This article presents evidence for how sleep problems and chronic inactivity interact negatively to cause obesity. Some believe that fully understanding pathophysiology requires a full understanding of our native, healthy state. This state derives from a genome crafted by natural selection in conditions very different from modern life (5,11,41). Based on this premise, the article reviews current work from a biological/evolutionary perspective, which is not always used in medical literature. Interdisciplinary integration of sleep medical and exercise science findings may provide new explanations for the obesity epidemic, which in turn may yield new approaches to curbing it.
AN EVOLUTIONARY PERSPECTIVE: WHAT IS OUR GENETIC HISTORY FOR SLEEP AND ACTIVITY?
Food-gathering and other physical activity dominated the daily lives of our early ancestors (28,72). Depending on locality and season, this activity involved the walking, running, climbing, swimming, earthmoving, lifting, manual labor, and so on necessary to gather, farm, hunt, raise, and otherwise procure and process nutrition sources, maintain shelter, and sustain life. The activity was often vigorous and prolonged. Furthermore, physical games or dance often filled leisure time (13,59). It is safe to say that very few, if any, people 10,000 yr ago regularly sat for 10-14 h·d−1: their lifestyle created the high fitness level upon which their survival depended (5,11,41).
But what about their nights? Fire provided the only light source after sundown that could be created or controlled, so darkness limited activity. Melatonin is a key endogenous hormone responsible for priming our body for sleep (61). Blue light impinging on the retina, such as that from the daytime sky, activates neural pathways that suppress melatonin secretion (67). Given our diurnal circadian rhythm, it makes teleologic sense that sky blue inhibits somnolence. Conversely, firelight contains predominantly yellow and longer wavelengths, and therefore probably offers minimal interference with melatonin secretion. These observations suggest that with sunset, our early ancestors' central nervous systems initiated preparations for sleep onset.
Thereafter, the adults probably slept 8-9 h each night, because this is how long healthy adult subjects sleep today in conditions where no incentive or pressure exists to stay up late, and they wake on their own without an alarm (19,33). The full night of sleep allowed ample time for delta sleep, which the brain prioritizes early in the sleep period, and for a full quota of REM sleep, most of which is delayed to the latter part of sleep period. An early bedtime provided the adaptive advantage of being awake at or before sunrise, so as to make full use of the coming daylight. Adequate nightly sleep provided the adaptive advantage of optimal daytime cognitive (21,30) and physical performance (39,40,52), and therefore minimized risk of detrimental or life-threatening performance deficits (25,66).
Furthermore, a positive synergism existed between their daytime activity and nightly sleep. Multiple studies and meta-analyses demonstrate that regular exercise increases sleep duration and improves sleep quality in a variety of ways, the most important of which may be increased delta (slow-wave, or N3) sleep (20,34). Recent studies confirm these findings in older adults (17,32). Much of our daily growth hormone secretion occurs during delta sleep (69), and the anabolic properties of this hormone in part mediate the restorative properties of sleep (70). Who hasn't witnessed or heard anecdotes about how long and well everyone slept after the long hike or day at the amusement park? In Shakespeare's words, "Weariness can snore upon the flint, when resty sloth finds the down pillow hard." As noted previously, the enhanced sleep duration and quality, in turn, further facilitate next-day physical activity and performance (39,40,52), thus closing the synergistic loop (Fig. 1).
These collective observations define our genotype as trained athletes who go to sleep soon after sundown and sleep 8-9 h each night. The observations also reveal a synergistic interdependence between physical activity and sleep, whereby each benefits from and optimizes quality of and capability for the other. "Normative" sleep and circadian rhythm data gathered from sedentary, sleep-deprived populations after the industrial revolution do not represent accurately our evolutionary heritage. Further, natural selection created genetic underpinnings that conflict with our modern lifestyle and the phenotype it generates (5,11,41).
WHAT CAN GO WRONG WITH SLEEP? ARE WE OUR OWN WORST ENEMY?
Behaviorally-induced insufficient sleep syndrome is the most common sleep disorder, as well as the most common cause of daytime sleepiness and fatigue (36,44,47). Also consider that sampling bias skews estimates of sleep disorder prevalence derived from patients seeking help for sleep problems. It virtually is certain that the large majority of people who choose not to sleep enough also choose not to tell their doctor or otherwise seek medical help for the problem. Insufficient sleep syndrome meets the definition of a pandemic.
A more fundamental problem may be simple ignorance of sleep need or value: for example, an informal survey by the author found that only 32% of 25 respondents understood that regular dependence on an alarm clock implies either insufficient or unhealthy sleep. A survey given by Men's Health magazine (April 2009 issue) included the question "What's the most important factor for good health?," but sleep was not among the seven possible answers, which included "avoiding vices"! The U.S. Centers for Disease Control and Prevention Web site lacked any information about sleep disorders until about 2 yr ago.
Current research supports the natural propensity for humans to sleep significantly longer each night than our current approximately 6-7 h (6,25). As noted previously, studies where healthy sleepers sleep as much as they want document adult sleep needs of 8-9 h each night (19,33), with children requiring still more. Most of the decline in our nightly sleep occurred very recently in terms of geologic time: we now sleep roughly 2 h less per night than we did even 50-100 yr ago (47,57,73). Research terminology presents further evidence of our current sleep restricted state: we use "sleep extension" to describe studies involving nightly sleep duration beyond current "norms" (18,30,39,40). "Sleep repletion" may describe the concept better.
Other common sleep disorders include obstructive sleep apnea (OSA), restless legs syndrome (RLS), and insomnia (55). Insomnia is much more often a symptom than a primary disorder (46). For example, RLS commonly interferes with sleep onset at the beginning of the night (31,75), whereas sleep interruption from OSA commonly causes sleep-maintenance insomnia (4). Still other cause-effect relationships exist between sleep disorders. For example, simple sleep restriction can cause OSA in otherwise healthy individuals (63). A common lament in a sleep clinic: "His snoring is much worse when he's very tired." Similarly, sleep restriction exacerbates RLS symptoms, such that first-line treatment for RLS includes getting adequate nightly sleep (31,75).
These observations illustrate an insidious feature of many sleep disorders: pathophysiologic vicious cycles. In these examples, OSA reduces sleep continuity (quality) and duration, and these factors increase sleep drive, which then feeds back to exacerbate OSA severity. Similarly, RLS commonly provokes insomnia, and the resulting sleep restriction intensifies the RLS. Clearly, sleep problems such as insomnia, OSA, and RLS occur as primary disorders and are beyond the control of many patients. However, the degree to which self-imposed insufficient sleep followed by pathophysiologic cycling initiates and perpetuates these disorders remains an open question. These negative processes epitomize the exact antithesis of the natural positive synergism between healthy activity and sleep described previously.
DO SLEEP PROBLEMS LEAD TO INACTIVITY?
The answer to this question seems obvious: the current International Classification of Sleep Disorders lists over 80 total sleep and circadian disorders, and most lead to dysfunction while awake in the form of somnolence, tiredness, and/or fatigue (55). These symptoms, in turn, tend to discourage or limit physical activity (66). Insufficient sleep reduces daytime physical activity in healthy subjects (52). Also, OSA repeatedly interrupts sleep and thereby makes adults sleepy during the day; this daytime sleepiness translates into inactivity, and both sleepiness and inactivity correlate with OSA severity (3,27).
The above findings and observations derive from and apply to adults. Children react differently to sleep problems: instead of lethargy and inactivity, children commonly exhibit hyperactivity (53,74). In fact, attention-deficit/hyperactivity disorder (ADHD) in children often results at least in part from chronic sleep restriction and/or sleep pathology such as OSA or RLS (12,45). This connection informs the logic behind use of stimulant medications ("You're prescribing my son what?") to reduce hyperactivity in children (42).
Roemmich and colleagues (53) studied outcomes after treatment of OSA in children with adenotonsillectomy. They quantified physical activity before and 6-27 months after correction of OSA. Both parental assessments and actigraphy showed reduced activity at follow-up: in simplistic terms, fidgeting decreased significantly. Therefore, an age-related dichotomy exists in how sleep problems affect activity, with adolescents in the transition between hyperactive responses in younger children and hypoactive responses of adults.
HOW ELSE CAN SLEEP DISORDERS CONTRIBUTE TO OBESITY?
Inactivity unquestionably promotes weight gain, but other factors also may explain how sleep disorders contribute to obesity. Effects of sleep restriction or disruption on energy metabolism constitute one such mechanism. Multiple recent reviews conclude that sleep restriction exhibits independent association with obesity (48). Accumulating data indicate that inadequate or poor-quality sleep, and OSA in particular, adversely affect glucose metabolism (64,68). For example, Tasali and colleagues (65) recently documented that selective reduction of delta sleep compromises insulin sensitivity. Hormones known importantly to regulate energy metabolism, such as growth hormone, are secreted during delta sleep (69). Sleep restriction appears to affect reversibly secretion of and/or responsiveness to the adipocyte hormone leptin and the orexigenic hormone ghrelin, with associated increases in appetite (60).
OSA elicits cyclic hypoxemia and hypercapnia during sleep, and these synergistically interact to stimulate acute and eventually chronic elevation of sympathetic nervous system activity (SNA) (14). Chronic and inappropriate sympathoexcitation, in turn, is an established driver of energy dysmetabolism and diabetes (9). In addition to sympathoexcitation, hypoxemia accentuates free radical formation, which in turn incites the inflammatory response (2). Growing bodies of work implicate chronic tissue inflammation as a key pathophysiologic mediator of diabetes and obesity (1,15,29,54,62,71). Chronic excessive musculoskeletal loading from excess weight coupled with sustained tissue inflammation causes arthritis (1). The associated pain limits activity, which promotes further weight gain.
Medications for common comorbidities of obesity and sleep disorders may essentially produce iatrogenic exacerbation of the situation. Such comorbidities include type II diabetes, depression, and ADHD (3,9,12). Previous works summarize how drugs often prescribed for diabetes and depression promote weight gain as a side effect (8). In the present context, the paradox and opportunity is that regular physical activity provides treatment superior to medications for both diabetes (35) and depression (23), in part because exercise offers myriad other health benefits and lacks negative side effects. Not surprisingly, stimulants prescribed for ADHD sometimes cause insomnia (42). If the ADHD originally resulted from simple inadequate sleep, then the medication facilitates the very behavior that led to its prescription.
The previous discussion summarizes isolated cause-effect relationships that, when integrated into a "big picture," form multiple interwoven vicious cycles between sleep problems, inactivity, and obesity (Fig. 2). Tiredness from insufficient sleep leads to daytime inactivity that reduces sleep quality (20,34,52,66). Obesity from inactivity leads to orthopedic problems and deconditioning that further limit activity. Glucose and appetite dysregulation from OSA promote obesity that exacerbates OSA (8). Medications for diabetes and depression associated with OSA cause weight gain that worsens the OSA, diabetes, and depression (8). Some links are more hypothetical than others depending on the number and type of published works that test specific pathophysiologic relationships (Fig. 2). Detailed mechanisms of many relationships remain described only partially. Nevertheless, existing findings reveal how chronic sleep dysfunction coupled with sedentary living initiates multiple self-perpetuating and unhealthy processes. It is frightening to consider that most of the morbidity shown (exceptions include arthritis) now occurs in children (24,43); this would have been unthinkable 50 yr ago.
DOES TREATING OSA FACILITATE WEIGHT LOSS?
Given its growing prevalence and clinical significance, OSA provides a common, albeit impure, model of how sleep disorders may cause obesity. Based on the evidence presented previously in this article, it is reasonable to expect that treating OSA increases activity and facilitates weight loss. To test this idea, we reviewed follow-up data for 28 randomly selected patients with obesity and OSA (13 women, 15 men) at 8-126 months (mean = 42) after initiation of successful positive airway pressure (PAP) treatment. We define treatment success as nightly all-night PAP use confirmed by PAP machine data, along with stable arterial oxygen saturation during treatment demonstrated by nocturnal oximetry. Our follow-up protocol uses a questionnaire to assess subjective responses to treatment. Specific questions include whether PAP treatment negatively or positively affects daytime energy levels and physical activity.
A total of 79% of patients reported increased daytime energy relative to pre-treatment, and 64% reported increased activity. Anecdotes included a father who exhausted his young children while playing at the local park, whereas pre-treatment he couldn't be convinced to go to the park. In spite of patient perceptions of increased energy and activity, mean weight increased 4% from 106.1 (standard deviation [SD] 23.9) kg at baseline to 110.1 (SD 23.1) kg at follow-up (P = 0.001). Weight increased 5% in the 64% of patients who reported increased activity. Similarly, Harsch and colleagues saw no weight reduction with months to years of PAP treatment of OSA in two different studies (26,49), although their treatment success criteria were more inclusive than ours.
Given the prevalence of insufficient sleep discussed previously, most subjects in these studies probably exhibited restricted sleep regardless of OSA treatment. In fact, our experience suggests many patients sleep fewer hours per night after starting PAP treatment than they did beforehand: the improved sleep quality enables them to further restrict their sleep duration. This tendency may circumvent beneficial metabolic effects of PAP treatment (48,68). Nevertheless, current reports do not suggest that treatment of adult OSA leads to weight loss. For the patient with obesity and severe OSA, associated inactivity, and strong motivation to lose weight, it seems certain that successful treatment of OSA facilitates weight loss, but this remains to be demonstrated.
Does treating OSA facilitate weight loss in children? Recall the study by Roemmich and colleagues (53) discussed previously in which activity decreased in children after correction of OSA by adenotonsillectomy. Not surprisingly, percentage overweight for the group increased from 25% at baseline to 30% at follow-up. Reduction in activity correlated with weight gain. "Honey, I blew up the kids!" These observations imply that treatment of childhood OSA constitutes a prescription for adult OSA. Obviously, OSA in children deserves treatment, but to achieve chronic success, such treatment must be much more comprehensive than simply opening the airway with surgery. These findings go directly to the larger societal problems of sleep restriction, inactivity, and poor diet.
Before establishment of PAP to treat OSA, first-line treatment consisted of weight loss (38). It is interesting to note that Quan and colleagues (50) observed that exercise may reduce OSA severity both in association with, and independent of, reduction in body weight. In overweight children, Davis and colleagues found that regular vigorous exercise reduced snoring without affecting weight (16). This benefit of exercise illustrates that factors other than obesity contribute to severity of sleep-disordered breathing. While mechanisms underlying these findings remain unclear, they reinforce the complexity of interrelationships between sleep disorders and activity.
Our historically recent penchant for sleep restriction follows directly from our ability to illuminate our retinas with physiologically significant levels of blue light after sundown. This capability enables us to delay nightly sleep onset by artificially suppressing pineal melatonin secretion (67). More than simple blue wavelengths, however, drive the most recent and important encroachment on sleep duration: first television starting in the 1950s, and then evening computer and video game use starting in the 1990s (7,10), provide mental stimulation that helps postpone sleep. Furthermore, computer use post-2000 imposes a substantially stronger stimulus than television viewing pre-1990 for at least three reasons. First, computer use is interactive, and increased broadband access has accelerated this interactivity. Even with remote channel changing, television provides far less interactive stimulation. Second, computer monitors at a typical workstation occupy about twice the field of view of a television in a typical viewing environment (author's calculations). Third, common computer "desktops" and viewing backgrounds tend to be brighter than television programming. The latter two characteristics suggest that computer use may inhibit melatonin secretion more strongly than television. This combination of factors should increase significantly the wake-promoting influence of computer use relative to television, although this idea remains to be tested.
The timelines of the post-industrial revolution reductions in activity and sleep seem roughly parallel, including the somewhat accelerated reductions over the last few years (5,11,47,73). Adding insult to injury, the pastimes engaged in instead of sleep are themselves largely sedentary (7,10). The increased availability, variety, and strength of caffeine sources unquestionably factors into the sleep restriction pandemic by further enabling delay of sleep (7). The modern office workplace imposes still another challenge: daytime activity remains limited for those with sedentary jobs, regardless of how much or how well they sleep. How much less active can we become? How much less sleep can we get? Modern society shows interest in exploring these limits.
DOES NUTRITION FACTOR INTO ACTIVITY-SLEEP INTERDEPENDENCE?
Diet unquestionably plays a central role in causing obesity, yet diet may not influence activity-sleep interdependence importantly. Revisiting the evolutionary perspective, much of what developed societies eat today is just as foreign to our genetics as inactivity and limited sleep. Results presented previously in this article illustrate how sleep dysfunction adversely affects diet (60) (Fig. 2). Increased physical activity obviously increases nutritional requirements, such that inactivity decreases them. However, aside from the previously mentioned caffeine sources, what and how much people eat is not a major determinant of activity levels, bedtimes, or sleep quality under normal circumstances. Yes, some foods such as those containing tryptophan may aid sleep onset or elicit subtle effects on sleep architecture (58), but neither our ancestors nor present-day humans routinely consume the same such foods every evening.
Consider nutrition, physical activity, and sleep as the three principle determinants of physical health. In terms of relative importance, our culture prioritizes nutrition highest, exercise closely second, and sleep a distant third. For example, a recent Internet search of health along with nutrition + diet, exercise + activity, or sleep + rest yielded 28.8 million, 28.3 million, and 19.8 million hits, respectively. This ranking is not new, and the Internet statistics may in fact represent an increased awareness and appreciation of sleep's importance compared to antiquity: Booth and Lees (5) quoted Hippocrates, "If there is any deficiency in food or exercise the body will fall sick."
From a biological perspective, the current hierarchy may deserve reconsideration, and not only because sleep dysfunction is now implicated in causing obesity. Time budgets provide one means to compare nutrition, activity, and sleep. Organisms devote time to bodily functions in part according to the relative importance of the function for survival. In even the most sleep-restricted modern humans, sleep occupies about 20% of their time, eating requires perhaps 12%, and true exercise may occupy 0%.
The strength of innate drive for a given function provides another biologically-based point of comparison. The brain sleeps according to a relatively uncomplicated but undeniably powerful drive. Unlike drinking, eating, or exercising, we cannot choose to sleep more than the central nervous system deems necessary, nor can we choose not to succumb to the eventually inevitable need for sleep. Put another way, both fasting and sleep deprivation are eventually fatal, but fasting takes substantially more time (22,51). Furthermore, humans volitionally can fast until death (e.g., Bobby Sands), whereas the sleep drive makes suicide by sleep deprivation impossible. Extracellular adenosine accumulation and probably other neurochemical factors favoring wake-sleep transition become overwhelming (56): the very cortex attempting to kill itself will succumb to delta sleep in a few days at most, and well before death.
No question exists that nutrition, activity, and sleep are all three important, and none substitutes for another. Hippocrates admonition, however, remains at best only two-thirds correct. Now even more than in his time, we ignore the critical role of adequate, healthy sleep at our peril.
IMPLICATIONS FOR RESEARCH, EDUCATION, AND MEDICAL PRACTICE
The sleep-activity-obesity relationships described previously in this article suggest many opportunities for research and education. The superficial Figure 1 creates more questions than answers about specific mechanisms underlying activity-sleep synergism. These questions go directly to the exact functions of sleep, which appear to depend on sleep stage, and which remain elusive. In this regard, studies of how sleep duration, type (stage), and quality affect cognitive performance and mood state far exceed studies concerning effects of sleep on physical activity and exercise performance. Understanding these effects and their mechanisms will allow investigation of methods to manipulate and exploit activity-sleep interdependence for medical and athletic purposes.
A need exists for studies comparing outcomes of medication use versus sleep and/or activity optimization. Our current medical culture relies heavily on medications. The pharmaceutical industry generously and rightfully supports basic and applied research directed at evaluating their medications. However, far less effort goes toward comparing benefits (and side effects) of medication use to benefits of sleep repletion and/or exercise interventions. As one hypothetical example, should a "magic pill" emerge to treat obesity, one would hope to see a study comparing long-term results from the medication to results from individual and combined diet, exercise, and sleep interventions.
As noted previously in this article, cultural and medical ignorance about sleep continues. This emphasizes the need to improve the sleep medical education of our doctors. While this sounds straightforward, know that some medical educators continue to support resident on-call scheduling that imposes profound sleep restriction. Such sleep restriction causes threefold greater medical errors leading to patient fatality compared with when residents work 16-h shifts (37).
Practicing caregivers receive little if any continuing education about specific disease-related benefits of activity and sleep. This void falls in stark contrast to the plethora of information doctors receive about medications. Drug companies fund representatives to provide lunch to doctor's offices, where they tout the benefits of their company's medication directly to the prescribing caregivers. Of course, there is nothing fundamentally wrong with this, but there are no advocates, educators, or lunch programs to explain, for example, how regular exercise provides treatment for depression superior to medication (23). If there were, doctors might be much more prone to formally prescribe daily enjoyable physical activity and/or increased sleep.
Equally important are educational initiatives like the R.E.M. Sleep Program offered by Sweet Dreamzzz, Inc. in Detroit. This organization teaches disadvantaged grade-school children about the necessity and value of sleep for their health and development and provides them with specific take-home guidance to inculcate healthy, long-term sleep habits. Education must avoid misinformation. Authoritative sleep medical organizations recommend no exercise within 3-6 h of bedtime. Given that they also recommend a bedtime to permit adequate nightly sleep, their exercise limitation effectively pits exercise against sleep for people whose workday evening provides the best time window for activity. The rationale for the recommendation holds that evening exercise increases body temperature at a time when body temperature decline should prepare us for sleep onset, and that vigorous exercise near bedtime is "activating." However, the recommendation conflicts with the substantial body of literature demonstrating benefits of exercise for sleep (17,20,32,34,75). Paradoxically, the body temperature argument may explain why evening is a good time to exercise: the post-exercise body temperature drop exaggerates the natural evening temperature decline heralding sleep onset. The admonitions to avoid all exercise within 3+ h of bedtime deserve reassessment.
As always, reality looms over the most well-meaning medical guidelines. No one believes we will all suddenly incorporate 1 h of enjoyable, vigorous physical activity into every day, avoid all evening television and computer use, and then go to bed every night at 9:00 p.m. However, our current situation offers much "low-hanging fruit." A large and growing segment of our population is obese, almost fully inactive, and sleeping less than 6.5 h per night.
Our inactive, sleep-restricted lifestyle might more accurately be termed a "deathstyle." Self-imposed inactivity coupled with insufficient sleep initiates pathophysiologic vicious cycling, which then perpetuates the initial problems and eventually leads to others. The collective observations call for a higher prioritization of sleep in our general medical care and our battle against obesity.
I thank ACSM for the opportunity to write this article, Drs. John Burk, Wendy Eubank, Mike Smith, Peter Raven, and especially Robert Carter III for numerous helpful discussions, my co-workers for their assistance, and Shannon Watenpaugh and my family for their support, interest, and patience.
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