Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy

Psychiatry and Behavioural Sciences, Stanford University, Palo Alto, CA 94304-5742, USA
The Journal of Physiology (Impact Factor: 5.04). 07/2007; 581(Pt 2):649-63. DOI: 10.1113/jphysiol.2007.129510
Source: PubMed


Recent population studies have identified important interrelationships between sleep duration and body weight regulation. The hypothalamic hypocretin/orexin neuropeptide system is able to influence each of these. Disruption of the hypocretin system, such as occurs in narcolepsy, leads to a disruption of sleep and is often associated with increased body mass index. We examined the potential interrelationship between the hypocretin system, metabolism and sleep by measuring locomotion, feeding, drinking, body temperature, sleep/wake and energy metabolism in a mouse model of narcolepsy (ataxin-ablation of hypocretin-expressing neurons). We found that locomotion, feeding, drinking and energy expenditure were significantly reduced in the narcoleptic mice. These mice also exhibited severe sleep/wake fragmentation. Upon awakening, transgenic and control mice displayed a similar rate of increase in locomotion and food/water intake with time. A lack of long wake episodes partially or entirely explains observed differences in overall locomotion, feeding and drinking in these transgenic mice. Like other parameters, energy expenditure also rose and fell depending on the sleep/wake status. Unlike other parameters, however, energy expenditure in control mice increased upon awakening at a greater rate than in the narcoleptic mice. We conclude that the profound sleep/wake fragmentation is a leading cause of the reduced locomotion, feeding, drinking and energy expenditure in the narcoleptic mice under unperturbed conditions. We also identify an intrinsic role of the hypocretin system in energy expenditure that may not be dependent on sleep/wake regulation, locomotion, or food intake. This investigation illustrates the need for coordinated study of multiple phenotypes in mouse models with altered sleep/wake patterns.

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    • "Our results are in line with human studies demonstrating increased hunger and appetite, increased food intake, decreased energy expenditure and increased body weight after sleep restriction (5–25). The decreased energy expenditure here appears due to excessive active period sleep and lower physical activity (34), as suggested by the 24 h recording, which show enhanced sleep during the active phase in PSD rats. "
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    ABSTRACT: Objective Sleep-restriction in humans increases risk for obesity, but previous rodent studies show weight loss following sleep deprivation, possibly due to stressful-methods used to prevent sleep. Obesity-resistant (OR) rats exhibit consolidated-sleep and resistance to weight-gain. We hypothesized that sleep disruption by a less-stressful method would increase body weight, and examined effect of partial sleep deprivation (PSD) on body weight in OR and Sprague-Dawley (SD) rats. Design and Methods OR and SD rats (n=12/group) were implanted with transmitters to record sleep/wake. After baseline recording, six SD and six OR rats underwent 8 h PSD during light-phase for 9 d. Sleep was reduced using recordings of random noise. Sleep/wake states were scored as wakefulness (W), slow-wave-sleep (SWS) and rapid-eye-movement-sleep (REMS). Total number of transitions between stages, SWS-delta-power, food intake and body weight were documented. Results Exposure to noise decreased SWS and REMS time, while increasing W time. Sleep-deprivation increased number of transitions between stages and SWS-delta-power. Further, PSD during the rest phase increased recovery-sleep during active phase. The PSD SD and OR rats had greater food intake and body weight compared to controls Conclusions PSD by less-stressful means increases body weight in rats. Also, PSD during rest phase increases active period sleep.
    Obesity 07/2013; 21(7). DOI:10.1002/oby.20182 · 3.73 Impact Factor
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    • "orexin neurons are ablated at 4 months of age. They showed that orexin KO mice have elevated body temperature during sleep (Mochizuki et al., 2006) and that orexin neuron-ablated mice have an attenuated body temperature fluctuation (Zhang et al., 2007). Recently, they investigated the implication of orexin in stress-induced hyperthermia and found that orexin KO mice show normal temperature changes in response to handling stress, while orexin neuron-ablated mice showed the expected attenuation of stressinduced hyperthermia (Zhang et al., 2010). "
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    ABSTRACT: In this chapter, we give an overview of the current status of the role of orexins in feeding and energy homeostasis. Orexins, also known as hypocretins, initially were discovered in 1998 as hypothalamic regulators of food intake. A little later, their far more important function as regulators of sleep and arousal came to light. Despite their restricted distribution, orexin neurons have projections throughout the entire brain, with dense projections especially to the paraventricular nucleus of the thalamus, the arcuate nucleus of the hypothalamus, and the locus coeruleus and tuberomammillary nucleus. Its two receptors are orexin receptor 1 and orexin receptor 2. These receptors show a specific and localized distribution in a number of brain regions, and a variety of different actions has been demonstrated upon their binding. Our group showed that through the autonomic nervous system, the orexin system plays a key role in the control of glucose metabolism, but it has also been shown to stimulate sympathetic outflow, to increase body temperature, heart rate, blood pressure, and renal sympathetic nerve activity. The well-known effects of orexin on the control of food intake, arousal, and wakefulness appear to be more extensive than originally thought, with additional effects on the autonomic nervous system, that is, to increase body temperature and energy metabolism.
    Progress in brain research 07/2012; 198:47-64. DOI:10.1016/B978-0-444-59489-1.00005-7 · 2.83 Impact Factor
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    • ". The F group had increased levels of blood glucose during the 2 h sampling ( +43 – 47% , P < 0 . 01 compared with QC and MC ) . F , sleep - fragmented group ; MC , motor control group ; QC quiet control group . this point , SF displayed by a murine model of narcolepsy is thought to be responsible for the metabolic changes observed in these mice ( Zhang et al . , 2007 ) . Altogether , these and our data indicate that SF represents an allostatic load on endocrine and autonomous systems that might , in the long term , lead to the development of diseases ."
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    ABSTRACT: Sleep fragmentation is present in numerous sleep pathologies and constitutes a major feature of patients with obstructive sleep apnea. A prevalence of metabolic syndrome, diabetes and obesity has been shown to be associated to obstructive sleep apnea. While sleep fragmentation has been shown to impact sleep homeostasis, its specific effects on metabolic variables are only beginning to emerge. In this context, it is important to develop realistic animal models that would account for chronic metabolic effects of sleep fragmentation. We developed a 14-day model of instrumental sleep fragmentation in mice, and show an impact on both brain-specific and general metabolism. We first report that sleep fragmentation increases food intake without affecting body weight. This imbalance was accompanied by the inability to adequately decrease brain temperature during fragmented sleep. In addition, we report that sleep-fragmented mice develop glucose intolerance. We also observe that sleep fragmentation slightly increases the circadian peak level of glucocorticoids, a factor that may be involved in the observed metabolic effects. Our results confirm that poor-quality sleep with sustained sleep fragmentation has similar effects on general metabolism as actual sleep loss. Altogether, these results strongly suggest that sleep fragmentation is an aggravating factor for the development of metabolic dysfunctions that may be relevant for sleep disorders such as obstructive sleep apnea.
    Journal of Sleep Research 06/2012; 22(1). DOI:10.1111/j.1365-2869.2012.01029.x · 3.35 Impact Factor
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