Roles of orexins in regulation of feeding and wakefulness

Maintenance of energy homeostasis requires the coordination of systems that regulate feeding, body temperature, autonomic and endocrine functions with those that govern an appropriate state of arousal (wakefulness). Historically, the hypothalamus has been recognized to play a critical role in maintaining energy homeostasis by integrating these factors and coordinating metabolic, neuroendocrine and behavioral responses and arousal states. Recent studies have suggested that orexin-containing neurons in the lateral hypothalamic area (LHA) constitute an important central pathway that promotes adaptive behavioral and arousal responses to metabolic and environmental signals. Orexins, also called hypocretins, are neuropeptides originally identified as endogenous ligands for two orphan G-protein-coupled receptors termed orexin receptors -1 and -2. Orexin-A and -B are expressed by a specific population of neurons in the LHA. These neurons project to numerous brain regions, with monoaminergic and cholinergic nuclei of the hypothalamus, midbrain, and pons receiving particularly strong innervations. The orexinergic system is anatomically well-placed to coordinate the metabolic, motivational, motor, autonomic, and arousal processes necessary to elicit environmentally appropriate behaviors. Recent studies on orexin suggest that the orexinergic system plays a significant role in feeding and sleep-wakefulness regulation, possibly by coordinating the complex behavioral and physiological responses of these complementary homeostatic functions. Orexin neurons may provide an integrative link between peripheral metabolism and central regulation of behaviors required for an adaptive response to homeostatic challenges.