Orexin

Orexins, also called hypocretins, are the common names given to a pair of highly excititory neuropeptide hormones that were simultaneously discovered by two groups of reseachers in rat brains. Masashi Yanagisawa and colleagues at a Howard Hughes Medical Institute-funded lab at the University of Texas, coined the term orexin to reflect the orexigenic (appetite-stimulating) activity of these hormones. Luis DeLecea, Tom Kilduff, and colleagues also reported discovery of these same peptides, dubbing them hypocretins to indicate that they are synthesized in the hypothalamus and to reflect their similarity to a class of hormones called incretins (i.e., hypothalamic incretin). The two highly-related peptides (Orexin A and B, or Hypocretin-1 and -2) are produced by cleavage of a single precursor protein. Although these peptides are produced by a very small population of cells in the lateral and posterior hypothalamus, they send projections throughout the brain.

The hypocretin/orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of hypocretin-1 increases food intake. The discovery that hypocretin dysregulation causes the sleep disorder narcolepsy subsequently indicated a major role for this system in sleep regulation. Narcolepsy results in excessive daytime sleepiness, inablity to consolidate wakefulness in the day (and sleep at night), and cataplexy (loss of muscle tone in response to strong, usually positive, emotions). Dogs that lack an important receptor for hypocretin have narcolepsy, while animals and people lacking the hypocretin/orexin neuropeptide itself also have narcolepsy. Hypocretin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine and histamine systems and appear to play an important role in stabilizing wakefulness and sleep.

Recent studies indicate that a major role of the orexin/hypocretin system may be to integrate metabolic, circadian and sleep debt influences to determine whether the animal should be resting or awake and active. Central administration of hypocretin-1 strongly promotes wakefulness, increases body temperature, locomotion and elicits a strong increase in energy expenditure. Sleep deprivation also increases hypocretin-1 transmission. The hypocretin system may thus be more important in the regulation of energy expenditure than food intake. In fact, hypocretin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if hypocretin were primarily an appetite stimulating peptide. Leptin is a hormone produced by fat cells and acts as a long-term internal measure of energy state. Ghrelin is a short term factor secreted by the stomach just before an expected meal, and strongly promotes food intake. Hypocretin-producing cells have recently been shown to be inhibited by leptin and to carry leptin receptors and are activated by ghrelin and hypoglycemia. Hypocretin may therefore be a very important link between metabolism and sleep regulation. Such a relationship has been long suspected based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, with lethal consequences on a long term basis.

The research on orexin is still in an early phase, although many scientists believe that orexin-based drugs could help narcoleptics and increase alertness in the brain without the side effects of amphetamines.