Internal and external modulation factors of the orexin system (REVIEW)

Orexin-A and -B (identical to hypocretin-1 and -2) are neuropeptides synthesized in the lateral hypothalamus and perifornical area, and orexin neurons project their axon terminals broadly throughout the entire central nervous system (CNS). The activity of orexins is mediated by two specific G protein-coupled receptors (GPCRs), termed orexin type1 receptor (OX1R) and orexin type2 receptor (OX2R). The orexin system plays a relevant role in various physiological functions, including arousal, feeding, reward, and thermogenesis, and is key to human health. Orexin neurons receive various signals related to environmental, physiological, and emotional stimuli. Previous studies have reported that several neurotransmitters and neuromodulators influence the activation or inhibition of orexin neuron activity. In this review, we summarize the modulating factors of orexin neurons in the sleep/wake rhythm and feeding behavior, particularly in the context of the modulation of appetite, body fluids, and circadian signaling. We also describe the effects of life activity, behavior, and diet on the orexin system. Some studies have observed phenomena that have been verified in animal experiments, revealing the detailed mechanism and neural pathway, while their applications to humans is expected in future research.