Night-time sleep duration and postpartum weight retention in primiparous women.

Objectives: Approximately 75% of women weigh more at 1-year postpartum than pre-pregnancy. More than 47% retain >10 lbs at 1-year postpartum, which is associated with adverse health outcomes for mother and child. Disturbed sleep may contribute to risk of postpartum weight retention (PWR) as short sleep duration is associated with increased risk of obesity. Thus, we investigated whether night-time sleep duration is associated with risk for excessive PWR. We also explored night-time sleep duration and change in postpartum waist circumference. Methods: This is an ancillary analysis from a prospective cohort study. Participants were healthy primiparous adults with a singleton birth. Excessive PWR at 1-year postpartum was defined as ≥7% of pre-pregnancy weight. Log-binomial and linear regression assessed associations between night-time sleep duration at 6 months postpartum and PWR at 1-year postpartum. Linear regression assessed the association between night-time sleep duration and change in postpartum waist circumference. Results: Mean age of participants (N = 467) was 29.51 (SD ±â€…4.78) years. Night-time sleep duration by actigraphy or self-report was not associated with risk for excessive PWR (risk ratio 0.96, [95%CI 0.87-1.06]; risk ratio 0.95 [95%CI 0.83-1.07], respectively) or change in waist circumference. Conclusion: Night-time sleep duration at 6 months postpartum was not associated with PWR at 1-year postpartum. Mixed findings among our results and previous research could be due to our focus on night-time sleep, and differences in sleep measurement methods and timeframes across studies. More comprehensively assessing sleep, including multiple sleep dimensions, may help advance our understanding of potential links between sleep and PWR. Trial Registration: The parent study, Motherhood and Pelvic Health (MAP Study), is registered at https://clinicaltrials.gov/ct2/show/NCT02512016, NCT02512016.

Sleep extension and cardiometabolic health: what it is, possible mechanisms and real-world applications.

Short sleep duration is associated with heightened cardiometabolic disease risk and has reached epidemic proportions among children, adolescents and adults. Potential mechanisms underlying this association are complex and multifaceted, including disturbances in circadian timing, food intake and appetitive hormones, brain regions linked to control of hedonic eating, physical activity, an altered microbiome and impaired insulin sensitivity. Sleep extension, or increasing total sleep duration, is an emerging and ecologically relevant intervention with significant potential to advance our understanding of the mechanisms underlying the association between short sleep duration and the risk of cardiometabolic disease. If effective, sleep extension interventions have potential to improve cardiometabolic health across the lifespan. Existing data show that sleep extension is feasible and might have potential cardiometabolic health benefits, although there are limitations that the field must overcome. Notably, most existing studies are short term (2-8 weeks), use different sleep extension strategies, analyse a wide array of cardiometabolic health outcomes in different populations and, frequently, lack adequate statistical power, thus limiting robust scientific conclusions. Overcoming these limitations will require fully powered, randomized studies conducted in people with habitual short sleep duration and existing cardiometabolic risk factors. Additionally, randomized controlled trials comparing different sleep extension strategies are essential to determine the most effective interventions. Ongoing and future research should focus on elucidating the potential cardiometabolic health benefits of sleep extension. Such studies have high potential to generate crucial knowledge with potential to improve health and quality of life for those struggling with short sleep duration.

Distribution of dim light melatonin offset (DLMOff) and phase relationship to waketime in healthy adults and associations with chronotype.

OBJECTIVES: Dim light melatonin onset, or the rise in melatonin levels representing the beginning of the biological night, is the gold standard indicator of circadian phase. Considerably less is known about dim light melatonin offset, or the decrease in melatonin to low daytime levels representing the end of the biological night. In the context of insufficient sleep, morning circadian misalignment, or energy intake after waketime but before dim light melatonin offset, is linked to impaired insulin sensitivity, suggesting the need to characterize dim light melatonin offset and identify risk for morning circadian misalignment. METHODS: We examined the distributions of dim light melatonin offset clock hour and the phase relationship between dim light melatonin offset and waketime, and associations between dim light melatonin offset, phase relationship, and chronotype in healthy adults (N = 62) who completed baseline protocols measuring components of the circadian melatonin rhythm and chronotype. RESULTS: 74.4% demonstrated dim light melatonin offset after waketime, indicating most healthy adults wake up before the end of biological night. Later chronotype (morningness-eveningness, mid-sleep on free days corrected, and average mid-sleep) was associated with later dim light melatonin offset clock hour. Later chronotype was also associated with a larger, positive phase relationship between dim light melatonin offset and waketime, except for morningness-eveningness. CONCLUSIONS: These findings suggest morning circadian misalignment risk among healthy adults, which would not be detected if only dim light melatonin onset were assessed. Chronotype measured by sleep timing may better predict this risk in healthy adults keeping a consistent sleep schedule than morningness-eveningness preferences. Additional research is needed to develop circadian biomarkers to predict dim light melatonin offset and evaluate appropriate dim light melatonin offset timing to promote health.

Insufficient sleep and weekend recovery sleep: classification by a metabolomics-based machine learning ensemble.

Although weekend recovery sleep is common, the physiological responses to weekend recovery sleep are not fully elucidated. Identifying molecular biomarkers that represent adequate versus insufficient sleep could help advance our understanding of weekend recovery sleep. Here, we identified potential molecular biomarkers of insufficient sleep and defined the impact of weekend recovery sleep on these biomarkers using metabolomics in a randomized controlled trial. Healthy adults (n = 34) were randomized into three groups: control (CON: 9-h sleep opportunities); sleep restriction (SR: 5-h sleep opportunities); or weekend recovery (WR: simulated workweek of 5-h sleep opportunities followed by ad libitum weekend recovery sleep and then 2 days with 5-h sleep opportunities). Blood for metabolomics was collected on the simulated Monday immediately following the weekend. Nine machine learning models, including a machine learning ensemble, were built to classify samples from SR versus CON. Notably, SR showed decreased glycerophospholipids and sphingolipids versus CON. The machine learning ensemble showed the highest G-mean performance and classified 50% of the WR samples as insufficient sleep. Our findings show insufficient sleep and recovery sleep influence the plasma metabolome and suggest more than one weekend of recovery sleep may be necessary for the identified biomarkers to return to healthy adequate sleep levels.

Sleep duration, plasma metabolites, and obesity and diabetes: a metabolome-wide association study in US women.

Short and long sleep duration are associated with adverse metabolic outcomes, such as obesity and diabetes. We evaluated cross-sectional differences in metabolite levels between women with self-reported habitual short (<7 h), medium (7-8 h), and long (≥9 h) sleep duration to delineate potential underlying biological mechanisms. In total, 210 metabolites were measured via liquid chromatography-mass spectrometry in 9207 women from the Nurses' Health Study (NHS; N = 5027), the NHSII (N = 2368), and the Women's Health Initiative (WHI; N = 2287). Twenty metabolites were consistently (i.e. praw < .05 in ≥2 cohorts) and/or strongly (pFDR < .05 in at least one cohort) associated with short sleep duration after multi-variable adjustment. Specifically, levels of two lysophosphatidylethanolamines, four lysophosphatidylcholines, hydroxyproline and phenylacetylglutamine were higher compared to medium sleep duration, while levels of one diacylglycerol and eleven triacylglycerols (TAGs; all with ≥3 double bonds) were lower. Moreover, enrichment analysis assessing associations of metabolites with short sleep based on biological categories demonstrated significantly increased acylcarnitine levels for short sleep. A metabolite score for short sleep duration based on 12 LASSO-regression selected metabolites was not significantly associated with prevalent and incident obesity and diabetes. Associations of single metabolites with long sleep duration were less robust. However, enrichment analysis demonstrated significant enrichment scores for four lipid classes, all of which (most markedly TAGs) were of opposite sign than the scores for short sleep. Habitual short sleep exhibits a signature on the human plasma metabolome which is different from medium and long sleep. However, we could not detect a direct link of this signature with obesity and diabetes risk.

Keeping an eye on circadian time in clinical research and medicine.

BACKGROUND: Daily rhythms are observed in humans and almost all other organisms. Most of these observed rhythms reflect both underlying endogenous circadian rhythms and evoked responses from behaviours such as sleep/wake, eating/fasting, rest/activity, posture changes and exercise. For many research and clinical purposes, it is important to understand the contribution of the endogenous circadian component to these observed rhythms. CONTENT: The goal of this manuscript is to provide guidance on best practices in measuring metrics of endogenous circadian rhythms in humans and promote the inclusion of circadian rhythms assessments in studies of health and disease. Circadian rhythms affect all aspects of physiology. By specifying minimal experimental conditions for studies, we aim to improve the quality, reliability and interpretability of research into circadian and daily (i.e., time-of-day) rhythms and facilitate the interpretation of clinical and translational findings within the context of human circadian rhythms. We describe protocols, variables and analyses commonly used for studying human daily rhythms, including how to assess the relative contributions of the endogenous circadian system and other daily patterns in behaviours or the environment. We conclude with recommendations for protocols, variables, analyses, definitions and examples of circadian terminology. CONCLUSION: Although circadian rhythms and daily effects on health outcomes can be challenging to distinguish in practice, this distinction may be important in many clinical settings. Identifying and targeting the appropriate underlying (patho)physiology is a medical goal. This review provides methods for identifying circadian effects to aid in the interpretation of published work and the inclusion of circadian factors in clinical research and practice.

Sleep and Circadian Disruption and the Gut Microbiome-Possible Links to Dysregulated Metabolism.

Insufficient sleep and circadian misalignment are associated with adverse metabolic health outcomes. Alterations in gut microbial diversity occur with insufficient sleep and circadian misalignment, which can lead to modifications in microbial structure and function. Changes in microbially produced and modified metabolites such as short chain fatty acids and secondary bile acids may contribute to chronic inflammation, positive energy balance and endocrine changes, and represent potential mechanisms linking insufficient sleep and circadian misalignment with metabolic dysregulation. Literature primarily from the last two years is reviewed here, examining the impact of sleep and circadian rhythms and their disruption on the gut microbiome in human and non-human models, with an emphasis on the hypothesis that the altered gut microbiome may be one pathway by which insufficient sleep and circadian misalignment dysregulate metabolism.

Challenges and Opportunities for Applying Wearable Technology to Sleep.

Wearable technology has a history in sleep research dating back to the 1970s. Because modern wearable technology is relatively cheap and widely used by the general population, this represents an opportunity to leverage wearable devices to advance sleep medicine and research. However, there is a lack of published validation studies designed to quantify device performance against accepted gold standards, especially across different populations. Recommendations for conducting performance assessments and using wearable devices are now published with the goal of standardizing wearable device implementation and advancing the field.

Bone turnover marker responses to sleep restriction and weekend recovery sleep.

BACKGROUND: Prior data demonstrated three weeks of sleep restriction and concurrent circadian disruption uncoupled bone turnover markers (BTMs), indicating decreased bone formation and no change or increased bone resorption. The effect of insufficient sleep with or without ad libitum weekend recovery sleep on BTMs is unknown. METHODS: BTMs were measured in stored serum from 20 healthy adults randomized to one of three study groups consisting of a control group (N = 3 men; 9 h/night) or one of two nocturnal sleep restriction groups in an inpatient laboratory environment. One Sleep Restriction group ("SR"; N = 9; 4 women) had 5 h sleep opportunity per night for nine nights. The other sleep restriction group had an opportunity for ad libitum Weekend Recovery sleep ("WR"; N = 8; 4 women) after four nights of 5 h sleep opportunity per night. Food intake was energy balanced at baseline and ad libitum thereafter. Fasted morning BTM levels and hourly 24 h melatonin levels were obtained on study days 3 (baseline), 5 (after 1 night of sleep restriction for WR and SR), and 11 (after a sleep restricted workweek with weekend recovery sleep in WR or 7 nights of sleep restriction in SR). Linear mixed-effects modeling was used to examine the effect of study duration (e.g., change over time), study condition, age, and sex on BTMs. Pearson correlations were used to determine associations between changes in BTMs and changes in weight and morning circadian misalignment (i.e., duration of high melatonin levels after wake time). RESULTS: There was no significant difference between the three study groups in change over time (p ≥ 0.4 for interaction between assigned group and time for all BTMs), adjusted for age and sex. There was no significant change in N-terminal propeptide of procollagen type I (P1NP), osteocalcin, or C-telopeptide of type I collagen (CTX) from baseline to day 11 (all p ≥ 0.3). In women <25 years old, there was a non-significant decline in P1NP from day 3 to day 5 (= -15.74 ± 7.80 ng/mL; p = 0.06). Change in weight and morning circadian misalignment from baseline to day 11 were correlated with statistically non-significant changes in BTMs (all p ≤ 0.05). CONCLUSION: In this small secondary analysis, we showed that nine nights of prescribed sleep restriction with or without weekend recovery sleep and ad libitum food intake did not alter BTMs. It is possible that age, sex, weight change and morning circadian misalignment modify the effects of sleep restriction on bone metabolism.

Effects of ad libitum food intake, insufficient sleep and weekend recovery sleep on energy balance.

STUDY OBJECTIVES: Insufficient sleep is believed to promote positive energy balance (EB) and weight gain. Increasing weekend sleep duration to "recover" from weekday sleep loss is common, yet little is known regarding how weekend recovery sleep influences EB. We conducted a randomized controlled trial to assess how: (1) 2 days and 8 days of insufficient sleep and (2) ad libitum weekend recovery sleep impact EB (energy intake [EI] - energy expenditure [EE]). METHODS: Following ten baseline days with 9 h per night sleep opportunities, participants completed one of three 10-day experimental protocols with ad libitum EI: control (9 h sleep opportunities; n = 8; 23 ± 5 years [mean ± SD]); sleep restriction (SR; 5 h sleep opportunities; n = 14; 25 ± 5 years); sleep restriction with weekend recovery sleep (SR + WR; 5 days insufficient sleep, 2 days ad libitum weekend recovery sleep, 3 days recurrent insufficient sleep; n = 14; 27 ± 4 years). RESULTS: Twenty-four hour EB increased (p < 0.001; main effect) by an average of 797.7 ± 96.7 (±SEM) kcal during the 10-day experimental protocol versus baseline with no significant differences between groups. Percent change from baseline in 24 h-EE was higher (p < 0.05) on day 2 of insufficient sleep (SR and SR + WR groups; 10 ± 1%) versus adequate sleep (control group; 4 ± 3%). CONCLUSIONS: In this between-group study, the effects of adequate sleep and insufficient sleep, with or without or weekend recovery sleep, on 24 h-EB were similar. Examining EB and body weight changes using within-subject cross-over designs and "free-living" conditions outside the laboratory (e.g. sleep extension) are needed to advance our understanding of the links between insufficient sleep, weekend recovery sleep and weight-gain.

Sleep in university students prior to and during COVID-19 Stay-at-Home orders.

Sleep health has multiple dimensions including duration, regularity, timing, and quality [1-4]. The Coronavirus 2019 (COVID-19) outbreak led to Stay-at-Home orders and Social Distancing Requirements in countries throughout the world to limit the spread of COVID-19. We investigated sleep behaviors prior to and during Stay-at-Home orders in 139 university students (aged 22.2 ± 1.7 years old [±SD]) while respectively taking the same classes in-person and remotely. During Stay-at-Home, nightly time in bed devoted to sleep (TIB, a proxy for sleep duration with regard to public health recommendations [5]) increased by ∼30 min during weekdays and by ∼24 mins on weekends and regularity of sleep timing improved by ∼12 min. Sleep timing became later by ∼50 min during weekdays and ∼25 min on weekends, and thus the difference between weekend and weekday sleep timing decreased - hence reducing the amount of social jetlag [6,7]. Further, we find individual differences in the change of TIB devoted to sleep such that students with shorter TIB at baseline before the first COVID-19 cases emerged locally had larger increases in weekday and weekend TIB during Stay-at-Home. The percentage of participants that reported 7 h or more sleep per night, the minimum recommended sleep duration for adults to maintain health [5] - including immune health - increased from 84% to 92% for weekdays during Stay-at-Home versus baseline. Understanding the factors underlying such changes in sleep health behaviors could help inform public health recommendations with the goal of improving sleep health during and following the Stay-at-Home orders of the COVID-19 pandemic.

Developing preliminary blood metabolomics-based biomarkers of insufficient sleep in humans.

STUDY OBJECTIVE: Identify small molecule biomarkers of insufficient sleep using untargeted plasma metabolomics in humans undergoing experimental insufficient sleep. METHODS: We conducted a crossover laboratory study where 16 normal-weight participants (eight men; age 22 ± 5 years; body mass index < 25 kg/m2) completed three baseline days (9 hours sleep opportunity per night) followed by 5-day insufficient (5 hours sleep opportunity per night) and adequate (9 hours sleep opportunity per night) sleep conditions. Energy balanced diets were provided during baseline, with ad libitum energy intake provided during the insufficient and adequate sleep conditions. Untargeted plasma metabolomics analyses were performed using blood samples collected every 4 hours across the final 24 hours of each condition. Biomarker models were developed using logistic regression and linear support vector machine (SVM) algorithms. RESULTS: The top-performing biomarker model was developed by linear SVM modeling, consisted of 65 compounds, and discriminated insufficient versus adequate sleep with 74% overall accuracy and a Matthew's Correlation Coefficient of 0.39. The compounds in the top-performing biomarker model were associated with ATP Binding Cassette Transporters in Lipid Homeostasis, Phospholipid Metabolic Process, Plasma Lipoprotein Remodeling, and sphingolipid metabolism. CONCLUSION: We identified potential metabolomics-based biomarkers of insufficient sleep in humans. Although our current biomarkers require further development and validation using independent cohorts, they have potential to advance our understanding of the negative consequences of insufficient sleep, improve diagnosis of poor sleep health, and could eventually help identify targets for countermeasures designed to mitigate the negative health consequences of insufficient sleep.

Wearable technologies for developing sleep and circadian biomarkers: a summary of workshop discussions.

The "International Biomarkers Workshop on Wearables in Sleep and Circadian Science" was held at the 2018 SLEEP Meeting of the Associated Professional Sleep Societies. The workshop brought together experts in consumer sleep technologies and medical devices, sleep and circadian physiology, clinical translational research, and clinical practice. The goals of the workshop were: (1) characterize the term "wearable" for use in sleep and circadian science and identify relevant sleep and circadian metrics for wearables to measure; (2) assess the current use of wearables in sleep and circadian science; (3) identify current barriers for applying wearables to sleep and circadian science; and (4) identify goals and opportunities for wearables to advance sleep and circadian science. For the purposes of biomarker development in the sleep and circadian fields, the workshop included the terms "wearables," "nearables," and "ingestibles." Given the state of the current science and technology, the limited validation of wearable devices against gold standard measurements is the primary factor limiting large-scale use of wearable technologies for sleep and circadian research. As such, the workshop committee proposed a set of best practices for validation studies and guidelines regarding how to choose a wearable device for research and clinical use. To complement validation studies, the workshop committee recommends the development of a public data repository for wearable data. Finally, sleep and circadian scientists must actively engage in the development and use of wearable devices to maintain the rigor of scientific findings and public health messages based on wearable technology.

Trait-like vulnerability of higher-order cognition and ability to maintain wakefulness during combined sleep restriction and circadian misalignment.

STUDY OBJECTIVES: Determine stability of individual differences in executive function, cognitive processing speed, selective visual attention, and maintenance of wakefulness during simulated sustained operations with combined sleep restriction and circadian misalignment. METHODS: Twenty healthy adults (eight female), aged 25.7 (±4.2 SD), body mass index (BMI) 22.3 (±2.1) kg/m2 completed an 18-day protocol twice. Participants maintained habitual self-selected 8-hour sleep schedules for 2 weeks at home prior to a 4-day laboratory visit that included one sleep opportunity per day: 8 hours on night 1, 3 hours on night 2, and 3 hours on mornings 3 and 4. After 3 days of unscheduled sleep at home, participants repeated the entire protocol. Stability and task dependency of individual differences in performance were quantified by intra-class correlation coefficients (ICC) and Kendall's Tau, respectively. RESULTS: Performance on Stroop, Visual Search, and the Maintenance of Wakefulness Test were highly consistent within individuals during combined sleep restriction and circadian misalignment. Individual differences were trait-like as indicated by ICCs (0.54-0.96) classified according to standard criteria as moderate to almost perfect. Individual differences on other performance tasks commonly reported in sleep studies showed fair to almost perfect ICCs (0.22-0.94). Kendall's rank correlations showed that individual vulnerability to sleep restriction and circadian misalignment varied by task and by metric within a task. CONCLUSIONS: Consistent vulnerability of higher-order cognition and maintenance of wakefulness to combined sleep restriction and circadian misalignment has implications for the development of precision countermeasure strategies for workers performing safety-critical tasks, e.g. military, police, health care workers and emergency responders.

Ad libitum Weekend Recovery Sleep Fails to Prevent Metabolic Dysregulation during a Repeating Pattern of Insufficient Sleep and Weekend Recovery Sleep.

People commonly increase sleep duration on the weekend to recover from sleep loss incurred during the workweek. Whether ad libitum weekend recovery sleep prevents metabolic dysregulation caused by recurrent insufficient sleep is unknown. Here, we assessed sleep, circadian timing, energy intake, weight gain, and insulin sensitivity during sustained insufficient sleep (9 nights) and during recurrent insufficient sleep following ad libitum weekend recovery sleep. Healthy, young adults were randomly assigned to one of three groups: (1) control (CON; 9-h sleep opportunities, n = 8), (2) sleep restriction without weekend recovery sleep (SR; 5-h sleep opportunities, n = 14), and (3) sleep restriction with weekend recovery sleep (WR; insufficient sleep for 5-day workweek, then 2 days of weekend recovery, then 2 nights of insufficient sleep, n = 14). For SR and WR groups, insufficient sleep increased after-dinner energy intake and body weight versus baseline. During ad libitum weekend recovery sleep, participants cumulatively slept ∼1.1 h more than baseline, and after-dinner energy intake decreased versus insufficient sleep. However, during recurrent insufficient sleep following the weekend, the circadian phase was delayed, and after-dinner energy intake and body weight increased versus baseline. In SR, whole-body insulin sensitivity decreased ∼13% during insufficient sleep versus baseline, and in WR, whole-body, hepatic, and muscle insulin sensitivity decreased ∼9%-27% during recurrent insufficient sleep versus baseline. Furthermore, during the weekend, total sleep duration was lower in women versus men, and energy intake decreased to baseline levels in women but not in men. Our findings suggest that weekend recovery sleep is not an effective strategy to prevent metabolic dysregulation associated with recurrent insufficient sleep.

Mistimed food intake and sleep alters 24-hour time-of-day patterns of the human plasma proteome.

Proteomics holds great promise for understanding human physiology, developing health biomarkers, and precision medicine. However, how much the plasma proteome varies with time of day and is regulated by the master circadian suprachiasmatic nucleus brain clock, assessed here by the melatonin rhythm, is largely unknown. Here, we assessed 24-h time-of-day patterns of human plasma proteins in six healthy men during daytime food intake and nighttime sleep in phase with the endogenous circadian clock (i.e., circadian alignment) versus daytime sleep and nighttime food intake out of phase with the endogenous circadian clock (i.e., circadian misalignment induced by simulated nightshift work). We identified 24-h time-of-day patterns in 573 of 1,129 proteins analyzed, with 30 proteins showing strong regulation by the circadian cycle. Relative to circadian alignment, the average abundance and/or 24-h time-of-day patterns of 127 proteins were altered during circadian misalignment. Altered proteins were associated with biological pathways involved in immune function, metabolism, and cancer. Of the 30 circadian-regulated proteins, the majority peaked between 1400 hours and 2100 hours, and these 30 proteins were associated with basic pathways involved in extracellular matrix organization, tyrosine kinase signaling, and signaling by receptor tyrosine-protein kinase erbB-2. Furthermore, circadian misalignment altered multiple proteins known to regulate glucose homeostasis and/or energy metabolism, with implications for altered metabolic physiology. Our findings demonstrate the circadian clock, the behavioral wake-sleep/food intake-fasting cycle, and interactions between these processes regulate 24-h time-of-day patterns of human plasma proteins and help identify mechanisms of circadian misalignment that may contribute to metabolic dysregulation.

Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease.

Obese and type 2 diabetic (T2DM) patients have a high prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD is a continuum of chronic liver diseases ranging from benign hepatosteatosis to nonalcoholic steatohepatitis (NASH), cirrhosis and primary hepatocellular cancer (HCC). Because of its strong association with the obesity epidemic, NAFLD is rapidly becoming a major public health concern worldwide. Surprisingly, there are no FDA approved NAFLD therapies; and current therapies focus on the co-morbidities associated with NAFLD, namely, obesity, hyperglycemia, dyslipidemia, and hypertension. The goal of this review is to provide background on the disease process, discuss human studies and preclinical models that have examined treatment options. We also provide an in-depth rationale for the use of dietary ω3 polyunsaturated fatty acid (ω3 PUFA) supplements as a treatment option for NAFLD. This focus is based on recent studies indicating that NASH patients and preclinical mouse models of NASH have low levels of hepatic C20-22 ω3 PUFA. This decline in hepatic PUFA may account for the major phenotypic features associated with NASH, including steatosis, inflammation and fibrosis. Finally, our discussion will address the strengths and limitations of ω3 PUFA supplements use in NAFLD therapy.

Circadian Entrainment to the Natural Light-Dark Cycle across Seasons and the Weekend.

Reduced exposure to daytime sunlight and increased exposure to electrical lighting at night leads to late circadian and sleep timing [1-3]. We have previously shown that exposure to a natural summer 14 hr 40 min:9 hr 20 min light-dark cycle entrains the human circadian clock to solar time, such that the internal biological night begins near sunset and ends near sunrise [1]. Here we show that the beginning of the biological night and sleep occur earlier after a week's exposure to a natural winter 9 hr 20 min:14 hr 40 min light-dark cycle as compared to the modern electrical lighting environment. Further, we find that the human circadian clock is sensitive to seasonal changes in the natural light-dark cycle, showing an expansion of the biological night in winter compared to summer, akin to that seen in non-humans [4-8]. We also show that circadian and sleep timing occur earlier after spending a weekend camping in a summer 14 hr 39 min:9 hr 21 min natural light-dark cycle compared to a typical weekend in the modern environment. Weekend exposure to natural light was sufficient to achieve ∼69% of the shift in circadian timing we previously reported after a week's exposure to natural light [1]. These findings provide evidence that the human circadian clock adapts to seasonal changes in the natural light-dark cycle and is timed later in the modern environment in both winter and summer. Further, we demonstrate that earlier circadian timing can be rapidly achieved through natural light exposure during a weekend spent camping.

Impact of dietary fat on the development of non-alcoholic fatty liver disease in Ldlr-/- mice.

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased in parallel with central obesity and is now the most common chronic liver disease in developed countries. NAFLD is defined as excessive accumulation of lipid in the liver, i.e. hepatosteatosis. The severity of NAFLD ranges from simple fatty liver (steatosis) to non-alcoholic steatohepatitis (NASH). Simple steatosis is relatively benign until it progresses to NASH, which is characterised by hepatic injury, inflammation, oxidative stress and fibrosis. Hepatic fibrosis is a risk factor for cirrhosis and primary hepatocellular carcinoma. Our studies have focused on the impact of diet on the onset and progression of NASH. We developed a mouse model of NASH by feeding Ldlr-/- mice a western diet (WD), a diet moderately high in saturated and trans-fat, sucrose and cholesterol. The WD induced a NASH phenotype in Ldlr-/- mice that recapitulates many of the clinical features of human NASH. We also assessed the capacity of the dietary n-3 PUFA, i.e. EPA (20 : 5,n-3) and DHA (22 : 6,n-3), to prevent WD-induced NASH in Ldlr-/- mice. Histologic, transcriptomic, lipidomic and metabolomic analyses established that DHA was equal or superior to EPA at attenuating WD-induced dyslipidemia and hepatic injury, inflammation, oxidative stress and fibrosis. Dietary n-3 PUFA, however, had no significant effect on WD-induced changes in body weight, body fat or blood glucose. These studies provide a molecular and metabolic basis for understanding the strengths and weaknesses of using dietary n-3 PUFA to prevent NASH in human subjects.

Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity.

Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration.