Orexin

Orexins, also called hypocretins, are the common names given to a pair of highly excitatory neuropeptide hormones that were simultaneously discovered by two groups of researchers in rat brains.

The two related peptides (orexin A and B, or hypocretin-1 and -2), with approximately 50% sequence identity, are produced by cleavage of a single precursor protein. Studies suggest that orexin A/hypocretin-1 may be of greater biological importance than orexin B/hypocretin-2. 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 orexin peptides bind to the orexin receptor, a G-protein coupled receptor.

The orexins/hypocretins are strongly conserved peptides, found in all major classes of vertebrates. The peptides are thought to have arisen early in vertebrate evolution.

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Functions

The orexin/hypocretin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin A/hypocretin-1 increases food intake. In addition, it stimulates wakefulness and energy expenditure.

Wakefulness

Orexin seems to promote wakefulness.

The discovery that orexin/hypocretin dysregulation causes the sleep disorder narcolepsy^[1] subsequently indicated a major role for this system in sleep regulation. Narcolepsy results in excessive daytime sleepiness, inability 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 a functional receptor for orexin/hypocretin have narcolepsy, while animals and people lacking the orexin/hypocretin neuropeptide itself also have narcolepsy. Orexin/hypocretin neurons strongly excite various brain nuclei with important roles in wakefulness including the dopamine, norepinephrine, histamine and acetylcholine 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 is to integrate metabolic, circadian and sleep debt influences to determine whether the animal should be asleep or awake and active. Central administration of orexin A/hypocretin-1 strongly promotes wakefulness, increases body temperature, locomotion and elicits a strong increase in energy expenditure. Sleep deprivation also increases orexin A/hypocretin-1 transmission. The orexin/hypocretin system may thus be more important in the regulation of energy expenditure than food intake. In fact, orexin/hypocretin-deficient narcoleptic patients have increased obesity rather than decreased BMI, as would be expected if orexin/hypocretin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30-36 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.^[2][3]

Food intake

Orexin increases the craving for food, and correlates with the function of the substances that promote its production.

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 (by leptin receptors), but are activated by ghrelin and hypoglycemia (glucose inhibits orexin production). Orexin/hypocretin, as of 2007, is claimed to 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, i.e., catabolism, with lethal consequences on a long-term basis.

Pharmacologic potential

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

Preliminary research has been conducted that shows potential for orexin blockers in the treatment of alcoholism. Lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.^[4]

History and nomenclature

Masashi Yanagisawa and colleagues at the University of Texas Southwestern Medical Center at Dallas, coined the term orexin to reflect the orexigenic (appetite-stimulating) activity of these hormones.

Luis DeLecea, Thomas 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 name of this family of peptides is currently in dispute. The name "orexin" has been rejected by some due to evidence that the orexigenic effects of these peptides may be incidental or trivial, while other groups maintain that the name "hypocretin" is awkward, pointing out that many neuropeptides have names that are unrelated to their most important functions. The name "hyporexin" has been suggested as a compromise, but as of yet has not been commonly used. Both "orexin" and "hypocretin" will likely continue to appear in published works until a preferred name has been accepted by the scientific community.

Drugs

SB649868 is under development by GlaxoSmithKline for sleep disorders; it is an orexin receptor antagonist. ACT-078573 is a similar compound under development by Actelion.

References

1. ^ Siegel J (1999). "Narcolepsy: a key role for hypocretins (orexins)". Cell 98 (4): 409-12. PMID 10481905. full text
2. ^ http://www.wired.com/science/discoveries/news/2007/12/sleep_deprivation
3. ^ Systemic and Nasal Delivery of Orexin-A (Hypocretin-1) Reduces the Effects of Sleep Deprivation on Cognitive Performance in Nonhuman Primates, Deadwyler et al. The Journal of Neuroscience, December 26, 2007, 27(52):14239-14247; doi:10.1523/JNEUROSCI.3878-07.2007
4. ^ Helen Puttick. "Hope in fight against alcoholism", The Herald, December 26, 2006.