Article

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: 4.54). 07/2007; 581(Pt 2):649-63. DOI: 10.1113/jphysiol.2007.129510
Source: PubMed

ABSTRACT 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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    • ". 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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    • "Obesity is a multi-factorial condition in humans and characteristics of obesity are common in animal models. Some models show deficient leptin or orexin signaling similar to obese individuals and narcoleptic patients (Beck et al., 2001; Laposky et al., 2006; Megirian et al., 1998; Sanchez-Alavez et al., 2007; Tschop and Heiman, 2001; Zhang et al., 2007), but unlike human obesity, obesity in several models results from a single gene deficiency. Sleep architecture in these animal models resemble the abnormalities observed in human obesity (excessive sleep, specifically during the active phase; sleep fragmentation; decreased REM sleep during the resting phase). "
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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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