Orexins modulate food intake, energy balance, and arousal and sleep patterns as a consequence of activation of two GPCRs (OX1R and OX2R) by two ligands (OXA and OXB).7374 Components of the orexin system are similarly distributed anatomically but remain functionally distinct. The ultimate physiological outcomes are determined by the specific receptor-ligand pairings; OX1R appears to bind OXA exclusively, whereas both orexin ligands have affinity for OX2R. Extensive studies have been conducted that detail expression patterns for the receptors.75-79 They are expressed in the lateral and posterior regions of the hypothalamus, known to modulate feeding behavior, where OXR neurons are proximal to, but distinct from, MCH neurons.77-80
As expected for receptors that coordinate complex feeding behavior, an extensive network of projections extends throughout the CNS. Transcriptional profiling and immunohistochemical staining79 indicate that OXA is expressed in the periphery, including ganglia and endocrine cells in the kidney, adrenals, stomach, and intestine. In the pancreas, the majority of cells that are insulin positive also express OXA. OX1R is selective for OXA and appears to explain the preponderant data implicating the orexins in feeding behavior. Accumulating data from animal models8182 confirm that the OXA ligand stimulates appetite, but experimental outcomes have been found to vary, depending upon site and time of delivery. Xu and co-workers83 suggest that apparent inconsistencies could derive from responsiveness of the orexin system to circadian rhythm and its involvement in determining wakefulness and, thereby, activity levels. Whereas the hypophagia observed in orexin ligand-knockout mice84 supports a role for the orexins in appetitive behavior, the absence of a related phenotype in OXIR-null mice85 suggests that the system requires further analysis to define its potential as a therapeutic target for the treatment of obesity.
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