OREXINS, ENERGY BALANCE, TEMPERATURE, SLEEP-WAKE CYCLE. Miklós Székely

Transcription

1 Page Articles 1 of 15 in PresS. Am J Physiol AJP: Regul Regulatory, Integr Integrative Comp Physiol and Comparative (March 23, Physiology 2006). doi: /ajpregu R FINAL ACCEPTED VERSION OREXINS, ENERGY BALANCE, TEMPERATURE, SLEEP-WAKE CYCLE Miklós Székely Department of Pathophysiology and Gerontology, Faculty of Medicine, University of Pécs, Hungary Number of pages: 15 Correspondence: Dr. Miklós Székely Department of Pathophysiology and Gerontology Faculty of Medicine University of Pécs 12 Szigeti H-7624 Pécs, Hungary Phone: Fax: miklos.szekely@aok.pte.hu Copyright 2006 by the American Physiological Society.

2 AJP: Regulatory, Integrative and Comparative Physiology Page 2 of 15 R Key-words: metabolic rate, heat loss, NPY, hypothermia, food intake

3 Page 3 of 15 AJP: Regulatory, Integrative and Comparative Physiology R 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, sleep, etc. 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 might be related, possibly offering a pattern (alertness is a natural precondition of feeding), but they might as well be unrelated. While 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 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 (NPY) 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

4 AJP: Regulatory, Integrative and Comparative Physiology Page 4 of 15 R 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). Since basal metabolic rate (BMR) cannot be decreased by physiological means, injections of NPY can only suppress the excess metabolism above BMR, e.g. 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 hyperhagia, 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 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 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 corticotrophinreleasing hormone (28) or to enhanced activity of prostaglandins (22). In contrast, SB , a food intake suppressing antagonist of orexin receptor (12), elevated thermogenesis (9). Although other data reported on hypermetabolism, hyperthermia (15, 22, 23), or increased non-exercise activity thermogenesis (25) upon central administration of orexin-a,

5 Page 5 of 15 AJP: Regulatory, Integrative and Comparative Physiology R most of these measurements were performed long (2-6 hours) 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 narcolepsycataplexy both the number of orexin neurons (36) and the orexin levels in the plasma (10) or cerebrospinal fluid (19) were decreased. In orexin neuron-ablated mice with narcolepsy and cataplexy exogenous orexin inhibited the cataplexy and improved wakefulness for hours (18). Conversely, SB 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. Since orexin-containing neurons have widespread connections between the hypothalamus and various sites of the central nervous system (2, 26), it is likely that they have simultaneous effects in different systems. It still remains an open question whether or not the orexin effects related to energy balance and to sleep-wake cycle can be explained as concurrent but independent activities, or rather as interrelated ones. Since, however, the activity of orexin neurons is influenced fundamentally just by the main factors of energy balance, namely by monoamines, acetylcholine, nutrients, glucose, leptin, ghrelin (3, 29), a rather strong coordination might be assumed to exist between the regulations of energy balance and sleep/wakefulness (38).

6 AJP: Regulatory, Integrative and Comparative Physiology Page 6 of 15 R Some evidence, indeed, support the existence of this assumed coordination. Low plasma glucose or absence of food stimulated orexin expression in rats (4), and food deprivation improved vigilance and daytime performance in humans (17). Besides such factors of energy balance, forced physical exercise also elevated the orexin level of the cerebrospinal fluid in rats and dogs (16, 37) and sleep deprivation induced similar effects in dogs (37). The wakefulness induced by hunger (3), exercise (37) or sleep withdrawal (37) is often followed by overwhelming somnolence, e.g. in postprandial states (1, 3) and following exertion or sleep deprivation. Leptin deficiency, which primarily influences energy balance, also disrupts the normal sleep pattern in ob/ob mice (14), and orexin has also been implicated in the insomnia-associated obesity (11, 14). Although the data are sometimes controversial, both early (24) and more recent (32) findings allow an interpretation that orexins have a primary hypothermic action. Well before discovering the existence of orexins, earlier reports (24) demonstrated an elevated mesor of 24-hour body temperature in narcoleptic patients. The cited study of Mochizuki et al. (21) using more sophisticated and precise experimental conditions demonstrated somewhat similar findings: in orexin knockout mice alterations were found in the circadian body temperature rhythm, and the characteristic temperature fall in the inactive phase (with or without sleep deprivation) was shown to lag behind that seen in control animals. Healthy animals eat, move, exhibit various forms of activity in the active phase, and have a slightly elevated metabolic rate and body temperature, which may or may not be orexinrelated. The reported observations (21) do not suggest orexin-dependence since in this phase orexin knockout mice had similar body temperatures as their control counterparts did. In the inactive phase the animals sleep and may develop a temperature fall by a decrease in

7 Page 7 of 15 AJP: Regulatory, Integrative and Comparative Physiology R metabolic rate (approaching BMR) and/or by a rise in heat loss (21). Orexins did not seem to influence heat loss mechanisms (32). Since in the active phase the orexin levels increase gradually (7), participation of orexins in various phases might easily be understood, provided that orexins indeed enhance metabolic rate and body temperature. In this case, in the inactive phase the low orexin levels could contribute to a temperature fall in orexin knockout mice a lack of fall in orexin level possibly explains the attenuated temperature fall during the resting period. Alternatively, orexins may be suppressors of metabolism. However, in the active phase the metabolic rate may depend on general activity (an enhancer of metabolic rate) and may be unrelated to presence of orexin, while the hypometabolic effects of the peptide may be more expressive in the inactive phase. In this phase sleep starts, but the gradually falling orexin levels, now unopposed by general activity, may still be high enough to contribute to a metabolic suppression. In orexin knockout mice the lack of such mechanism could also result in attenuation of temperature fall in the inactive period. Apparently, the orexins (or their lack) seem to interfere normally mainly with processes of the inactive phase. Chronic orexin administration affected the daytime (inactive phase) food intake only, but it did not alter the whole-day consumption or the weight gain rate (40). In accordance with the short time of effectiveness, chronic orexin administration failed to induce any time-consuming tonic alterations in thyroid activity or brown fat metabolism (27). It follows that in the circadian temperature changes the orexins possibly play a more important role during rest than in the active period: their action may be limited to a temporary modification (suppression) of metabolic rate and body temperature, without altering heat loss. Accordingly, a chronic lack of orexin effects should be presumed not to influence either the thyroid and brown fat functions or the metabolic rate during the active period. In contrast, they may be thought to impair the metabolic suppression during the rest period and to result in

8 AJP: Regulatory, Integrative and Comparative Physiology Page 8 of 15 R attenuation of temperature fall in this period (perhaps because of narcolepsy-cataplexy, the knockout animals do not have a proper quiet rest). Such interpretation of complex orexin effects still ought to be confirmed, or possible other explanations established through detailed analysis of orexins and energy balance vs. orexins and sleep/wake cycle. For understanding the mechanism of action of orexins in various physiological or pathological processes, it would be important to clarify whether they cause parallel enhancement of food intake and metabolic rate, together with increased alertness, or they act in a different way. Further studies may open new horizons regarding the problem of role of orexins in these regulations and may reveal connections between abnormalities of food intake, body weight, body temperature and sleep/wake state.

9 Page 9 of 15 AJP: Regulatory, Integrative and Comparative Physiology R References 1. Bazar KA, Yun AJ and Lee PY. Debunking a myth: neurohormonal and vagal modulation of sleep centers, not redistribution of blood flow, may account for postprandial somnolence. Med Hypotheses 63: , Berthoud H-R, Patterson LM, Sutton GM, Morrison C and Zheng H. Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem Cell Biol 123: , Burdakov D and Alexopoulos H. Metabolic state signaling through central hypocretin/orexin neurons. J Cell Mol Med 9: , Cai XJ, Widdowson PS, Harrold J, Wilson S, Buckingham RE, Arch JR, Tadayyon M, Clapham JC, Wilding J and Williams G. Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes 48: , Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB and Yanagisawa M. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98: , de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS 2 nd, Frankel WN, van den Pol AN, Bloom

10 AJP: Regulatory, Integrative and Comparative Physiology Page 10 of 15 R FE, Gautvik KM and Sutcliffe JG. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95: , Fujiki N, Yoshida Y, Ripley B, Honda K, Mignot E and Nishino S. Changes in CSF hypocretin-1 (orexin A) levels in rats across 24 hours and in response to food deprivation. Neuroreport 12: , Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M and Sakurai T. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30: , Haynes AC, Chapman H, Taylor C, Moore GBT, Cawthorne MA, Tadayyon M, Clapham JC and Arch JRS. Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice. Regul Pept 104: , Higuchi S, Usui A, Murasaki M, Matsushita S, Nishioka N, Yoshino A, Matsui T, Muraoka H, Ishizuka Y, Kanba S and Sakurai T. Plasma orexin-a is lower in patients with narcolepsy. Neurosci Lett 318: 61-64, Horvath TL, Gao XB. Input organization and plasticity of hypocretin neurons: possible clues to obesity s association with insomnia. Cell Metab 1: , Ishii Y, Blundell JE, Halford JC, Upton N, Porter R, Johns A, Jeffrey P, Summerfield S and Rodgers RJ. Anorexia and weight loss in male rats 24 h following

11 Page 11 of 15 AJP: Regulatory, Integrative and Comparative Physiology R single dose treatment with orexin-1 receptor antagonist SB Behav Brain Res 157: , Jászberényi M, Bujdosó E, Kiss E, Pataki I and Telegdy G. The role of NPY in the mediation of orexin-induced hypothermia. Regul Pept 104: 55-59, Laposky AD, Shelton J, Bass J, Dugovic C, Perrino N and Turek FW. Altered sleep regulation in leptin deficient mice. Am J Physiol Regul Integr Comp Physiol Nov 17, 2005; /ajpregu Lubkin M and Stricker-Krongrad A. Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 253: , Martins PJ, D Almeida V, Pedrazzoli M, Lin L, Mignot E and Tufik S. Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity. Regul Pept 117: , Michalsen A, Schlegel F, Rodenbeck A, Ludtke R, Huether G, Teschler H and Dobos GJ. Effects of short-term modified fasting on sleep patterns and daytime vigilance in nonobese subjects: results of a pilot study. Ann Nutr Metab 47: , Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T and Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA 101: , 2004.

12 AJP: Regulatory, Integrative and Comparative Physiology Page 12 of 15 R Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, Vankova J, Black J, Harsh J, Bassetti C, Schrader H and Nishino S. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 59: , Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T and Scammell TE. Behavioral state instability in orexin knock-out mice. J Neurosci 24: , Mochizuki T, Klerman EB, Sakurai T and Scammell TE. Elevated body temperature during sleep in orexin knockout mice. Am J Physiol Regul Integr Comp Physiol (Present issue. Just accepted for publication, not yet in Medline) 22. Monda M, Viggiano A, Mondola P and De Luca V. Inhibition of prostaglandin synthesis reduces hyperthermic reactions induced by hypocretin-1/orexin A. Brain Res 909: 68-74, Monda M, Viggiano AN, Viggiano A, Lanza A and De Luca V. Hyperthermic reactions induced by orexin A: role of the ventromedial hypothalamus. Eur J Neurosci 22: , Mosko SS, Hollowach JB and Sassin JF. The 24-hour rhythm of core temperature in narcolepsy. Sleep 6: , 1983.

13 Page 13 of 15 AJP: Regulatory, Integrative and Comparative Physiology R Novak CM, Kotz CM and Levine JA. Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet-resistant rats. Am J Physiol Endocrinol Metab 290: E396-E403, Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG and Kilduff TS. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18: , Russell SH, Small CJ, Sunter D, Morgan I, Dakin CL, Cohen MA and Bloom SR. Chronic intraparaventricular nuclear administration of orexin A in male rats does not alter thyroid axis or uncoupling protein-1 in brown adipose tissue. Regul Pept 104: 61-68, Sakamoto, F, Yamada S and Ueta Y. Centrally administered orexin-a activates corticotropin-releasing factor-containing neurons in the hypothalamic paraventricular nucleus and central amygdaloid nucleus of rats: possible involvement of central orexins on stress-activated central CRF neurons. Regul Pept 118: , Sakurai T: Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 9: , Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ and Yanagisawa M. Orexins and orexin receptors: a family of hypothalamic

14 AJP: Regulatory, Integrative and Comparative Physiology Page 14 of 15 R neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92: , Smith MI, Piper DC, Duxon MS and Upton N. Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in rats. Neurosci Lett 341: , Székely M, Pétervári E, Balaskó M, Hernádi I and Uzsoki B. Effects of orexins on energy balance and thermoregulation. Regul Pept 104: 47-53, Székely M, Pétervári E, Pákai E, Hummel Z and Szelényi Z. Acute, subacute and chronic effects of central neuropeptide Y on energy balance in rats. Neuropeptides 39: , Székely M and Szelényi Z. Regulation of energy balance by peptides: a review. Curr Protein Pept Sci 6: , Szentirmai E and Krueger JM. Central administration of neuropeptide Y induces wakefulness in rats. Am J Physiol Regul Integr Comp Physiol Feb 23, 2005; /ajpregu Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, Cornford M and Siegel JM. Reduced number of hypocretin neurons in human narcolepsy. Neuron 27: , 2000.

15 Page 15 of 15 AJP: Regulatory, Integrative and Comparative Physiology R Wu MF, John J, Maidment N, Lam HA and Siegel JM. Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating and movement. Am J Physiol Regul Integr Comp Physiol 283: R1079-R1086, Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M and Sakurai T. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38: , Yamanaka A, Kunii K, Nambu T, Tsujino N, Matsuzaki I, Miwa Y, Goto K and Sakurai T. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 859: , Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M and Goto K. Chronic intracerebroventricular administration of orexin-a to rats increases food intake in daytime, but has no effect on body weight. Brain Res 849: , Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, Mignot E and Nishino S. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci 14: , 2001.