Elsevier

Sleep Medicine

Volume 3, Supplement 2, December 2002, Pages S3-S9
Sleep Medicine

Roles of orexins in the regulation of feeding and arousal

https://doi.org/10.1016/S1389-9457(02)00156-9Get rights and content

Abstract

Maintenance of energy homeostasis requires the coordination of systems that regulate feeding, autonomic and endocrine functions with those that govern an appropriate state of arousal. The hypothalamus play a critical role in maintaining energy homeostasis by integrating and coordinating these systems. Recent studies have suggested that orexin-containing neurons in the lateral hypothalamic area constitute an important central pathway that promotes adaptive behavioral and arousal responses to metabolic and environmental signals. This article review recent studies on orexin to suggest that orexin neurons play a significant role in feeding and arousal regulation, possibly by coordinating the complex behavioral and physiological responses of these complementary homeostatic functions.

Section snippets

Structure of orexins

Orexin-A and -B are neuropeptides originally identified from the rat brain as endogenous ligands for two orphan G-protein-coupled receptors [1]. Mammalian orexin-A is a 33-amino-acid peptide with an N-terminal pyroglutamyl residue, C-terminal amidation, and two sets of intrachain disulfide bonds (Fig. 1A). The primary structure of orexin-A is completely conserved among human, rat, mouse, cow, dog, and pig [1], [2], [3]. Orexin-B is a 28-amino-acid, C-terminally amidated peptide with 46% (13/28)

Orexin receptors

Two orexin receptor subtypes, orexin-1 receptor (OX1R) and orexin-2 receptor (OX2R), have been identified in mammals. OX1R and OX2R have 64% amino-acid identity with each other [1]. OX1R has a 1-order-of-magnitude greater affinity for orexin-A compared with orexin-B. In contrast, orexin-A and -B bind OX2R with equal affinity. Studies using receptor-transfected cell lines and isolated receptor-expressing hypothalamic neurons suggest that OX1R is coupled exclusively to the Gq subclass of

The orexin neuronal system

Orexin-producing neurons are exclusively localized to the LHA and adjacent regions [1], [4], [7], [8], [9], and diffusely project to the entire neuroaxis (Fig. 2). Particularly abundant projections are found in the cerebral cortex, olfactory bulb, hippocampus, amygdala, septum, diagonal band of Broca, bed nucleus of the stria terminalis, thalamus, anterior and posterior hypothalamus, midbrain, brainstem, and spinal cord [7], [8], [9], [10].

Although a variety of neurotransmitters are localized

Physiological roles of orexins

Intracerebroventricular (i.c.v) administration of orexins to rats has been shown to increase food consumption [1], water intake [16], wakefulness [17], and locomotor activity [18] in rodents. It also increases plasma corticosteron level and decreases prolactin level [17]. Targeted disruption of the prepro-orexin gene results in a syndrome strikingly similar to human narcolepsy [19]. These mice are also significantly hypophagic compared with weight- and age-matched littermates, suggesting

Regulation of orexin neurons

The LHA receives innervation from much of the neuroaxis and can also be influenced by peripheral humoral factors, such as leptin, insulin, and other hormones, as well as diffusible factors including glucose, electrolytes, amino acids, and peptides [20].

Reciprocal connections from NPY/AgRP neurons to orexin neurons in the LHA have been identified [12], [25]. Furthermore, orexin neurons are also innervated by αMSH-immunoreactive fibers from the ARC [12]. Orexin neurons may also be directly

Conclusion

Sleep is promoted homeostutically by prior wakefulness [49] and ‘sleep factors’ such as adenosine that accumulate in the brain during wakefulness and dissipate during sleep [50], [51]. Vigilance state is also influenced by an animal's nutritional state and the circadian influence. On the other hand, feeding behavior is critically dependent on appropriate sleep-wakefulness cycling at environmentally advantageous times and in response to homeostatic needs. During periods of nutritional depletion,

References (53)

  • A. Yamanaka et al.

    Orexin-induced food intake involves neuropeptide Y pathway

    Brain Res

    (2000)
  • H. Yamada et al.

    Inhibition of food intake by central injection of anti-orexin antibody in fasted rats

    Biochem Biophys Res Commun

    (2000)
  • A.C. Haynes et al.

    A selective orexin-1 receptor antagonist reduces food consumption in male and female rats

    Regul Pept

    (2000)
  • J.S. Flier et al.

    Obesity and the hypotalamus: novel peptides for new pathways

    Cell

    (1998)
  • J. Danguir et al.

    Cortical activity and sleep in the rat lateral hypothalamic syndrome

    Brain Res

    (1980)
  • L. Lin et al.

    The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin(orexin) receptor 2 gene

    Cell

    (1999)
  • T.C. Thannickal et al.

    Reduced number of hypocretin neurons in human narcolepsy

    Neuron

    (2000)
  • J. Hara et al.

    Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia and obesity

    Neuron

    (2001)
  • A. Yamanaka et al.

    Orexins activate histaminergic neurons via the orexin 2 receptor

    Biochem Biophys Res Commun

    (2002)
  • L.L. Bernardis et al.

    The lateral hypothalamic area revisited:neuroanatomy, body weight regulation, neuroendocrinology and metabolism

    Neurosci Biobehav Rev

    (1993)
  • A. Schuld et al.

    Increased body-mass index in patients with narcolepsy

    Lancet

    (2000)
  • W.K. Samson et al.

    Cardiovascular regulatory actions of the hypocretins in brain

    Brain Res

    (1999)
  • M. Lopez et al.

    Leptin regulation of prepro-orexin and orexin receptor mRNA levels in the hypothalamus

    Biochem Biophys Res Commun

    (2000)
  • Y. Yamamoto et al.

    Down regulation of the prepro-orexin gene expression in genetically obese mice

    Brain Res Mol Brain Res

    (1999)
  • T. Moriguchi et al.

    Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia

    Neurosci Lett

    (1999)
  • A.A. Borbely

    Sleep in the rat during food deprivation and subsequent restitution of food

    Brain Res

    (1977)
  • Cited by (0)

    View full text