Body Mass Index-Independent Metabolic Alterations in Narcolepsy with Cataplexy

Poli, Francesca; Plazzi, Giuseppe; Dalmazi, Guido Di; Ribichini, Danilo; Vicennati, Valentina; Pizza, Fabio; Mignot, Emmanuel; Montagna, Pasquale; Pasquali, Renato; Pagotto, Uberto

doi:10.1093/sleep/32.11.1491

Cited by 103 publications

(70 citation statements)

References 33 publications

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“…Narcoleptic patients, despite consuming 15% less calories daily, had higher body and fat mass as well as circulating levels of leptin and triacylglycerols, among other metabolic abnormalities. Altogether, these data suggest that the implication of the orexinergic system on metabolism seems to go beyond the food intake and energy expenditure and may involve specific actions on glucose and lipid metabolism control (44). In summary, based on our results, 3 days of continuous sleep deprivation are sufficient to trigger hyperphagia in rats fed a liquid diet.…”

Section: Discussionsupporting

confidence: 57%

Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation

Martins¹,

Marques²,

Tufik³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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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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Section: Discussionsupporting

confidence: 57%

Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation

Martins¹,

Marques²,

Tufik³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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“…Orexin regulates the sleep-wake rhythm, energy homeostasis, and autonomic nerve balance through orexin receptor-1 (OX1R) or -2 (OX2R) (16). Moreover, orexin appears to be involved in the maintenance of insulin sensitivity, because orexindeficient male mice fed normal chow diet exhibited agerelated development of systemic insulin resistance despite normal body weight (17,18), and because orexin-deficient narcoleptic patients with cataplexy showed BMI-independent metabolic alterations, including insulin resistance (19). However, the role of orexin in glucose homeostasis remains elusive, since orexin A is reported to cause the blood glucose-elevating and -lowering effects in rodents depending on the experimental conditions (20)(21)(22).…”

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confidence: 99%

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

et al. 2014

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Circadian rhythm is crucial for preventing hepatic insulin resistance, although the mechanism remains uncovered. Here we report that the wake-active hypothalamic orexin system plays a key role in this regulation. Wildtype mice showed that a daily rhythm in blood glucose levels peaked at the awake period; however, the glucose rhythm disappeared in orexin knockout mice despite normal feeding rhythm. Central administration of orexin A during nighttime awake period acutely elevated blood glucose levels but subsequently lowered daytime glucose levels in normal and diabetic db/db mice. The glucose-elevating and -lowering effects of orexin A were suppressed by adrenergic antagonists and hepatic parasympathectomy, respectively. Moreover, the expression levels of hepatic gluconeogenic genes, including Pepck, were increased and decreased by orexin A at nanomolar and femtomolar doses, respectively. These results indicate that orexin can bidirectionally regulate hepatic gluconeogenesis via control of autonomic balance, leading to generation of the daily blood glucose oscillation. Furthermore, during aging, orexin deficiency enhanced endoplasmic reticulum (ER) stress in the liver and caused impairment of hepatic insulin signaling and abnormal gluconeogenic activity in pyruvate tolerance test. Collectively, the daily glucose rhythm under control of orexin appears to be important for maintaining ER homeostasis, thereby preventing insulin resistance in the liver.Maintaining glucose and energy homeostasis throughout the day is essential for survival. Therefore, different metabolic functions are timely activated according to the circadian rhythm. Recently, it has also become clear that fine tuning of daily metabolic rhythms is crucial for preventing metabolic abnormalities. For instance, chronic disruption of circadian rhythm in humans, as seen in shift workers, increases the risk of obesity and type 2 diabetes (1,2), and circadian rhythms of glucose regulation are impaired in diabetic animals and patients with diabetes (3).Circadian rhythms of peripheral tissues, including liver, are entrained to the central biological clock located in the suprachiasmatic nuclei (SCN) via autonomic and hormonal pathways (4). The liver plays a pivotal role in maintaining optimal glucose levels via hepatic glucose production (HGP) and glucose uptake. The daily rhythm of HGP is regulated by the autonomic nervous system under SCN control, leading to generation of a daily rhythm in basal blood glucose levels independently of the feeding rhythm (5). The central clock is also crucial for preventing metabolic abnormalities

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“…The hypocretin system is involved in a broad range of functions, including autonomic and hormonal regulation. Therefore, recent research has focused on consequences of the hypocretin deficiency in narcolepsy beyond disordered sleep regulation, such as metabolic and endocrine changes (33).…”

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confidence: 99%

Effect of sodium oxybate on growth hormone secretion in narcolepsy patients and healthy controls

Donjacour

Aziz

Roelfsema³

et al. 2011

American Journal of Physiology-Endocrinology and Metabolism

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Donjacour CE, Aziz NA, Roelfsema F, Frölich M, Overeem S, Lammers GJ, Pijl H. Effect of sodium oxybate on growth hormone secretion in narcolepsy patients and healthy controls. Am J Physiol Endocrinol Metab 300: E1069 -E1075, 2011. First published March 29, 2011 doi:10.1152/ajpendo.00623.2010Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems and body composition. Additionally, growth hormone (GH) alterations my influence weight in narcolepsy. Symptoms can be treated effectively with sodium oxybate (SXB; ␥-hydroxybutyrate) in many patients. This study compared growth hormone secretion in patients and matched controls and established the effect of SXB administration on GH and sleep in both groups. Eight male hypocretin-deficient patients with narcolepsy and cataplexy and eight controls matched for sex, age, BMI, waist-to-hip ratio, and fat percentage were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken two times 3 g/night for 5 consecutive nights. Both groups underwent 24-h blood sampling at 10-min intervals for measurement of GH concentrations. The GH concentration time series were analyzed with AutoDecon and approximate entropy (ApEn). Basal and pulsatile GH secretion, pulse regularity, and frequency, as well as ApEn values, were similar in patients and controls. Administration of SXB caused a significant increase in total 24-h GH secretion rate in narcolepsy patients, but not in controls. After SXB, slow-wave sleep (SWS) and, importantly, the crosscorrelation between GH levels and SWS more than doubled in both groups. In conclusion, SXB leads to a consistent increase in nocturnal GH secretion and strengthens the temporal relation between GH secretion and SWS. These data suggest that SXB may alter somatotropic tone in addition to its consolidating effect on nighttime sleep in narcolepsy. This could explain the suggested nonsleep effects of SXB, including body weight reduction.hypocretin; orexin; ␥-hydroxybutyrate CLASSICALLY, NARCOLEPSY IS DEFINED as a sleep disorder with excessive daytime sleepiness and cataplexy as the main symptom (31). However, in recent years, there has been increasing attention paid to other core features of the syndrome. For example, fragmented nighttime sleep is a prominent symptom in many narcoleptic patients and often warrants treatment (9). In addition, patients are frequently overweight, storing excess fat in abdominal depots (21). The increasing interest for the broad symptomatology of narcolepsy was further fueled by new insights in the pathophysiology of the disease. In the last decade, it has been shown that deficiencies in hypothalamic hypocretin (orexin) neurotransmission are the primary cause of narcolepsy both in humans and in several animal models of the disease (3, 23, 34). The hypocretin system is involved in a broad range of functions, including autonomic and hormonal regulation. Therefore, recent research has focused on consequences of the hypocretin deficiency in narcolepsy beyond disordered sleep regu...

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Body Mass Index-Independent Metabolic Alterations in Narcolepsy with Cataplexy

Cited by 103 publications

References 33 publications

Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation

Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation

Hypothalamic Orexin Prevents Hepatic Insulin Resistance via Daily Bidirectional Regulation of Autonomic Nervous System in Mice

Effect of sodium oxybate on growth hormone secretion in narcolepsy patients and healthy controls

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