The effects of sleep disruption on metabolism, hunger, and satiety, and the influence of psychosocial stress and exercise: A narrative review

Sleep deficiency is a ubiquitous phenomenon among Americans. In fact, in the United States, ∼78% of teens and 35% of adults currently get less sleep than recommended for their age‐group, and the quality of sleep appears to be getting worse for many. The consequences of sleep disruption manifest in a myriad of ways, including insulin resistance and disrupted nutrient metabolism, dysregulation of hunger and satiety, and potentially increased body weight and adiposity. Consequently, inadequate sleep is related to an increased risk of various cardiometabolic diseases, including obesity, diabetes, and heart disease. Exercise has the potential to be an effective therapeutic to counteract the deleterious effects of sleep disruption listed above, whereas chronic psychosocial stress may causally promote sleep disruption and cardiometabolic risk. Here, we provide a narrative review of the current evidence on the consequences of short sleep duration and poor sleep quality on substrate metabolism, circulating appetite hormones, hunger and satiety, and weight gain. Secondly, we provide a brief overview of chronic psychosocial stress and its impact on sleep and metabolic health. Finally, we summarise the current evidence regarding the ability of exercise to counteract the adverse metabolic health effects of sleep disruption. Throughout the review, we highlight areas where additional interrogation and future exploration are necessary.

-1 of 27 https://doi.org/10.1002/dmrr.3667caloric intake, and weight gain. 3,5Based on this robust emerging evidence, sleep is becoming recognised as a key behavioural determinant of cardiometabolic health.Accordingly, the American Heart Association has recently added sleep health to its list of essential, modifiable factors for improving and maintaining cardiovascular health (i.e., Life's Essential 8), 1 and the American Diabetes Association has recognised sleep as an important behaviour for the management of hyperglycemia in individuals with Type 2 Diabetes (T2D). 2 Given the ease with which it is measured and experimentally manipulated, sleep duration is the most well-studied sleep dimension and is therefore the dimension for which the strongest body of evidence exists.However, sleep is multi-dimensional, and both sleep quality and consistency are likely unique contributors to cardiometabolic health.Notably, there has been a worldwide decline in sleep quality over the last several decades. 3The NSF defines sleep quality as a combination of sleep continuity and sleep architecture and suggests that the ideal sleep architecture consists of spending ≤5% of time in stage 1 sleep, <81% in stage 2 sleep, 16%-20% in slow wave sleep (SWS), and 21%-30% in rapid eye movement (REM) sleep. 4Reductions in sleep quality (i.e., reduced SWS) may also negatively impact whole body insulin sensitivity and impair substrate metabolism. 5,6Similarly, disruption to natural sleep patterns or increased sleep variability can cause chronobiological misalignment, promoting cardiometabolic risk. 6For example, shift work, which is characterised by variable day and night shifts and constantly changing circadian alignments, has been shown to be an independent risk factor for the development of T2D, 7 and shift workers have a 40% increased risk of T2D compared with non-shift workers. 7rthermore, a small but emerging body of evidence indicates that less extreme variability in sleep patterns, such as variability in bedtimes or bedtime delays, may promote cardiometabolic disruption as evidenced by insulin resistance 8 and increased adiposity. 9However, given the emerging nature of this evidence, we chose not to conduct an in-depth review of the effect of sleep variability on metabolic health herein, which has very recently been reviewed elsewhere. 10e purpose of this review is to evaluate the existing epidemiological and experimental evidence linking short sleep duration and poor sleep quality with altered substrate metabolism, hunger and satiety, and body weight regulation, while highlighting current gaps and limitations with recommendations for future studies.We also briefly highlight the potential roles of psychosocial stress and physical exercise in the association of sleep with cardiometabolic health.

| Epidemiologic evidence on sleep disruption
Data from both small and large cohort studies suggest that short sleep duration is associated with impaired insulin sensitivity and glucose metabolism (Table 1).For example, Rafalson et al. reported that those who sleep fewer than 6 h per night are 3 times more likely to have impaired fasting glucose compared with those who sleep 6-8 h per night. 11Among 276 adults, Chaput et al. 12 reported that individuals who sleep ≤6 h per night had a 2.8-fold greater probability (relative risk = 2.78 [1.61-4.12])and those who slept ≥9 h per night had 2.54-times greater probability of developing type 2 diabetes or impaired glucose tolerance over ~6 years compared with those who slept 7-8 h per night.The inclusion of waist circumference, BMI, or relative body fat attenuated the relative risk ratios, suggesting that adiposity may partially mediate the association of sleep disruption with impaired insulin sensitivity and glucose metabolism.Importantly, however, the data from these studies were derived from primarily White, non-Hispanic cohorts and sleep durations were obtained from retrospective, self-report.Wong et al.   reported that the association of self-reported short sleep duration with lower insulin sensitivity was only significant in White individuals and additional sex stratification indicated that this relationship persisted only for white men and not white women. 13wever, this study was also conducted in primarily (89%) White, non-Hispanic adults.Thus, it is highly plausible that null findings among non-White individuals were due to small sample size and limited by retrospective, self-reported assessments of sleep duration.Accordingly, these findings should be interpreted with caution, especially in light of well-documented racial disparities in sleep health. 15,21ong a more diverse samples (43% non-White) of adolescents, actigraphy-measured short sleep duration was associated with insulin resistance even after adjustment for age, sex, race, and activity levels. 14This association was attenuated but still significant following adjustment for adiposity.Similarly, among 426 individuals from the Midlife in the United States Cohort Study, actigraphymeasured sleep time explained 41% of the difference in composite cardiometabolic risk (which included insulin resistance and glucose control [e.g., HbA1c]) between White and Black adults. 15In a crosssectional cohort study of Chinese twins, self-reported short sleep duration was associated with greater insulin resistance in women but not in men, an effect that was partially mediated by visceral adiposity. 16Finally, in the large (n = 70,026), prospective Nurse's Health Study, self-reported sleep durations ≤5 h per day were associated with a 1.57-fold increase in risk of diabetes diagnosis among women, an effect that was mediated by body mass index (BMI). 17ken together, there is strong evidence that short sleep duration is associated with greater insulin resistance and disrupted glucose metabolism.Further, whereas it has been suggested that the effects of short sleep duration on insulin and glucose metabolism are strongest in White men, 22 such findings are limited and likely influenced by a lack of representation of understudied minoritised racial/ ethnic groups and small sample sizes.Studies with greater representation of minoritised racial/ethnic groups instead suggest that short sleep duration may partially explain racial differences in metabolic health, 15 while findings from large cohorts composed only of women indicate that short sleep duration also negatively impacts  women's cardiometabolic health. 17Furthermore, it appears that the effect of short sleep duration on impaired insulin and glucose metabolism may be mediated by increased central adiposity.The directionality of this association is not clear at present, but as we discuss below, experimental sleep disruption causes insulin resistance and negatively impacts hunger, satiety, and body weight regulation.Finally, these epidemiologic and cohort studies are limited in so much that they primarily rely on fasting assessments of insulin sensitivity and glucose metabolism, such as fasting insulin and fasting glucose, or the homoeostatic model assessment of insulin resistance (HOMA-IR) method and mostly self-reported sleep duration.However, as discussed below, these findings are bolstered by studies examining the effect of experimental sleep restriction on insulin sensitivity and glucose metabolism and also by robust evidence indicating that individuals with short sleep durations (≤6-7 h/night) are at 30% greater risk for developing T2D. 23,24though the data are less robust, epidemiologic evidence also shows that poor sleep quality promotes impairments in insulin and glucose metabolism.For example, cross-sectional evidence in a sample subset from the Midlife Development in the United States II study indicated that actigraphy-measured sleep onset latency was linked with greater insulin resistance among men and women in univariate analyses. 18When this relationship was explored in men and women separately, the association persisted for women but not men and was robust to inclusion of additional covariates such as inflammatory markers, BMI, and depression. 18Among postmenopausal women both with and without metabolic syndrome, greater self-reported sleep onset latencies and more restless sleep have been associated with greater insulin resistance by HOMA-IR. 19milarly, among individuals with obesity or who are overweight, sleep quality and sleep onset latency-assessed using the Pittsburgh Sleep Quality Index-were associated with 1.33-and 1.23-fold increased risk of insulin resistance defined as a HOMA-IR ≥3.4. 19terestingly, evidence also exists to suggest that the strength of the association between poor sleep quality and insulin resistance is dependent on chronotype, such that individuals with an evening chronotype may be at greatest risk. 20Importantly, the evening chronotype has been linked to greater risk of depression and anxiety, 25 greater dietary energy density, 26 as well as reduced physical activity and lower cardiorespiratory fitness, 27 33 together indicating that sleep has effects specific to peripheral tissues that may contribute to or exacerbate metabolic disorders. 32Finally, while all of the aforementioned studies have used multiple days (e.g., ≥4 days) of sleep restriction, the deleterious effects of short sleep on insulin sensitivity have been shown to begin after just 1 night of sleep restriction (4-h TIB) in healthy subjects. 34,35perimental manipulation of sleep quality is not as straight forward as employing sleep restriction to modify sleep duration.
Studies that have manipulated sleep quality typically do so by suppressing stage 3 non-REM sleep, also known as SWS.SWS is associated with neural, hormonal, and metabolic changes that influence glucose homoeostasis, such as growth hormone release, decreased corticotropic activity, decreased sympathetic nervous system activity, and increased vagal tone. 6In an elegantly designed study, Tasali et al. 6

| Epidemiologic evidence on sleep disruption
8][39] However, in comparison to glucose metabolism, data on the associations between sleep and lipid metabolism are scarce.self-reported sleep insufficiency was also quantified. 40Participants who had shorter self-reported sleep durations had fewer large HDL-C particles in circulation in both cohorts, and this effect was independent of age and gender.In addition, gene expression data from the DILGOM study indicated that sleep restriction was associated with reduced cholesterol and sterol transporter expression (e.g., ABCG1) independent of BMI, which was replicated in the YFS cohort. 40Together, these findings show that short sleep duration suppresses cholesterol transport, particularly from peripheral macrophages to HDL particles.A 2017 systematic review and metaanalysis of prospective studies indicated that the available evidence does not support a significant association of short sleep with dyslipidemia, 41 although there may be meaningful associations between short sleep and low HDL-C and elevated total cholesterol to HDL-C ratio.However, these conclusions were drawn based on a small available body of evidence that, as described by the authors, is insufficient to inform public health policy. 41Further, given the apparent importance of particle-size and the particle-size specific effects of short sleep, 40 it may not be sufficient (or sufficiently sensitive) to simply measure traditional lipid and lipoprotein profiles to understand the effects of short sleep duration on lipid metabolism.
Apolipoproteins, including apolipoprotein B (ApoB), are core structural proteins of cholesterol particles and subendothelial trapping of ApoB is a primary mechanism for the development of atherosclerosis. 42In contrast, among a sample of 644 children and 992 adults, actigraphy-measured sleep duration was not significantly associated with ApoB levels (β = −0.50 in children, β = −0.05 in adults) where sleep duration was modelled continuously. 45Clearly, additional work is needed with careful consideration of lipoprotein sizes, such as can be provided by metabolomic analyses or by specific interrogation of ApoB to understand the influence of short sleep duration on lipid metabolism and atherogenic risk.
Very few data are available quantifying the effects of sleep quality on lipid metabolism.However, poor sleep quality has also been identified as a risk factor for cardiometabolic disease. 46 were associated with a 59% increase in the likelihood that dyslipidemia medication would be prescribed during 5 years of follow-up, suggesting a link between poor sleep quality and dyslipidemia.Overall, the size and quality of the current body of evidence make it difficult to draw concrete conclusions regarding the association of poor sleep quality with altered lipid metabolism/dyslipidemia.

| Experimental sleep manipulation
In our search, we found only one study that directly examined the effects of experimental sleep restriction on postprandial lipaemic responses to a high-fat meal, 48 while one other reported the effects of experimental sleep restriction on fasting serum lipids and lipoprotein profiles as well as the activity of lipid transfer proteins. 40In the-curve and non-esterified fatty acid (NEFA) levels compared with control.However, while the provided meal was high in fat (49 g), it was also high in carbohydrate (111 g) and elicited a robust postprandial insulin response.Importantly, the insulin response to the meal was greater following sleep restriction. 48Therefore, it is reasonable to speculate that this augmented insulin response resulted in enhanced TG clearance by insulin-stimulated lipoprotein lipase translocation; however, this should be investigated in future studies.Insulin resistance affects both peripheral tissues such as skeletal muscle and the liver, where it manifests as decreased insulinstimulated glucose disposal and elevated endogenous glucose production, respectively.Notably, insulin resistance is also associated with a decreased ability to suppress lipolysis in adipose tissue and altered fatty acid oxidation. 50,51Thus, a few studies have also determined the effects of experimental sleep restriction on indicators of postprandial lipid metabolism in response to either glucose tolerance tests or hyperinsulinemic-euglycemic clamps. 33Rao et al. reported that a 4-h versus 8-h TIB induced a modest increase in cortisol and catecholamines, a 62% increase in fasting NEFA levels, and a decrease in the respiratory quotient indicating an increase in whole body fat oxidation that was coincident with a 24% decrease in fasting TG levels, but no effect on total or LDL-cholesterol.Importantly, these effects were observed alongside a 25% decrease in whole-body insulin sensitivity and a 29% decrease in peripheral insulin sensitivity. 33However, there was no effect on hepatic insulin sensitivity as evidenced by a lack of change in endogenous glucose production (due to a modest increase gluconeogenesis and a decrease in glycogenolysis). 33These findings led the authors to speculate that sleep restriction impacts lipid metabolism by (1) causing stress-hormone induced lipolysis, which elevates circulating NEFA levels that promote peripheral insulin resistance by decreasing skeletal muscle glucose uptake and (2) by decreasing de novo lipogenic flux. 33These findings demonstrate that it may be Overall, it appears that the effects of acute (e.g., experimental) sleep restriction on lipid metabolism are opposite to what may be expected in light of the extant epidemiological evidence.It has been hypothesised that this may be subsequent to the acute phase inflammatory response that is induced by sleep restriction. 53Sleep restriction may also impair adipocyte function while increasing sympathetic tone and stress hormone production, thus augmenting intracellular lipolysis and altering NEFA metabolism. 32,33,52,54portantly, it appears that elevated circulating NEFAs are at least partially responsible for decreased peripheral insulin sensitivity caused by experimental sleep restriction. 55Experimental studies will be necessary to understand how and if sleep fragmentation or SWS suppression impair lipid metabolism.increasing energy expenditure via activation of hypothalamic circuits. 56,57Circulating leptin changes rapidly in response to acute caloric intake or restriction, assisting in the control of short-term feeding via mechanisms such as augmentation of the anorectic effects of cholecystokinin, [57][58][59] and is thought to be an important mediator of long-term energy balance regulation. 57Ghrelin is commonly referred to as the hunger hormone and is produced primarily in the oxyntic glands of the gastric fundus and stomach.

| HUNGER AND SATIETY HORMONES
Ghrelin has potent orexigenic (or appetite stimulating) and gastric emptying effects and acts on hypothalamic receptors. 60Typically, ghrelin rapidly decreases postprandially and then returns to baseline levels in the late postprandial and inter-digestive periods in a pattern that is reciprocal of insulin. 61Both leptin and ghrelin release also display diurnal rhythms that are in phase with each other, falling throughout the night until reaching a nadir between 0800 and 1000. 61Data also exist suggesting that the release of these hormones may be influenced by the autonomic nervous system, with cholinergic (vagal) activity suppressing ghrelin secretion and sympathetic activity decreasing leptin production. 62,63Thus, sleep disruption has the potential to disrupt leptin and ghrelin metabolism via circadian disruption or altered vagal and sympathetic activity.

| Epidemiologic evidence on sleep disruption
In a study of 1024 participants enroled in the Wisconsin Sleep Cohort Study, Taheri et al. 64 65 reported that fasting and morning leptin concentrations were positively associated with self-reported sleep duration, such that women reporting ≤6 h of sleep had lower leptin concentrations than those reporting ≥8 h of sleep.Among children, it has been reported that short sleep is associated with lower leptin concentrations at age 7 in girls and during adolescence in boys, suggesting potential sex-specific associations that should be explored more carefully. 66Notably, a recent meta-analysis also demonstrated that short sleep duration is associated with increased ghrelin levels among cross-sectional studies. 67ong men with primary insomnia who have reduced stage 2 and REM sleep, lower sleep efficiency, and greater stage 1 sleep, nocturnal ghrelin levels were reduced compared to control participants; however, no differences were observed in leptin concentration. 68Finally, among 95 adults with obesity, it was reported that self-reported sleep efficiency was associated with lower postprandial cholecystokinin, and lower subjective sleep quality was linked with increased basal and postprandial active ghrelin in men only. 69ese data provide initial epidemiological evidence that short sleep duration is associated with altered circulating concentrations of ghrelin and leptin that may promote increased appetite.Both measured (i.e., WASO) and self-reported indicators of sleep quality appear to indicate that poor sleep quality may be associated with increased circulating ghrelin; however, the overall body of evidence is currently weak and future studies should be powered to examine potential sex-differences.Although there is preclinical 70 and crosssectional evidence 64 suggesting that low sleep quality (i.e., high sleep fragmentation) may be associated with impaired leptin metabolism, it appears that these associations may be weaker than for sleep duration.However, additional work is needed to replicate and better understand these links before firm conclusions can be made.Accordingly, mean, maximal, and rhythm amplitude leptin levels were 19%, 26%, and 20% lower, respectively, during the 4-h TIB condition compared to the 12-h TIB condition. 71Similarly, another study by Speigel et al. examined the effect of 4-h versus 10-h TIB on leptin and ghrelin levels as well as on subjective hunger and appetite across a 12-h period from 0900 to 2100 during which a constant intravenous infusion of glucose (5 g/kg) was provided. 72Notably, sleep restriction promoted 18% lower leptin and 28% greater ghrelin across the day.

| Experimental sleep manipulation
These hormonal differences were accompanied by a 24% increase in hunger and a 23% increase in appetite ratings for all food categories, which tended to be greatest for sweet, salty, and starchy foods (33%-45%).St. Onge et al. observed that 4-h TIB sleep restriction promoted an increase in fasting ghrelin concentrations among men but not women when compared to 9-h TIB habitual sleep.Interestingly, there was no effect of sleep restriction on fasting leptin in this study, although 24-h leptin concentrations were also lower in men but not women. 73bsequent studies have found mixed results regarding leptin, with some showing elevations as opposed to decreases in leptin levels following sleep restriction [74][75][76][77] and others showing no changes. 77,78This discrepancy may be partially explained by the caloric intake of the participants during the study period.If participants were allowed to overeat or if they gained weight, an increase in leptin levels would be expected.Indeed, Markwald et al. reported increased 24-h leptin levels following sleep restriction that were accompanied by both greater caloric intake and significant weight gain. 75In a study that controlled for diet and maintained body weight, Hanlon et al. observed a significant decrease in diurnal leptin variation amplitude. 79Similarly, in a study performed by Reynolds et al. in 2012, leptin levels were significantly reduced following 5 nights of 4-h TIB compared with 2 nights of 10-h TIB. 804][85] However, given the cross-sectional nature of much of this epidemiologic evidence, it is hard to determine the directionality of these associations.
Among those studies that longitudinally observed weight change in individuals with short versus optimal sleep durations, weight gain may be greater among those with short sleep duration (see Table 2 for study summaries).However, among adults, this association is inconsistent.Furthermore, in studies where the association is present, the size of this effect is rather modest, with ~2 kg greater weight gain noted across a 6-year period in Canadian adults 86 and 0.7-1.14kg greater weight gain across a 16-year period noted in those with short sleep (≤5-6 h/night) in the Nurses' Health Study. 92 a 5-year study of African Americans and Hispanic Americans adults, individuals 40 years and younger who self-reported sleeping ≤5-h per night had a 1.8 kg/m 2 greater change in BMI than those reporting 6-7 h of sleep per night. 87In contrast, using data from the NHANES I studies, Gangwisch et al. 88  It is also possible that the effect of short sleep on weight gain is attenuated over time with advancing age or development.Notably, among children, the longitudinal association between short sleep and weight gain appears to be stronger and more consistent 107 (Table 2), suggesting strong developmental origins.Future longitudinal prospective cohort studies beginning in early life and continuing into adulthood will be necessary to more clearly understand the causal links between short sleep duration and body weight gain across the lifespan.It is also important to point out that while body weight is a commonly used end point, it may not accurately reflect adiposity.As such, the measurement of body composition and particularly of visceral adiposity, will continue to be important in future studies such as these.We also note that the association of sleep duration with bodyweight appears to be best described by a U-shape, where long sleep durations may also be associated with increased bodyweight. 108Finally, it has been cautioned that the longitudinal association of sleep duration with changes in BMI may be upwardly biased by unobserved and/or unmeasured time-invariant confounders, and also that confounding, mediating, or moderating factors such as psychosocial or mental health-related factors may influence the sleep and BMI association but have not always been well characterised in prior studies. 109

| Experimental sleep manipulation
In support of these epidemiological data, Markwald et

| THE ROLE OF PSYCHOSOCIAL STRESS IN THE ASSOCIATION OF POOR SLEEP WITH CARDIOMETABOLIC DYSFUNCTION
Psychosocial stress is increasingly being recognised as an important determinant of cardiometabolic health.Psychosocial stressors are characterised by both a psychological and social component.7][118][119][120] Acutely, the neural response to psychosocial stress includes activation of the limbic system (e.g., the hippocampus, amygdala, and hypothalamus) and subsequently the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary (SAM) axes. 121The acute downstream effects of HPA and SAM axis activation include increased peripheral resistance, parasympathetic withdrawal, increased sympathetic nervous system activity (SNA), increased release of stress hormones such as norepinephrine and cortisol, and immune system activation. 122These effects act to increase peripheral resistance, cardiac output, heart rate, blood pressure, circulating inflammatory cytokines, and thrombotic factors, as well as to increase the availability of metabolic substrates, including glucose and free fatty acids, by enhancing lipolysis and gluconeogenesis and decreasing insulin sensitivity. 123[128] While these responses are typically adaptive and transient, they may instead synergistically act to promote cardiometabolic disease when psychosocial stressors are frequent and recurrent. 127,129,130is hypothesis is supported by several bodies of literature illustrating that chronic psychosocial stress exposure, including exposure to adverse childhood experiences (ACEs) or social or socioeconomic stress, promotes increased lifetime risk of cardiometabolic diseases such as T2D, [131][132][133] obesity, 134,135 and cardiovascular disease. 119,131,136e effects of chronic psychosocial stress exposure on metabolism likely also explain cardiometabolic health disparities, such as racial differences in T2D prevalence.In a recent analysis of biomarker data from 1170 adults (20% Black, 56% women) enrolled in the Midlife in the United States Study, Fuller-Rowell et al. examined whether ACEs and adult psychosocial stress-including discriminatory and socioeconomic stressors-mediated race differences in insulin resistance. 137Notably, ACEs and adult stress together mediated 65% of the difference in HOMA-IR between Black and White adults in the United States. 137In a prospective, longitudinal study of 342 Black individuals (59% women) from the southeastern US, Barton et al. 138 assessed childhood socioeconomic status (years living in poverty) using the income-to-needs ratio based on family size at ages 11-18 years and quantified insulin resistance in young adulthood at ages 25, 27, and 29 years using the updated HOMA-IR method.Childhood socioeconomic status predicted insulin resistance in young adulthood, such that every additional year living in poverty in childhood was associated with a 1.04-unit increase in HOMA-IR. 138Perceived life chances partially mediated this association, suggesting that a more hopeful outlook may provide resilience to the adverse effect of psychosocial stress on glucose metabolism. 138Together, these data support that a life course psychosocial perspective should be taken to understand and reduce the risk of cardiometabolic disease development.
Notably, via the disruption of stress regulatory systems that also play an important role in the homoeostatic regulation of sleep, psychosocial stress is associated with sleep disturbance.For example, stress promotes activation of the HPA and SAM axes, which may promote heightened arousal and impair sleep (Figure 1).ACEs have recently been linked with reduced medial prefrontal cortex activation, which is an area of the brain important to normal sleep physiology and thought to play a role in initiating slow wave (stage N3) sleep. 139,140wever, it should be noted that all of these findings rely on selfreported sleep measures that may be vulnerable to bias, and studies are needed to confirm and better understand the sleep disturbances experienced by individuals with ACE exposure.Using a unique, within person prospective study design, Fuller-Rowell et al. 144 recently reported that on days when African American college students experienced greater discrimination, they also had poorer sleep quality.Moreover, internalised racism, or the degree to which African American students internalised negative racial stereotypes, moderated this relationship such that those with greater internalisation experienced greater sleep disruption. 144ese findings show that psychosocial stressors such as childhood adversities and racism play a causal role in adult sleep disturbance.
Together, this body of evidence suggests that disrupted sleep is a downstream effect of chronic psychosocial stress that could plausibly mediate or moderate the association of psychosocial stress with cardiometabolic risk.However, both prospective cohort and experimental studies will be necessary to carefully untangle the role of sleep in this association.Given the bidirectional relationships between sleep and stress 145,146 and because peripheral metabolic signals may also influence biological stress responses, 147,148 it is also possible that intervening to improve sleep could reduce the physiological stress response to psychosocial stress 147,149,150 and thus reduce cardiometabolic risk.Again, longer-term experimental studies will be necessary to test this hypothesis.Finally, it is evident that chronic psychosocial stress does not influence health outcomes equally across individuals.High levels of social and emotional support, access to social resources, greater psychological coping (e.g., control, self-efficacy, resilience, hope) and lower negative effect have all been suggested to provide a measure of resilience to the effects of psychosocial stress. 120,151Work will also be needed to understand how these factors moderate the association of psychosocial stress with disrupted sleep and cardiometabolic health.

| THE ROLE OF PHYSICAL EXERCISE IN THE ASSOCIATION OF POOR SLEEP WITH CARDIOMETABOLIC DYSFUNCTION
Exercise is a primary zeitgeber, or an external stimulus that regulates circadian rhythms by regulating molecular clocks.not normalise any of these outcomes.Thus, Porter et al. concluded that exercise is not an optimal strategy for ameliorating the negative effects of sleep restriction in individuals with obesity. 157Of note, this was the first sleep restriction and exercise study completed in individuals with obesity, it appears to be the only one to date to also include women.Premenopausal women have previously been shown to be protected against other insulin resistance-inducing behaviours, namely consuming sugar sweetened beverages and reducing the daily physical activity over 10 days, compared to men. 158Thus, future studies should specifically explore whether there are sex differences in the metabolic responses to sleep restriction and sleep restriction with exercise.It is also plausible that an un-measured attribute strongly related to obesity such as low cardiorespiratory fitness may explain the inability of exercise to rescue the cardiometabolic impairments caused by sleep restriction in individuals with obesity.In partial support of this hypothesis, there is evidence that habitual moderate intensity physical activity has a strong effect on the relationship between sleep quality and insulin concentrations, whereas light intensity activity does not. 159Similarly, a very recent study indicates that performing a high volume of physical activity attenuates associations of short sleep duration with all causes and CVD mortality compared with performing low volumes of physical activity. 160 can be hypothesised that these individuals, that is, those performing higher-intensity physical activity, would have greater cardiorespiratory fitness.Thus, it is plausible that cardiorespiratory fitness may moderate the adverse cardiometabolic effects of impaired sleep, but to our knowledge, there is no direct evidence that this is the case.Thus, future experimental studies will be needed to understand if and how fitness may interact with sleep to promote cardiometabolic health.restriction, but exercise counteracted this pattern of gene set enrichment. 166It should be noted that the degree of enrichment was much smaller than in prior studies that used total sleep deprivation, suggesting that moderate sleep restriction is not as detrimental as total sleep deprivation.It should also be noted that these findings were observed alongside reduced skeletal muscle mitochondrial function and impaired glucose tolerance following sleep restriction that were also counteracted by exercise. 154A very recent study using accelerometer data from the UK Biobank provides additional evidence supporting the protective effect of physical activity for counteracting the negative effects of disturbed sleep. 160 A secondary analysis of the FIT-AGEING study indicated that neither actigraphymeasured sleep efficiency nor wake after sleep onset was associated with resting whole-body fat oxidation rate among 70 middle-aged sedentary adults, although PSQI global score was (R 2 = 0.225-0.391).In 812 middle-aged and older adults from the communitybased Heart Strategies Concentrating on Risk Evaluation study, loud snoring was associated with an increased risk of low HDL-C, perhaps by snoring related sleep fragmentation or via a sleep disordered breathing-related mechanism. 47Among ~6500 40 to 60-year-old Finnish adults, frequent insomnia symptoms, such as difficulty in initiating and maintaining sleep and having non-restorative sleep, former study, Ness et al. examined postprandial lipaemic responses following 4 consecutive nights of sleep restriction versus control (5-h vs. 10-h TIB) in 15 young healthy men.While an increase in postprandial lipaemia may have been expected, sleep restriction instead suppressed the postprandial triglyceride (TG) area-under- Aho et al. reported that 5 consecutive nights of sleep restriction (4-hvs.8-h TIB) promoted a decrease in the number of small, medium, and large LDL-C particles, as well as VLDL-C in circulation without impacting HDL-C levels, again a seemingly counterintuitive finding that does not entirely agree with the aforementioned epidemiological evidence.However, sleep restriction also promoted the downregulation of genes involved in intracellular lipid, cholesterol, and sterol transport and homoeostasis.40In contrast to the findings of Aho et al., O'Keeffe et al. reported that 5 consecutive nights of sleep restriction (4-h vs. 9-h TIB) had no effect on 24-h TG profiles or on LDL-C or HDL-C.49However, it is plausible that O'Keeffe et al. did not observe the effect of sleep restriction on lipoprotein levels because the traditional spectrophotometric-based quantification of lipoprotein levels used in this study cannot provide an indication of particle size.As previously described, it will be necessary for future studies to consider lipoprotein particle size to fully understand the effects of sleep disruption on lipid metabolism.
measured total sleep time from nocturnal polysomnography and average sleep duration from a 6day sleep diary, and quantified fasting leptin and ghrelin levels from a serum sample obtained soon after awakening.Ghrelin concentrations were strongly and inversely associated with total sleep time (β = −0.69,p = 0.008), and leptin concentrations were positively associated with average sleep duration (β = 0.11, p = 0.01).In addition, wakefulness after sleep onset, an indicator of sleep quality, was positively associated with ghrelin (β = 0.81, p = 0.05) but not with leptin concentrations (β = −0.04,p = 0.40).Similarly, in a cohort of 769 postmenopausal women, Stern et al.
In 11 healthy men, Speigel et al. assessed 24-h leptin levels at the end of three different conditions with varying sleep durations performed across a consecutive 16-night period: 3 nights of 8-h TIB, 6 nights of 4-h TIB, and 7 nights with 12-h TIB.Leptin levels decreased in a stepwise fashion across the 4-h, 8-h, and 12-h TIB conditions.

F I G U R E 1
Plausible pathways link psychosocial stress exposure with sleep disruption and altered metabolism.Note that these pathways are likely bidirectional and co-reinforcing.HPA, hypothalamic-pituitary-adrenal; SAM, sympathetic-adrenal medullary.Created using BioRender.com.
Lin et al. posited that skeletal muscle transcriptomic alterations may contribute to improvements in insulin sensitivity commonly observed in response to exercise.[161][162][163][164]Sleep deprivation alters the skeletal muscle transcriptome, increasing mRNA expression of inflammatory pathways, decreasing expression of oxidative phosphorylation and muscle protein synthesis pathways, and altering transcription of circadian clock genes.165As exercise alters these same pathways in opposite directions, Lin et al. hypothesised that exercise may be able to mitigate the adverse alterations in these transcriptional pathways caused by sleep restriction.To test their hypothesis, 20 young men completed one of three separate 5-night conditions: control (8-h TIB, n = 6), sleep restriction (4-h TIB n = 7), or sleep restriction + exercise (4-h TIB with 3 HIIT sessions, n = 7).In partial accordance with their hypothesis, gene set enrichment analyses revealed increased enrichment of immune response and inflammatory pathways, and decreased the enrichment of gene pathways associated with mitochondrial function following sleep

Study sample Study design Sleep assessment Dependent variable Primary findings
Epidemiological/cohort evidence linking disrupted sleep with impaired glucose and insulin metabolism.
T A B L E 1Abbreviations: BMI, body mass index; CI, confidence interval; HOMA-IR, Homeostatic Model Assessment of Insulin Resistance; OGTT, oral glucose tolerance test; OR, odds ratio; PSQI, Pittsburgh Sleep Quality Index.

2.2 | Experimental sleep manipulation
to separate the effects of sleep restriction on glucose versus 52These findings suggest a dissociation between the recovery of NEFA and glucose metabolism during sleep recovery (i.e., extending sleep duration to sufficient durations following restriction) that seems to be counter to the linked effects of sleep restriction on NEFA and glucose metabolism.Additional mechanistic studies utilising tracers are necessary to better understand these inter-relationships to determine tissue-specific (e.g., peripheral vs. hepatic) metabolic changes in response to acute and chronic sleep restriction as well as in response to sleep recovery.Finally, to our knowledge, little or no work has been done to understand sex-or age-specific effects, with many of the aforementioned studies completed primarily or only in young healthy men.
reported that while individuals between 32-49 years of age who self-reported sleeping less than 7 h 106That is, short sleep may cause initial, relatively dramatic weight gain, but this effect is tempered as weight increases.
Studies on sleep duration and body weight included are primarily those examining longitudinal associations of sleep duration with weight gain in general adult populations or children/adolescents. Abbreviations: BF%, relative body fat; BMI, body mass index; CI, confidence interval; OR, odds ratio; VAT, visceral adipose tissue; WASO, wakefulness after sleep onset.
75. reported that 5 days of insufficient sleep led to a significant 0.82 kg increase in body weight in a clinical, experimental study.75It is unclear whether this increase in weight was due to body fat gain or to some other cause.For ROGERS ET AL.T A B L E 2 Epidemiological/cohort evidence linking disrupted sleep with altered hunger, Satiety, and bodyweight regulation.T A B L E 2 (Continued) T A B L E 2 (Continued) T A B L E 2 (Continued) T A B L E 2 (Continued) Note: Liang et al. 160demonstrated that, among ~92,000 middle-aged and older adults (mean age 62 � 8 years), meeting the recommended weekly dose of moderate-to-vigorous physical activity (MVPA) reduced the incidence of all-cause and CVD-related mortality by 2.3-2.5-foldamongthose with short sleep duration (<6 h/day) compared to those who did not meet MVPA guidelines.Thus, these findings support that exercise (or physical activity) may be able to offset the metabolic impairments induced by short-term sleep restriction, but additional work is necessary to understand if these effects extend to populations other than young healthy men.CONCLUSIONS Overall, sleep should be considered an important modifiable risk factor whenever seeking to improve metabolic health in all populations, with both sleep duration and sleep quality considered.Collectively, the body of evidence demonstrates that short sleep duration and poor sleep quality are associated with, and causally promote, decreased peripheral insulin sensitivity.Evidence regarding the impact of sleep disruption on lipid metabolism is not as strong but also suggests that short sleep durations may causally promote impairments in lipid metabolism, although more work is needed to understand the effects of sleep quality (i.e., SWS suppression).Finally, there is evidence to suggest that sleep disruption alters leptin and ghrelin metabolism, hunger and satiety, and thus impairs the ability to regulate bodyweight.Notably, most studies examining the association of sleep disruption with bodyweight have done so using selfreported sleep with BMI as the primary endpoint.However, evidence exists to suggest that sleep disruption could alter body composition and perhaps where body fat is deposited (i.e., viscerally).Future studies should consider this and use a more specific endpoint (i.e., waist circumference) to better define the cardiometabolic impacts of long-term sleep disruption.Additional work is needed to better understand if there are sex-specific metabolic effects of sleep disruption, especially in experimental restriction studies, given that the vast majority of evidence currently exists using male-only subject populations.As we have shown, psychosocial stress represents an important and overlooked risk factor for cardiometabolic risk and poor sleep that can also explain extant racial disparities in cardiometabolic and sleep health.However, additional work is needed to carefully untangle the interplay between psychosocial stress, sleep 8 | disruption, and cardiometabolic risk.Finally, the assumption of reverse causality represents a major current weakness in the sleep and cardiometabolic health literature.That is, experimental evidence shows that disrupting sleep causes impairments to cardiometabolic health.However, very few data exist to show that improving sleep (duration or quality) in individuals with disrupted sleep causes ROGERS ET AL.