Orexins, energy balance, temperature, sleep-wake cycle.

THE LAST DECADES HAVE WITNESSED an upsurge of neuropeptide research. These substances regulate or influence various functions like appetite, water intake, learning and memory, adaptive responses to environmental stress, thermoregulation and fever, social behavior, and sleep. One function may be affected by several peptides, and a single peptide can be involved in different functions—a general approach is to find a coordinated pattern, which appears “meaningful” in explaining how a given peptide may participate in complex events. Orexins (hypocretins) have originally been described as peptides regulating feeding behavior (30) and as neuroexcitatory substances setting the threshold for arousal (6). These two functions may be related, possibly offering a pattern (alertness is a natural precondition of feeding), but they may as well be unrelated. Although food intake regulation is an integral component of the overall energy balance (together with metabolic rate and body temperature regulations) (34), not necessarily all factors of energy balance are coupled with the regulation of sleep-wake behavior, even if feeding behavior and arousal state prove to be related. This is what makes very interesting the recent article by Mochizuki et al. (21) in the present issue of American Journal of Physiology: Regulatory Integrative and Comparative Physiology. This paper suggests a relationship between orexin’s effects on the regulations of body temperature and sleep/wake cycle. The article also indicates an increasing need to analyze the spectrum of orexin’s effects in a complex way. The orexin-induced hyperphagia might be interpreted as part of a coordinated anabolic reaction. This approach resembles that applied in the analysis of neuropeptide Y’s (NPY’s) effects (33). Physiologically, NPY is activated during food deprivation and hunger. The anabolic regulatory pattern seen in fasting involves a tendency to gain calories (hunger) and another one to retain the already available calories by a regulated suppression of metabolic rate (decreased utilization of caloric substances in the body), with a consequent tendency for hypothermia. Central NPY administration induces food intake, tends to suppress metabolic rate (33), and enhances wakefulness (35). Because basal metabolic rate (BMR) cannot be decreased by physiological means, injections of NPY can only suppress the excess metabolism above BMR, for example, that seen during cold exposure or possibly during the active phase of the circadian cycle (33). Understandably, the hypometabolic-hypothermic action can be demonstrated mainly in cool environments. Later on, the hyperphagia, hypometabolism, and hypothermia are followed by a probably indirect catabolic effect causing a rise in metabolic rate and body temperature, as well as a suppression of normal food intake for 12–24 h. At or near thermoneutrality, only the catabolic effects are obvious (except for a persisting early hyperphagia), and here these appear somewhat earlier than in the cold. Some, although not all (15), data suggest that orexins possibly follow a similar anabolic pattern. Certain orexin actions are known to involve NPY mechanisms (39). Central injections of orexin-A in rats enhanced food intake for about 30–60 min, and they induced hypometabolism and hypothermia for a similar period in rats kept slightly energy-deficient in a cool (but not at thermoneutral) environment (32). However, similarly to NPY, they did not influence heat loss as represented by tail skin temperature. Central orexin injections also attenuated the experimental fever (13). These primary orexin effects were followed by a secondary hypermetabolism and hyperthermia (32), particularly at relatively warm ambient temperatures, possibly due to activation of catabolic neuropeptides like corticotrophin-releasing hormone (28) or to enhanced activity of prostaglandins (22). In contrast, SB-334867, a food intake suppressing antagonist of orexin receptor (12), elevated thermogenesis (9). Although other data reported on hypermetabolism, hyperthermia (15, 22, 23), or increased nonexercise activity thermogenesis (25) upon central administration of orexin-A, most of these measurements were performed long (2–6 h) after the injection and/or at room (not cold) temperature, and likely reflected the secondary, indirect effects of the peptide. The other line of orexin effects appears to be more clear-cut: orexins have an outstanding role in sleep-wake regulation. The hypothalamic orexin levels of rats exhibited a circadian pattern: the levels gradually increased in the active phase and gradually decreased in the rest phase (7, 41). Orexin-deficient mice showed severe abnormalities of their sleep-wake cycle (5, 8), with an enhanced number of behavioral phase shifts (20). In patients with narcolepsy-cataplexy, both the number of orexin neurons (36) and the orexin levels in the plasma (10) or cerebrospinal fluid (19) were decreased. In orexin neuronablated mice with narcolepsy and cataplexy exogenous orexin inhibited the cataplexy and improved wakefulness for hours (18). Conversely, SB-334867 prevented the orexin-induced reduction in paradoxical sleep and also the increase in latency of onset of such sleep (31). Sleep deprivation causes a rise in hypothalamic orexin levels (37), although the mediation of this process has not been clarified.