To Sleep, Perchance To Eat

Marlys R. Drange and Shlomo Melmed

Cedars-Sinai Research Institute University of California Los Angeles School of Medicine Los Angeles, California 90048

Address correspondence and requests for reprints to: Shlomo Melmed, M.D. Division of Endocrinology and Metabolism, Becker B-131, 8700 Beverly Boulevard, Los Angeles, California 90048.


    Introduction
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 Introduction
 References
 
Sleep, along with feeding, reproduction, and self-defense, is intuitively one of the most fundamental requirements for living creatures. Physiological mechanisms involved in sleep regulation are incompletely understood and undoubtedly complex. Pathological disturbances including infectious diseases, inflammation, and sleep deprivation result in excessive sleep, alter hypothalamic-pituitary function, and potentiate cytokine production. These observations have led to the suggestion that cytokines may be involved in normal sleep regulation.

Cytokines are small-to-medium size proteins that act as intercellular regulators of cellular changes in metabolism and function. Most cytokines have been well conserved throughout evolution, and many have redundant biological activities, suggesting that cytokines comprise a complex regulatory system for mediation of important physiological processes. Cytokines mediate a wide range of pleiotropic biological responses and regulate neuroendocrine function (1). For example, the known functions of Interleukin (IL)-1 and tumor necrosis factor (TNF) include local induction of adhesion molecules and chemotactic cytokines as well as systemic actions such as fever, the acute phase response, activation of bone marrow (2), and possibly, regulation of sleep. These inflammatory cytokines have been demonstrated to have somnogenic activity (3). TNF{alpha} and IL-1ß enhance non-rapid-eye movement sleep, increase the amplitude of electroencephalogram slow waves, and suppress rapid-eye-movement sleep in animals (4).

In this issue of JCEM (see page 1313), Vgontzas and colleagues provide a report that explores the role of circulating TNF{alpha}, IL-1ß, and IL-6 in disorders causing excessive daytime sleepiness such as sleep apnea, narcolepsy, and idiopathic hypersomnia (5). Their results reveal that plasma levels of TNF{alpha} were elevated in patients with both sleep apnea and narcolepsy, IL-6 levels were elevated only in sleep apnea patients, and interestingly, IL-1ß levels were not altered in sleep disorders. The authors conclude that TNF{alpha} and IL-6 may mediate sleepiness and fatigue in disorders associated with excessive daytime sleepiness. Also, these authors demonstrate for the first time an association between obesity and IL-6 levels. These results present the intriguing possibility of a novel function for IL-6. Nonetheless, several issues warrant greater scrutiny in the interpretation of these data.

The results of Vgontzas, et al. are based on cytokine levels measured in single blood samples drawn at 0600–0700 on a single morning following an 8 h polysomnographic-monitored sleep. There is conflicting data in the literature regarding the timing of cytokine release. Previous data have indicated that IL-1, IL-6, and TNF{alpha} increase during nocturnal sleep (6, 7, 8). Conversely, other reports have shown that the production of TNF{alpha} and IL-1ß increases during wakefulness (9). There are also reports purporting that cytokine release follows circadian rhythmicity (7, 8). However, elevations of these cytokines seen during wakefulness, shift with the period of sleep deprivation (9), while circadian-dependent processes persist during acute sleep deprivation (10). These findings suggest that circulating cytokine levels may not be under circadian control. Given the discrepancy regarding the relationship of peak cytokine levels to sleep cycle or time of day, the significance of elevated early morning IL-6 and TNF{alpha} levels in patients with nocturnal sleep disturbance is less clear.

The role of marked differences between the control subjects and sleep apneic patients in age (24.1 yr ± 0.8 vs. 40.9 yr ± 2.2) and body mass index (BMI) (24.6 ± 0.7 vs. 40.5 ± 3.2) must be considered when drawing conclusions as to the etiology of cytokine level differences between these groups. The authors address this by assessing a stepwise multiple regression in which BMI and age were found not to correlate with TNF{alpha} values, but BMI positively correlated with IL-6 values. These findings are enigmatic given that elevated expression of TNF{alpha} messenger RNA, and secretion of TNF{alpha} protein in adipose tissue has been demonstrated in rodents (11) and humans (12). Failure to previously demonstrate elevated plasma levels of TNF{alpha} in obese individuals was likely the result of insufficient sensitivity of the assay. Indeed, TNF{alpha} plasma levels were detectable in only 58% of obese animals (11). In the present study by Vgontzas and colleagues (5), the lower limit of TNF{alpha} detection (0.18 pg/mL) appears to be nearly an order of magnitude lower than previously reported assays. Thus, it is unclear if the elevated levels of TNF{alpha} detected are related solely to obesity or to altered sleep regulation associated with sleep apnea. Additional nonobese control subjects with sleep apnea would be valuable in making this distinction.

The suggestion that IL-6 plays a role in sleep regulation and the demonstration of an association with obesity are novel. IL-6 was found to be pyrogenic, but not somnogenic when injected intracerebroventricularly in rabbits (13). Moreover, enhanced expression of IL-6 messenger RNA was not detected in obese rodents (11). TNF{alpha} and IL-1 are known to induce IL-6 production (2). These findings suggest that plasma IL-6 levels may be indirectly elevated secondary to IL-1- or TNF{alpha}-mediated effects on sleep or obesity. Further investigation is necessary to establish if IL-6 levels are elevated independently of other cytokines and to determine the nature of IL-6 involvement in sleep regulation.

The manuscript by Vgontzas and colleagues (5) is unique and pivotal in the field of neurocytokine regulation of sleep research because it represents one of the first reports in which cytokine levels are directly determined in the plasma of nonpharmacologically-stimulated individuals. A number of the technical obstacles faced by Vgontzas in conducting this study and interpreting the data are shared by all investigators in the field of neurocytokine regulation of sleep. Among these are insufficient sensitivity of assays in the past to detect normal physiological cytokine levels. For this reason, many of the published reports employed indirect assays involving stimulation of cytokine production with microbial products. It is unclear if exogenous stimulation provides proportional cytokine production, or even if such stimulation alters normal physiology. This technical shortcoming of the assays to accurately detect normal levels of cytokines has led to confusing and often contradictory reports in the literature. Indeed, circulating cytokine levels may not accurately reflect timing or levels of production in the central nervous system where presumably the regulation of sleep is occurring. Additional factors that may confound interpretation of plasma cytokine levels are bioavailability, presence of coregulators, variable time courses of degradation, or indirect activation of additional mediators. Finally, normal physiology is difficult to model in vitro, and experimentation with human subjects is, of necessity, limited in scope. Animal studies provide an in vivo model; however, the sleep-wake cycles of the commonly used laboratory animals do not approximate those of humans.

Despite these obstacles, the future of research into the physiologic regulation of sleep remains potentially productive. Cytokine regulation of physiological sleep is perhaps one of the most exciting areas of neuroendocrine investigation and promises to become even more so as the tools for inquiry become more readily available. Although the circadian rhythmic secretion of anterior pituitary hormones is well-documented, mechanisms mediating sleep-related hormone rhythms remain unclear. Sleep disorders are important causes of morbidity and mortality in endocrine and nonendocrine disease. Morbidity of hypothalamic disease, acromegaly, diabetes, and thyroid disorders may to a large extent be ascribed to dysregulated sleep function (14). Thus, studies such as that by Vgontzas and colleagues (5) will provide important information toward understanding the etiology of sleep disorders and perhaps aid in their prevention or cure. Furthermore, the versatile and redundant functions of various cytokines are just beginning to be elucidated. Knowledge of the functional interrelationships between these mediator proteins will lead to a greater understanding of one of the most fundamental biological processes.

Received February 18, 1997.

Accepted February 24, 1997.


    References
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 Introduction
 References
 

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