There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/ feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle-achieved by scheduling a recurring 28-h ''day.'' Subjects ate 4 isocaloric meals each 28-h ''day.'' For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling Ϸ1,000 assays/ subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept Ϸ12 h out of phase from their habitual times, systematically decreased leptin (؊17%, P < 0.001), increased glucose (؉6%, P < 0.001) despite increased insulin (؉22%, P ‫؍‬ 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (؉3%, P ‫؍‬ 0.001), and reduced sleep efficiency (؊20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work. autonomic nervous system ͉ diabetes ͉ glucose metabolism ͉ leptin ͉ obesity A pproximately 8.6 million Americans perform shift work (1), which is associated with increased risk of obesity, diabetes, and cardiovascular disease (2-6). The endogenous circadian timing system, including the suprachiasmatic nucleus (SCN) in the hypothalamus and peripheral oscillators in vital organs, optimally regulates much of our physiology and behavior across the 24-h day when it is properly aligned with the sleep/wake cycle. However, shift work is generally associated with chronic misalignment between the endogenous circadian timing system and the behavioral cycles, including sleep/wake and fasting/ feeding cycles (7,8). Shift workers often experience symptoms akin to jet lag, with gastrointestinal complaints, fatigue, and sleepiness during the scheduled wake periods, and poor sleep during the daytime sleep attempts (9). Moreover, chronic circadian misalignment has been proposed to be the underlying cause for the adverse metabolic and cardiovascular health effects of shift work (10, 11). The SCN regulates circadian rhythms in leptin, plasma glucose, glucose tolerance, corticosteroids, and ...

There is consensus among experts regarding some indicators of sleep quality among otherwise healthy individuals. Education and public health initiatives regarding good sleep quality will require sustained and collaborative efforts from multiple stakeholders. Future research should explore how sleep architecture and naps relate to sleep quality. Implications and limitations of the consensus recommendations are discussed.

Sleep is an essential state of decreased activity and alertness but molecular factors regulating sleep duration remain unknown. Through genome-wide association analysis in 446,118 adults of European ancestry from the UK Biobank, we identify 78 loci for self-reported habitual sleep duration ( p < 5 × 10 −8 ; 43 loci at p < 6 × 10 −9 ). Replication is observed for PAX8 , VRK2 , and FBXL12/UBL5/PIN1 loci in the CHARGE study ( n = 47,180; p < 6.3 × 10 −4 ), and 55 signals show sign-concordant effects. The 78 loci further associate with accelerometer-derived sleep duration, daytime inactivity, sleep efficiency and number of sleep bouts in secondary analysis ( n = 85,499). Loci are enriched for pathways including striatum and subpallium development, mechanosensory response, dopamine binding, synaptic neurotransmission and plasticity, among others. Genetic correlation indicates shared links with anthropometric, cognitive, metabolic, and psychiatric traits and two-sample Mendelian randomization highlights a bidirectional causal link with schizophrenia. This work provides insights into the genetic basis for inter-individual variation in sleep duration implicating multiple biological pathways.

Background There is emerging literature demonstrating a relationship between the timing of feeding and weight regulation in animals. However, whether the timing of food intake influences the success of a weight-loss diet in humans is unknown. Objective To evaluate the role of food-timing in weight-loss effectiveness in a sample of 420 individuals who followed a 20-week weight-loss treatment. Methods Participants (49.5% females; age [mean+/−SD]: 42±11 years; BMI: 31.4±5.4 kg/m2) were grouped in early-eaters and late-eaters, according to the timing of the main meal (lunch in this Mediterranean population). 51% of the subjects were early-eaters and 49% were late-eaters (lunch time before and after 3:00 PM, respectively), energy intake and expenditure, appetite hormones, CLOCK genotype, sleep duration and chronotype were studied. Results Late lunch eaters lost less weight and displayed a slower weight-loss rate during the 20 weeks of treatment than early-eaters (P=0.002). Surprisingly, energy intake, dietary composition, estimated energy expenditure, appetite hormones and sleep duration was similar between both groups. Nevertheless, late-eaters were more evening-types, had less energetic breakfasts, and skipped breakfast more frequently that early-eaters (P<0.05). CLOCK rs4580704 SNP associated with the timing of the main meal (P=0.015) with a higher frequency of minor allele (C) carriers among the late-eaters (P=0.041). Neither sleep duration, nor CLOCK SNPs or Morning/Evening chronotype was independently associated with weight-loss (P>0.05). Conclusions Eating late may influence the success of weight-loss therapy. Novel therapeutic strategies should incorporate not only the caloric intake and macronutrient distribution—as is classically done—but also the timing of food.

Although major research efforts have focused on how specific components of foodstuffs affect health, relatively little is known about a more fundamental aspect of diet, the frequency and circadian timing of meals, and potential benefits of intermittent periods with no or very low energy intakes. The most common eating pattern in modern societies, three meals plus snacks every day, is abnormal from an evolutionary perspective. Emerging findings from studies of animal models and human subjects suggest that intermittent energy restriction periods of as little as 16 h can improve health indicators and counteract disease processes. The mechanisms involve a metabolic shift to fat metabolism and ketone production, and stimulation of adaptive cellular stress responses that prevent and repair molecular damage. As data on the optimal frequency and timing of meals crystalizes, it will be critical to develop strategies to incorporate those eating patterns into health care policy and practice, and the lifestyles of the population. metabolism | circadian rhythm | time-restricted feeding | feeding behavior | obesity

Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/ feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show-by using two 8-d laboratory protocols-in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower earlyphase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.circadian disruption | shift work | night work | glucose metabolism | diabetes I n healthy humans, there is a strong time-of-day variation in glucose tolerance, with a peak in the morning and a trough in the evening and night (1-6). Understanding the underlying mechanisms of the day/night variation in glucose tolerance is important for diurnally active individuals as well as shift workers, who are at increased risk for developing type 2 diabetes (7-9). The endogenous circadian system and circadian misalignment (i.e., misalignment between the endogenous circadian system and 24-h environmental/behavioral cycles) have been shown to affect glucose metabolism (4,(10)(11)(12)(13)(14). However, the relative and separate importance of the endogenous circadian system and circadian misalignment-after accounting for behavioral cycle effects (including the sleep/wake, fasting/feeding, and physical inactivity/activity cycles, etc.)-on 24-h variation in glucose tolerance is not well understood.Most species have evolved an endogenous circadian timing system that optimally times physiological variations and behaviors relative to the 24-h environmental cycle (15-17). The mammalian circadian system is comp...

Shift work is a risk factor for hypertension, inflammation, and cardiovascular disease. This increased risk cannot be fully explained by classic risk factors. One of the key features of shift workers is that their behavioral and environmental cycles are typically misaligned relative to their endogenous circadian system. However, there is little information on the impact of acute circadian misalignment on cardiovascular disease risk in humans. Here we show-by using two 8-d laboratory protocols-that short-term circadian misalignment (12-h inverted behavioral and environmental cycles for three days) adversely affects cardiovascular risk factors in healthy adults. Circadian misalignment increased 24-h systolic blood pressure (SBP) and diastolic blood pressure (DBP) by 3.0 mmHg and 1.5 mmHg, respectively. These results were primarily explained by an increase in blood pressure during sleep opportunities (SBP, +5.6 mmHg; DBP, +1.9 mmHg) and, to a lesser extent, by raised blood pressure during wake periods (SBP, +1.6 mmHg; DBP, +1.4 mmHg). Circadian misalignment decreased wake cardiac vagal modulation by 8-15%, as determined by heart rate variability analysis, and decreased 24-h urinary epinephrine excretion rate by 7%, without a significant effect on 24-h urinary norepinephrine excretion rate. Circadian misalignment increased 24-h serum interleukin-6, C-reactive protein, resistin, and tumor necrosis factor-α levels by 3-29%. We demonstrate that circadian misalignment per se increases blood pressure and inflammatory markers. Our findings may help explain why shift work increases hypertension, inflammation, and cardiovascular disease risk.circadian misalignment | hypertension | inflammatory markers | night work | shift work

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