Abstract
The orexin-A/hypocretin-1 and orexin-B/hypocretin-2 are neuropeptides synthesized by a cluster of neurons in the lateral hypothalamus and perifornical area. Orexin neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire CNS. Orexin neurons are “multi-tasking” neurons regulating a set of vital body functions, including sleep/wake states, feeding behavior, energy homeostasis, reward systems, cognition and mood. Furthermore, a dysfunction of orexinergic system may underlie different pathological conditions. A selective loss orexin neurons was found in narcolepsia, supporting the crucial role of orexins in maintaining wakefulness. In animal models, orexin deficiency lead to obesity even if the consume of calories is lower than wildtype counterpart. Reduced physical activity appears the main cause of weight gain in these models resulting in energy imbalance. Orexin signaling promotes obesity resistance via enhanced spontaneous physical activity and energy expenditure regulation and the deficiency/dysfunction in orexins system lead to obesity in animal models despite of lower calories intake than wildtype associated with reduced physical activity. Interestingly, orexinergic neurons show connections to regions involved in cognition and mood regulation, including hippocampus. Orexins enhance hippocampal neurogenesis and improve spatial learning and memory abilities, and mood. Conversely, orexin deficiency results in learning and memory deficits, and depression.
Highlights
Orexin A is a neuropeptide composed of 33 amino acids with an amino(N)-terminal pyroglutamyl residue, two intrachain disulphide bonds and carboxy (C)-terminal amidation, while Orexin B is a linear neuropeptide sized 28 amino acids, C-terminally amidated
- orexin receptor 2 (OX2R) is distributed in amygdala, tuberomammillary nucleus (TMN), arcuate nucleus (Arc), dorsomedial hypothalamic nucleus (DMH), paraventricular nucleus (PVN), Lateral hypothalamic area (LHA), bed nucleus of the stria terminalis (BST), paraventricular nucleus of hypothalamus (PVT), dorsal raphe (DR), ventral tegmental area (VTA), laterodorsal tegmental nucleus (LDT)/pedunculopontine nucleus (PPT), CA3 in the hippocampus, and medial septal nucleus (Lu et al, 2000)
Narcolepsy is the results of orexin-containing neurons loss, which tend to increase their activity during wakefulness activating aminergic nuclei such as locus coeruleus, raphe nuclei, and tuberomamillary nucleus with maintaining wake state and preventing of inappropriate transitions into sleep, REM sleep phases (Saper et al, 2001; España and Scammell, 2011)
Summary
Orexin A and B are excitatory hypothalamic neuropeptides playing a relevant role in different physiologic functions such as sleep/wake rhythms and thermoregulation, control of energy metabolism, cardiovascular responses, feeding behavior, and spontaneous physical activity (SPA). OX2R binds the two subtypes of orexin with similar affinities, probably associated to a G inhibitory protein class (Xu et al, 2013). These differences seem to suggest different physiological roles for OX1R and OX2R (Trivedi et al, 1998). - OX1R is distributed in prefrontal and infralimbic cortex (IL), hippocampus (CA2), amygdala, stria terminalis bed nucleus (BST), PVT, anterior hypothalamus, dorsal raphe (DR), ventral tegmental area (VTA), locus coeruleus (LC), and laterodorsal tegmental nucleus (LDT)/pedunculopontine nucleus (PPT) (Trivedi et al, 1998; Lu et al, 2000);. - OX2R is distributed in amygdala, TMN, Arc, dorsomedial hypothalamic nucleus (DMH), paraventricular nucleus (PVN), LHA, BST, PVT, DR, VTA, LDT/PPT, CA3 in the hippocampus, and medial septal nucleus (Lu et al, 2000)
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