Chapter Two - The Role of Orexin/Hypocretin in the Central Nervous System and Peripheral Tissues
Introduction
The neuropeptides orexin A and orexin B (also known as hypocretin 1 and hypocretin 2, respectively) were initially identified as endogenous ligands for two orphan G-protein-coupled receptors (GPCRs; de Lecea et al., 1998, Sakurai et al., 1998). They were initially recognized as regulators of feeding behavior due to their exclusive production in the lateral hypothalamic area (LHA), which is a well-known feeding center. Moreover, intracerebroventricular (i.c.v.) injection of synthetic orexin peptide induces feeding behavior (Edwards et al., 1999, Haynes et al., 1999, Sakurai et al., 1998).
Subsequent studies demonstrated that the orexin system also plays a crucial role in the regulation of sleep/wakefulness states since orexin deficiency in humans and animals produces characteristic symptoms of the sleep disorder narcolepsy (Chemelli et al., 1999, Hara et al., 2001, Lin et al., 1999, Peyron et al., 2000, Thannickal et al., 2000). Further investigation suggested roles for orexin in the coordination of emotion, energy and fluid homeostasis, reward, and arousal (Boutrel et al., 2005, Harris et al., 2005, Mieda et al., 2004, Narita et al., 2006, Tsunematsu et al., 2008, Yamanaka et al., 2003). Additionally, the orexin system also regulates autonomic functions, including blood pressure and heart rate and neuroendocrine axes, including the hypothalamic–pituitary–adrenal (HPA) axis (Jaszberenyi et al., 2000, Kuru et al., 2000, Sakamoto et al., 2004, Sakurai et al., 1998, Samson et al., 1999, Shirasaka et al., 1999). These findings suggest that orexin neurons play a critical, adaptive role in the coordination of central and peripheral states according to the environment, which is beneficial for survival.
In this review, we briefly discuss the basic biology of orexin and orexin receptors and then focus on the role of orexin neural systems in the regulation of feeding behavior, energy homeostasis, and neuroendocrine function.
Section snippets
Identification of orexin
Orexin/hypocretin was independently identified by two different groups in 1998 utilizing completely different methodologies. Orexin A and B were identified as endogenous ligands for two orphan GPCRs by a method called “reverse pharmacology” (Sakurai et al., 1998). Orexin-producing neurons (orexin neurons) were localized to the LHA, a region known as a feeding center. Further, i.c.v. injection of synthetic orexin peptide increased food consumption. Therefore, these neuropeptides were named
Pharmacological effects of orexin on feeding behavior
Initially, orexin neurons were thought to be involved in the regulation of feeding behavior due to their exclusive localization to the LHA and their pharmacological effects on feeding behavior. I.c.v. injection of orexin peptides during the light period induces feeding behavior (Edwards et al., 1999, Haynes et al., 2000, Haynes et al., 2002, Sakurai et al., 1998). Supporting this result, i.c.v. injection of an anti-orexin antibody or OX1R selective antagonist (SB334867) reduces spontaneous food
The effect of orexin on the autonomic nervous system
Several studies have reported that central administration of orexin induces the expression of c-Fos, a marker of neuronal activation, in the LC, Arc, central gray, raphe nuclei, nucleus of the solitary tract, supraoptic nucleus, and PVN. These regions are known to be involved in the regulation of autonomic and neuroendocrine function in rats (Date et al., 1999, Kuru et al., 2000). It was also demonstrated that i.c.v. injection of orexin increases blood pressure, heart rate, and renal
Conclusions and Future Directions
Over more than a decade of research, it has been demonstrated that the orexin peptide system plays a crucial role in the regulation of energy balance, emotion, reward function, and arousal through activation of OX1Rs and/or OX2Rs. Orexin receptors are expressed not only in the central nervous system but also in a variety of organs in peripheral tissues. However, the mechanism of action of orexins in peripheral tissues has not been completely clarified. Orexin peptide is present at detectable
Acknowledgments
This study was supported by JST PRESTO program and a Grant-in-Aid for Scientific Research (B) (23300142), Grant-in-Aid for Scientific Research on Innovative Area “Mesoscopic Neurocircuitry” (23115103) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan (A. Y.) and the Japan Society for Promotion of Science (JSPS) postdoctoral fellowship (T. T.).
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