Orexin-A and
orexin-B are
neuropeptides originally identified as endogenous
ligands for two orphan
G-protein-coupled receptors.
Orexin neuropeptides (also known as
hypocretins) are produced by a small group of neurons in the lateral hypothalamic and perifornical areas, a region classically implicated in the control of mammalian feeding behavior.
Orexin neurons project throughout the central nervous system (CNS) to nuclei known to be important in the control of feeding, sleep-wakefulness, neuroendocrine homeostasis, and autonomic regulation.
orexin mRNA expression is upregulated by fasting and
insulin-induced
hypoglycemia. C-fos expression in
orexin neurons, an
indicator of neuronal activation, is positively correlated with wakefulness and negatively correlated with rapid eye movement (REM) and non-REM sleep states. Intracerebroventricular administration of
orexins has been shown to significantly increase food consumption, wakefulness, and locomotor activity in rodent models. Conversely, an
orexin receptor antagonist inhibits food consumption. Targeted disruption of the
orexin gene in mice produces a syndrome remarkably similar to human and canine
narcolepsy, a
sleep disorder characterized by
excessive daytime sleepiness,
cataplexy, and other pathological manifestations of the intrusion of REM sleep-related features into wakefulness. Furthermore,
orexin knockout mice are hypophagic compared with weight and age-matched littermates, suggesting a role in modulating energy metabolism. These findings suggest that the
orexin neuropeptide system plays a significant role in feeding and sleep-wakefulness regulation, possibly by coordinating the complex behavioral and physiologic responses of these complementary homeostatic functions.