Orexin System: The Key for a Healthy Life

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.

Central Circadian Clock Regulates Energy Metabolism

“…Orexin is a neuropeptide secreted by the lateral hypothalamus (LH) with low levels in the CSF during sleep and high levels during wake (Chieffi et al, 2017). Darkness activates orexin neurons in nocturnal rodents (Marston et al, 2008), while orexin suppresses the SCN neurons either directly or indirectly through augmenting the IGL-mediated suppression of the SCN neurons (Belle et al, 2014; Palus et al, 2015).…”

Orexin/hypocretin treatment restores hippocampal-dependent memory in orexin-deficient mice

“…Thus, orexin enhancement of CREB phosphorylation would enhance TWAA memory retention in O/A3 mice. Finally, it is possible that exogenous OXA might improve memory in O/A3 mice through induction of dentate gyrus neurogenesis, as several studies have demonstrated that orexin A induces neurogenesis in the dentate gyrus of rats and mice [13,46,57]. …”

The key role of insomnia and sleep loss in the dysregulation of multiple systems involved in mood disorders: A proposed model

“…The results of several recent studies have led to propose the involvement of the orexinergic system in the pathophysiology of mood disorders. The orexinergic system orchestrates various aspects disturbed in mood disorders, such as sleep and arousal, behavioural and neuroendocrine responses to stress, reward‐seeking behaviours, energetic homeostasis, learning and memory, and in this is case this is achieved via direct projections to the medial prefrontal cortex (Chieffi et al., ; Li, Hu, & de Lecea, ; Li et al., ). Orexinergic neurons receive a variety of signals related to environmental, physiological and emotional stimuli, and project broadly to the entire central nervous system: the hypothalamic orexin system directly and strongly innervates and excites noradrenergic, dopaminergic, serotonergic, histaminergic and cholinergic neurons.…”