Orexins

Definition
Orexins (hypocretins) are neuropeptides primarily localized in the hypothalamus and are implicated in the regulation of a variety of activities, including feeding behavior and energy balance. Orexins have also been found to be linked to idiopathic narcolepsy (excessive daytime sleepiness) 1.

Related Peptides
Two homologous peptides, orexin-A (OXA) and orexin-B (OXB), are proteolytic cleavage products derived from a common precursor called prepro-orexin1.

Discovery
The orexins were discovered during a search for endogenous ligands that activate orphan G protein-coupled receptors by Sakurai et al., in 19982.

Structural Characteristics
OXA is 33 amino acids in length, with an N-terminal pyroglutamyl residue and an amidated C terminus. The peptide also contains two intrachain disulfide bonds, and sequencing of similar extracts from bovine brain revealed exact interspecies homology. OXB is 28 amino acids in length and is 46% (13/28) identical in sequence to OXA, with an amidated C-terminal2.

Mode of Action
The original HFGAN72 receptor, subsequently called OX1R, was shown to bind OXA with high affinity and bind OXB with 100- to 1,000-fold lower affinity. However, a related receptor, OX2R, identified by searching database entries with the OX1R sequence, was demonstrated to have equally high affinities for both peptides. Thus, OX2R was concluded to be a non-selective receptor for both OXA and OXB peptides, while OX1R was concluded to be moderately selective for orexin-A. The binding of both ligands to either receptor was associated with changes in intracellular calcium concentrations. Evidence from receptor-expressing cells suggests that OX1R is coupled exclusively to the Gq subclass of G proteins, whereas OX2R may couple to Gi/o and/or Gq 1.

Functions
The widespread projections of the orexin neurons throughout the neuroaxis suggest that activation of orexin circuits probably modulates a variety of systems, including those involved in the regulation of food intake. The fact that orexins can increase the release of either excitatory or inhibitory neurotransmitters, by acting directly on axon terminals, indicates that the peptides could ultimately increase or decrease the activity of innervated brain circuits.

OXA has been reported to increase food intake. Orexins appear to be involved in the short-term regulation of feeding, rather than the long-term maintenance of body weight. OXA appears to increase food intake by delaying behavioral satiety, i.e., the normal transition from eating through grooming to resting. Metabolic effects of orexins have also been shown to be dependent on circadian phase. Orexin neurons are not only play essential roles in the control of feeding and energy balance but also regulate wakefulness. OXA inhibits the activity of glucoresponsive neurons. They control vagal outflow to the gastrointestinal tract and modulate activities such as gastric acid secretion and/or motility. Orexins probably play a role in sensory transmission.

They increase blood pressure and heart rate, affect the release of luteinizing hormone, growth hormone, and Prolactin, increase drinking and locomotor activity, and maintain wakefulness. Since orexin receptors are expressed in the adrenal medulla, orexins may also modulate epinephrine release. These findings indicate that orexins play a role in the regulation of the autonomic and neuroendocrine systems, including stimulation of sympathetic nerves. Interestingly, many of these effects are also associated with changes in food intake and gastrointestinal motility. For example, sleep has been shown to be a major determinant of interdigestive and digestive motility. Sleep is associated with diminished intestinal motility during the night and the day, suggesting that intestinal motility is regulated not only by circadian rhythm. Fasting alters sleep-wake cycles and evokes a specific motor activity, the migrating motor complex, in the gut. Thus, sleep-wake, motility, and feeding patterns appear to be coordinated, and orexins may play a significant role in coordinating these complex physiological activities1.

References
1.Kirchgessner AL (2002). Orexins in the Brain-Gut Axis. Endocr Rev., 23(1):1-15
2.Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell.,92(4):573-585.


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