Review
The Hypocretin/Orexin Story

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Abstract

Newly described peptides, produced in neurons in the lateral hypothalamic area, have been shown to stimulate appetite and stereotypic behaviors associated with feeding. Discovered independently by two groups, the hypocretins/orexins stimulate autonomic function and have been shown to be physiological regulators of the arousal state. Neuroendocrine and metabolic effects of these peptides, some related to sleep–wakefulness and arousal state, are just now being discovered.

Section snippets

The Discovery of the Hypocretins: Subtraction Cloning Reveals a Novel Family of Neuropeptides

Using the subtraction cloning method1, Gautvik and colleagues2 constructed a rat cDNA library enhanced for hypothalamic-specific clones. From this library, they identified 38 distinct mRNAs that were expressed selectively in the hypothalamus, including some encoding well-characterized hypothalamic peptides such as oxytocin, vasopressin and proopiomelanocortin (POMC). Northern analysis then confirmed the highly selective nature of the hypothalamic localization of two of the cDNA clones, one

Discovery of the Orexins: an Orphan Receptor Provides the Tool for Peptide Discovery

One month after the publication of the discovery of the hypocretins, Yanagisawa and colleagues4 independently published the discovery of novel peptide ligands for a previously identified, G protein-coupled orphan receptor. Because most previously characterized peptide receptors are G protein linked, they reasoned that many of the ‘orphan’ receptors identified by cDNA homology cloning strategies might in fact have yet to be characterized peptides as their cognate ligands. Thus, they created a

What Do the Hypocretins/Orexins Do?

It is clear that the hypocretins/orexins (Hcrt/ORXs) can stimulate appetite; however, they are not as potent as other stimulatory neuropeptides. This does not negate the possibility that they play a physiologically relevant, modulatory role, and ultrastructural evidence for the synaptic action of Hcrt/ORXs on NPY-producing neurons supports that hypothesis7. One group8 failed to observe a significant effect of fasting on hypothalamic Hcrt/ORX levels and, furthermore, no significant differences

Which Hypothesized Actions of the Hcrt/ORXs are Physiologically Relevant?

Although there is evidence for the physiological relevance of the orexigenic action of Hcrt/ORX, based on inhibitory effects of anti-ORXA antibody administration on feeding after 24-h food deprivation18, the identification of a naturally occurring mutation in the gene encoding the OX2R receptor19 and the development of a knockout mouse lacking the gene for orexin20 convincingly placed the Hcrts/ORXs in a physiologically relevant context.

Once again, modern methodologies brought two independent

Quo vadis?

The convergence of modern molecular technologies and the more conventional physiological and behavioral methodologies has yielded insight into a human disease for which little mechanistic information and still less rational basis for potential therapies had existed. Is narcolepsy the only condition or sleep–wakefulness the only physiological behavior impacted by the Hcrts/ORXs? The metabolic consequences of ORX deficiency or excess merit full attention. How do these peptides act to inhibit

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