Effects of changes in energy homeostasis and exposure of noxious insults on the expression of orexin (hypocretin) and its receptors in the brain

Abstract

This review summarizes data regarding the brain expression of the orexin (hypocretin) system including: prepro-orexin (PPO), orexin A (OxA), orexin B (OxB) and the two orexin receptors 1 and 2 (OxR1, OxR2). Clinical data is limited to OxA and OxB in cerebral spinal fluid and serum/plasma, thus necessitating the development of animal models to undertake mechanistic studies. We focus on changes in animal models that were either exposed to a regime of altered sleep, metabolic energy homeostasis, exposed to drugs and noxious insults. Many more expressional studies are available for PPO, OxA and OxB levels, compared to studies of the receptors. Interestingly, the direction and pattern of change for PPO, OxA and OxB is inconsistent amongst studies, whereas for the receptors, there tends to be increased expression for both OxR1 and OxR2 after alterations in energy homeostasis, and an increased expression after noxious insults or exposure to some drugs. The clinical implications of these results from animal models are discussed in light of the findings from human studies, and future research directions are suggested to fill knowledge gaps with regard to the orexin system, particularly during early brain development.

Keywords: ARC; Animal model; Arcuate Nucleus; BMI; Body Mass Index; CO(2); CPAP; CSF; Carbon dioxide; Cerebral Spinal Fluid; Continuous positive airways pressure; DMH; DMN; DR; Dorsal Medial Hypothalamus; Dorsal Medial Nucleus; Dorsal Ralphe Nucleus; FR; Food restriction; HFD; High Fat Diet; Hypocretin; Hypothalamus; Hypoxia; IHC; ISH; Icv; Immunohistochemistry; In situ hybridization; Interperitoneal; Intracerebroventricular; Ischemia; LC; LHA; Lateral Hypothalamic Area; Locus Coeruleus; MHN; Medial hypothalamic nucleus; Messenger ribonucleic acid; Metabolism; Nac; Nicotine; Non-Rapid Eye Movement; Nucleus accumbuns; OSA; Obstructive Sleep Apnea; Orexin A; Orexin B; Orexin receptor 1; Orexin receptor 2; OxA; OxB; OxR1; OxR2; PCR; PD; PFA; PPO; PPT; PVN; Paraventricular Nucleus; Pedunculopontine Tegmental Nucleus; Perifornical Area; Polymerase chain reaction; Postnatal day; Prepro-orexin; REM; RIA; Radioimmunoassay; Rapid Eye Movement; SON; SONr; Subcutaneous; Supraoptic Nucleus; Supraoptic nucleus, retrochiasmatic part; TMN; Tuberal Mammillary Nucleus; VMH; VTA; Ventral medial hypothalamus; Ventral tegmental area; WB; Western blot; i.p.; mRNA; non-REM; s.c..