Study Title:

Hypocretins, Sleep, and Metabolism

Study Abstract

Sleep disturbances are associated with hormonal imbalances and may result in metabolic disorders including obesity and diabetes. Therefore, circuits controlling both sleep and metabolism are likely to play a role in these physiopathological conditions. The hypocretin (Hcrt) system is a strong candidate for mediating both sleep and metabolic imbalances because Hcrt neurons are sensitive to metabolic hormones, including leptin and ghrelin, and modulate arousal and goal-orientated behaviours. This review discusses the role of Hcrt neurons as a sensors of energy balance and arousal and proposes new ways of probing local hypothalamic circuits regulating sleep and metabolism with unprecedented cellular specificity and temporal resolution.

(Received 3 October 2008; accepted after revision 20 November 2008; first published online 1 December 2008)
Corresponding authors L. de Lecea and A. Adamantidis: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94304-5742, USA. Email: and

Although the neuronal substrates of the sleep/wake cycle have been extensively described (Pace-Schott & Hobson, 2002), the function of sleep remains unknown and may include cortical reorganization and processing associated with learning and memory, brain development and neurogenesis, cellular repair and replenishment of energy stores (Hobson & Pace-Schott, 2002; Frank, 2006; Cirelli & Tononi, 2008). Although a role for sleep in energy conservation is still a matter of debate (Zepelin & Rechtschaffen, 1974; Knutson & Van Cauter, 2008), sleep duration and the length of a sleep–wake cycle are inversely correlated with brain metabolic rate across species (Savage & West, 2007), suggesting that availability of metabolic fuels conditions sleep architecture. In addition, sleep restriction has been associated with alteration of endocrine functions and increased risk of obesity, diabetes and cardiovascular disease (Knutson & Van Cauter, 2008). Chronic sleep reduction in humans results in higher plasma concentration of leptin and lower levels of ghrelin, which ultimately may increase appetite, body weight and metabolic imbalances (Taheri et al. 2004; Chaput et al. 2007; Penev, 2007; Knutson & Van Cauter, 2008). Interestingly, short sleep duration results in increased levels of cortisol (Spiegel et al. 2004).

These studies suggest the existence of neuronal circuits regulating both sleep and metabolism. This review highlights a role for the hypothalamic hypocretin (Hcrt), also known as orexin, system as a sensor for metabolism and arousal in the modulation of wakefulness, sleep and comsumatory behaviours. Hcrt neurons and other hypothalamic neuronal populations are strongly interspersed, which makes the study of their physiological functions extremely difficult. Use of newly developed optogenetic methods to selectively interrogate neuronal circuits has been proposed to gain a better understanding of the neuronal circuits underlying sleep and metabolism imbalances.

Study Information

Antoine Adamantidis and Luis de Lecea.
The hypocretins as sensors for metabolism and arousal.
J Physiol
2009 January
Department of Psychiatry and Behavioural Sciences, Stanford University School of Medicine, Palo Alto, CA 94304-5742, USA.

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