Trends in Endocrinology & Metabolism
ReviewThe Hypocretin/Orexin Story
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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Cited by (43)
The hypothalamic paraventricular nucleus as a central hub for the estrogenic modulation of neuroendocrine function and behavior
2022, Frontiers in NeuroendocrinologyCitation Excerpt :The perifornical-lateral hypothalamic area contains a population of orexin-immunoreactive neurons sending fibers in several brain regions, including the parvocellular part of the PVN (Nambu et al., 1999; Peyron et al., 1998). Orexins are a family of peptides that stimulates appetite and behaviors associated with feeding (Sakurai et al., 1998; Samson and Resch, 2000), therefore, the presence of orexin positive fibers within the PVN is of particular interest for the control of feeding behaviors (Marraudino et al., 2021). In the PVN, orexin receptors (OX-R1 and OX-R2) are both present (Backberg et al., 2002; Cluderay et al., 2002), and OX-R1 is expressed in both vasopressin and OXT neurons, as well as in CRH and somatostatin neurons (Backberg et al., 2002).
Body temperature and sleep
2018, Handbook of Clinical NeurologyCellular location and major terminal networks of the orexinergic system in the brain of two megachiropterans
2013, Journal of Chemical NeuroanatomyCitation Excerpt :Orexinergic (hypocretinergic) neurons produce a hypothalamic neuromodulatory peptide (Chicurel, 2000; Samson and Resch, 2000) that functions in the control of the sleep–wake cycle, some respiratory functions, feeding and satiety, and certain locomotory and neuroendocrine functions (Mintz et al., 2001; Ferguson and Samson, 2003; Zeitzer et al., 2003; Kirouac et al., 2005; Takakusaki et al., 2005).
Effect of orexin-A on phagocytic activity of peritoneal macrophage in starved rats
2011, Cellular ImmunologyCitation Excerpt :Both neuropeptides are derived from the same 130 amino acid long precursor molecule called preproorexin. The preproorexin polypeptide has a secretory sequence and is cleaved to form the mature OXA and OXB peptides [5,7]. Orexins exert their effects by targeting two G protein-coupled receptors, namely orexin type 1 (OX1R) and orexin type 2 (OX2R) receptors.
Cellular location and major terminal networks of the orexinergic system in the brains of five microchiropteran species
2010, Journal of Chemical Neuroanatomy