Paradoxical sleep deprivation activates hypothalamic nuclei that regulate food intake and stress response
Introduction
Studies on the effects of sleep deprivation on food intake in rats have consistently shown a peculiar syndrome characterized by hyperphagia and loss of body weight—effects not dependent on the sleep deprivation method used (Bhanot et al., 1989, Elomaa, 1985, Kushida et al., 1989). Body weight loss takes place even in sleep-deprived rats fed high-calorie diets (Everson and Wehr, 1993, Koban et al., 2008, Suchecki et al., 2003). Numerous studies have addressed the mechanisms involved in such a major energy imbalance. On the one hand, total sleep or paradoxical sleep deprivation (PSD) reduces anabolic hormones such as leptin (Everson and Crowley, 2004, Koban and Swinson, 2005), testosterone (Andersen et al., 2005), and insulin (Hipolide et al., 2006). On the other hand, sleep deprivation increases sympathetic (Andersen et al., 2005, Meerlo et al., 2008) and hypothalamic–pituitary–adrenal (HPA) axis activity (Fadda and Fratta, 1997, Koban et al., 2006, Suchecki et al., 1998, Suchecki et al., 2002), increasing catabolic hormones such as corticosterone and adrenaline. Hyperphagia, in turn, can be explained by a progressive increase of neuropeptide Y (NPY) expression in the hypothalamic arcuate nucleus from 5 to 20 days of PS deprivation in addition to reduction of proopiomelanocortin, a well-known anorexic peptide (Koban et al., 2006). Recently, the same group used a high energy-containing liquid diet and reported a direct correlation between expression of NPY in the arcuate nucleus and food intake (Koban et al., 2008).
Orexin (ORX) is a recently identified orexigenic neuropeptide implicated in the regulation of food intake and energy metabolism (Bernardis and Bellinger, 1996, Date et al., 1999). This peptide is synthesized by neurons located in the lateral hypothalamic area (LHA), which project to waking-related areas, such as the locus coeruleus, dorsal raphe, and tuberomammilary nuclei indicating that ORX is involved in the regulation of waking (Hagan et al., 1999, Williams et al., 2004). Corticotropin releasing factor (CRH), in turn, is synthesized in neurons of the paraventricular nucleus of the hypothalamus (PVN) and orchestrates the neuroendocrine stress response, participates in metabolic pathways known to increase energy expenditure, decreases food intake (Woods et al., 1998) and, like ORX, also promotes waking (Chang and Opp, 2001, Sanford et al., 2008). CRH mRNA expression increases progressively from five to 20 days of PSD (Koban et al., 2006), whereas ACTH and corticosterone (CORT) levels are reported to be increased earlier—already by one day of sleep deprivation (Andersen et al., 2005, Suchecki et al., 1998).
Taken together, these data justify the investigation of ORX and CRH activities within the initial four days of PSD in rats. We sought to investigate ORX and CRH immunoreactivities (ORX-IR and CRH-IR) in the LHA and PVN, respectively, at the end of this period. In addition, we also evaluated food intake corrected for spillage, and daily ACTH and CORT plasma concentrations within the course of PSD.
Section snippets
Animals
Male Wistar rats (3–4 months of age) were bred and raised in the animal facility of the Department of Psychobiology of Universidade Federal de São Paulo (UNIFESP), housed in groups of four in plastic cages from weaning until the onset of the deprivation procedure. The animals were habituated to the sleep deprivation room for two weeks and handled every day for a week before the beginning of the experiment. Throughout the study, the animals were maintained under controlled temperature (21 ± 2 °C)
Body weight variation (Fig. 1A)
ANOVA revealed main effects of Group (F1,45 = 20.75; p < 0.001) and an interaction between Group and Day (F3,42 = 3.36; p < 0.03). Post-hoc analysis showed that whereas CTL rats did not significantly change their body weights, PSD rats exhibited body weight loss on Day 2, which differed from Days 1, 3 and 4 and from CTL rats on Day 2 (p < 0.05) (Fig. 1).
Food Intake (Fig. 1B)
ANOVA showed an interaction between Group and Day (F1,14 = 7.23; p < 0.001). Analysis of this interaction revealed that CTL rats ate significantly more on
Discussion
The present study showed that (1) PSD resulted in loss of body weight, with increased diurnal food intake, (2) plasma CORT levels were higher in PSD than in CTL rats throughout the experimental period, (3) PSD increased ORX-IR and CRH-IR in LHA and PVN, respectively, and (4) there was a negative correlation between overall CORT secretion and body weight gain.
These results confirm the well-known syndrome induced by PSD, namely, loss of body weight despite of increased food intake (Everson and
Role of the funding sources
The funding was granted from São Paulo Government's Research Foundation. There is no commercial interest involved in the funding.
Conflict of interest
The authors declare that they have no conflict of interests.
Acknowledgements
This work was supported by FAPESP-CEPID program (grant # 98-14303/3) and by the National Council of Research (CNPq). Our special thanks to Patrícia C. Milanez for her technical assistance in the microphotographic documentation and to Drs. Sabine Pompéia and Cicero G. Coimbra for critical reading of the manuscript. Drs. Sergio Tufik and Deborah Suchecki are recipients of research fellowships from the CNPq. Milene Lara Galvão received a graduate student fellowship from CAPES and Suzi E. Kawakami,
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