Orexins (hypocretins): their role in appetite and arousal

Serendipity and hypothesis-driven research both contributed to the discovery and characterization of two recently identified neuropeptides thought to be involved in the control of appetite and arousal. These two peptides, named hypocretin-1 and -2, or orexin-A and -B, originated from a common precursor, prepro-hypocretin or prepro-orexin, encoded by a gene localized to human chromosome 17q21. Orexin/hypocretin neuropetides are produced by a small set of neurons in the lateral hypothalamic and perifornical areas, classically involved in the control of feeding behavior, blood pressure and central regulation of immune function. Orexin-/hypocretin-containing neurons project widely to the CNS, and orexin receptors have been found in areas known to participate in the control of feeding, sleep, wakefulness, neuroendocrine homeostasis and autonomic regulation. Initially, a role in appetite control was suggested as the main action of the two hypothalamic neuropetides, as their site of synthesis and incretion, the lateral hypothalamus, is primarily involved in the control of food ingestion. Destruction of lateral hypothalamic areas results in underfeeding, and orexins were thought to be the substances mediating appetite-stimulating drives. Further studies indicate a more complex array of functions and effects. The orexin signaling pathway is now thought to participate in a complex cycle of energy homeostasis, including the control of food intake, waking time, motor activity, metabolic rate, heart rate and blood pressure.