Martins PJ, Marques MS, Tufik S, D'Almeida V. Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation. Am J Physiol Endocrinol Metab 298: E726 -E734, 2010. First published January 5, 2010 doi:10.1152/ajpendo.00660.2009.-Several pieces of evidence support that sleep duration plays a role in body weight control. Nevertheless, it has been assumed that, after the identification of orexins (hypocretins), the molecular basis of the interaction between sleep and energy homeostasis has been provided. However, no study has verified the relationship between neuropeptide Y (NPY) and orexin changes during hyperphagia induced by sleep deprivation. In the current study we aimed to establish the time course of changes in metabolite, endocrine, and hypothalamic neuropeptide expression of Wistar rats sleep deprived by the platform method for a distinct period (from 24 to 96 h) or sleep restricted for 21 days (SR-21d). Despite changes in the stress hormones, we found no changes in food intake and body weight in the SR-21d group. However, sleep-deprived rats had a 25-35% increase in their food intake from 72 h accompanied by slight weight loss. Such changes were associated with increased hypothalamus mRNA levels of prepro-orexin (PPO) at 24 h followed by NPY at 48 h of sleep deprivation. Conversely, sleep recovery reduced the expression of both PPO and NPY, which rapidly brought the animals to a hypophagic condition. Our data also support that sleep deprivation rapidly increases energy expenditure and therefore leads to a negative energy balance and a reduction in liver glycogen and serum triacylglycerol levels despite the hyperphagia. Interestingly, such changes were associated with increased serum levels of glucagon, corticosterone, and norepinephrine, but no effects on leptin, insulin, or ghrelin were observed. In conclusion, orexin activation accounts for the myriad changes induced by sleep deprivation, especially the hyperphagia induced under stress and a negative energy balance. neuropeptide Y; leptin; glucagon; insulin; liver glycogen; triacylglycerol SEVERAL PIECES OF EVIDENCE support that sleep duration plays a role in body weight control (4, 15, 56). Everson et al. (10), Kushida et al. (24), and Rechtschaffen et al. (46), using an animal model, characterized a syndrome induced in response to sleep deprivation especially composed of a progressive increase in food intake. Interestingly, Spiegel et al. (55) has shown that humans who are sleep restricted for 2 days (sleeping 4 h/night) were hungrier and developed a craving for food with a high carbohydrate content. Later, the hyperphagic behavior during sleep deprivation was attributed to an increase and decrease in the hypothalamic expression of neuropeptide Y (NPY) and proopiomelanocortin (POMC), respectively (20). Supporting such changes in these neuropeptides, earlier studies in different species have found a reduction in circulating levels of leptin in response to sleep loss (11,22,55,56). Although the d...

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