathways. The numbers of DEGs decreased steadily over time with no DEGs meeting both statistical significance and fold-change criteria at 26weeks. At 4 and 26weeks, some key transcription factors (TFs) - Nr1d1, Nr1d2, Dbp, Tef, Hlf, Per3, Per2 and Bhlhe40 - were upregulated (|FC|>1.5), while others - Npas, Arntl, Nfil3, Nr4a1, Nr4a2, and Nr4a3 - were down-regulated. At all times, consistent changes in gene expression only occurred in the parental strain. Our results support a MIE for styrene of direct mitogenicity from mouse-specific CYP2F2-mediated metabolites activating Nr4a signaling. Longer-term MFs include down-regulation of Nr4a genes and shifts in both circadian clock TFs and other TFs, linking circadian clock to cellular metabolism. We found no gene expression changes indicative of cytotoxicity or activation of p53-mediated DNA-damage pathways.
•Styrene response consistent with direct mitogenicity of Cyp2F2 and Nr4a signaling•Longer term exposure show changes in circadian pathways.•Changes in circadian pathways associated with Nr4a receptor family down-regulation•Consistent changes were seen only in wild type mice.•No evidence of activation of p53-mediated DNA-damage or cell stress pathways
Performance on tasks involving speed and accuracy fluctuate throughout the 24-h day negatively affecting shift workers and organizations. Two simulated work shifts common in occupational settings ...were used to assess performance on a vigilance and math task. In study 1, 33 sleep-deprived participants completed a nightshift. In study 2, 32 partially sleep-deprived participants completed a dayshift. These studies found that performance differed between the type of task and the type of simulated shift where performance during the nightshift was worse than during the dayshift. In addition, collapsing speed and accuracy on the math task into inverse efficiency scores provided a unique measure that captured the impact of circadian rhythms during shiftwork. The current study also indicated that participants adopted cognitive strategies including speed-accuracy tradeoff and regulatory foci regarding work motivation (prevention focus and promotion focus) when completing the tasks depending on time-of-day, type of shift, circadian rhythms, and amount of sleep deprivation. This suggests that researchers and organizations should consider cognitive strategies in addition to the physiological components of sleep deprivation and circadian rhythms when investigating and documenting the impact of time-of-day due to different types of shiftwork conditions on performance and safety.
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