Roles of orexins in the regulation of feeding and arousal
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,
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