Orexins
Orexins, also known as hypocretins, are neuropeptides originally identified in the hypothalamus, specifically the perifornical and lateral hypothalamic area (described as the feeding area). In view of their appetite stimulating effects they were named Orexins (Greek word orexis meaning appetite) They are presently thought to have a role in not only in feeding, but also in modulation of the secretomotor responses in the gut where their presence has been identified, as well as in the control of the state of wakefulness.Orexin A and B were described in 1998, as the endogenous ligands for Orexin receptors which were till then considered orphan G protein coupled receptors. Cell. 1998 Feb 20;92(4):573-85 Both Orexin A (33 aminoacid peptide) and Orexin B (28 aminoacid peptide) were found to be derived from the 130 aminoacid precursor molecule pre-pro-Orexin , the gene of which in humans has been mapped to chromosome 17. Molecules initially described as hypocretin 1 and hypocretin 2 Proc Natl Acad Sci U S A. 1998 Jan 6;95(1):322-7 were later found to be the same as Orexin A and B.
Orexin Receptors
Two Orexin receptors were identified. OX1R seems to show selective binding with higher affinity for Orexin A than Orexin B while OX2R non-selectively binds both Orexin A and B with similar affinity. OX1R is abundant in the ventromedial hypothalamic nucleus (VMH) which is considered as the satiety centre, as its destruction results in obesity. OX2R is expressed in Lateral hypothalamic area (LHA), and Paraventricular Nucleus (PVN) of the hypothalamus. J Comp Neurol. 2001 Jun 18;435(1):6-25. Orexin receptors are minimal in the dorsal vagal nuclear complex (NTS and DMV) despite an abundance of orexin containing neuronal fibres in this region, suggesting the possibility that Orexin actions here may be mediated through presynaptic activity.
Orexin Receptors
Two Orexin receptors were identified. OX1R seems to show selective binding with higher affinity for Orexin A than Orexin B while OX2R non-selectively binds both Orexin A and B with similar affinity. OX1R is abundant in the ventromedial hypothalamic nucleus (VMH) which is considered as the satiety centre, as its destruction results in obesity. OX2R is expressed in Lateral hypothalamic area (LHA), and Paraventricular Nucleus (PVN) of the hypothalamus. J Comp Neurol. 2001 Jun 18;435(1):6-25. Orexin receptors are minimal in the dorsal vagal nuclear complex (NTS and DMV) despite an abundance of orexin containing neuronal fibres in this region, suggesting the possibility that Orexin actions here may be mediated through presynaptic activity.
Orexins and CNS
Orexin Nerve fibres which have been identified in the hypothalamus project to various sites in the brain and the spinal cord suggesting the potential to influence multiple systems. Annu Rev Neurosci. 2001;24:429-58. Orexin Nerve fibres project to the arcuate nucleus where they innervate NPY- containing neurones (NPY is neuropeptide Y- a neuropeptide that stimulates feeding). Activation of these NPY neurones by orexin, probably through OX1R, has been demonstrated. J Neurosci. 1998 Oct 1;18(19):7962-71. Blockade of NPY receptors - Y1 and Y5 Regul Pept. 2000 Feb 8;87(1-3):19-24 ; Peptides. 2000 Oct;21(10):1557-60 decrease orexin-stimulated feeding. These suggest that Orexin may exert its orexigenic activities via NPY pathways. While arcuate NPY/AgRP neurons innervate orexin neurons, Regul Pept. 2000 Feb 8;87(1-3):19-24. with reciprocal input from orexin neurons to these nuclei, J Neurosci. 1999 Feb 1;19(3):1072-87 MCH neurons despite their proximity to orexin neurons do not seem to be involved in modulating orexin neuron activity. Int J Obes Relat Metab Disord. 2002 Oct;26(10):1289-95. Orexin fibres send axons to other orexin neurons possibly regulating their own activities. Peptides. 1999 Dec;20(12):1455-70. Orexin neurons also demonstrate reciprocal contact with the arcuate neurons that express POMC/CART. |
The vagal nuclei- Nucleus of Tractus solitarius (containing glucose-sensitive neurones responding to changes in blood glucose and food in the gut), and the Dorsal motor Nucleus of Vagus (DMV- containing motor neurones that regulate gut motility and secretion as well as the cephalic phase of digestion) - have both been shown to contain orexin-immunoreactive fibres. J Neurosci. 1998 Dec 1;18(23):9996-10015 Also, the area postrema-a part of the vagal complex which being BBB deficient facilitates circulating systemic factors as glucose and peptides to access the brain-contains orexin reactive fibres. These suggest that a vagal modulation by orexin fibres can potentially play a part in satiety signalling. Orexin A administration intra cisternally increases gastric acid secretion, a response abolished by vagotomy or atropine blockade. Biochem Biophys Res Commun. 1999 Jan 27;254(3):623-7. Orexin A injection into the DMV (dorsal motor nucleus of vagus) increases gastric motility. Gastric acid secretion and gastric motility are components of the cephalic phase of feeding which are mediated vagally, suggesting the role that orexins may play a part in mediating this phase of feeding. Orexin neurons in man also synthesise CART. Orexin neurons have functional leptin receptors. Regul Pept. 2000 Aug 25;92(1-3):31-5. Orexin neurons also express STAT-3 the transcription factor induced by Leptin receptor activation. Leptin when administered centrally reduces hypothalamic Orexin A levels. Biochem Biophys Res Commun. 1999 Apr 29;258(1):119-22 Interestingly, rodents with hypoleptinaemia due to food restriction Diabetes. 1999 Nov;48(11):2132-7. or due to genetic defects Regul Pept.2002 Mar 15;104(1-3):1-9. do not show over-expression of hypothalamic orexin. |
Orexin and appetite stimulation
Intraventricular injection of Orexin A or Orexin B increases food intake in rats in a dose dependent manner. Orexin A showed more potent orexigenic action than Orexin B. Cell. 1998 Feb 20;92(4):573-85 Both Anti-orexin antibody Biochem Biophys Res Commun. 2000 Jan 19;267(2):527-31 and anti OX1R receptor antagonist Regul Pept. 2000 Dec 22;96(1-2):45-51 have been shown to block the feeding stimulating action of Orexin A. Orexin B has minimal or variable effects on feeding Peptides. 1999;20(9):1099-105 although further clarification in this regard is needed. Orexin B promotes grooming and searching activities rather than feeding. Brain Res. 1999 Mar 13;821(2):526-9. Orexin A injected intracerebroventricularly is as potent an orexigen as MCH and Galanin but less potent than NPY. J Endocrinol. 1999 Mar;160(3):R7-12 Orexin knock- out mice eat less Neuron. 2001 May;30(2):345-54. but chronic Orexin A administration does not induce obesity in normal rats. Brain Res. 1999 Dec 4;849(1-2):248-52 presumably due to the compensatory hypophagia that follows the hyperphagic phase such that the 24 hour food intake is not increased following a single injection. Peptides. 1999;20(9):1099-105. This may suggest that the role of Orexins may be in short term appetite regulation rather than long term weight maintenance. Almost all orexin neurons in the Lateral hypothalamus (LH) co-express dynorphin, an endogenous opioid peptide that demonstrates orexigenic action. J Neurosci. 2001 Oct 1;21(19):RC168. Orexin A induced feeding is blocked by a non-specific opioid receptor antagonist Endocrinology. 2002 Aug;143(8):2995-3000. suggesting that opioid pathways may be involved in the mediation of Orexin A action. In fact, Orexin administration results in rats opting for palatable fat rich food, a behaviour similar to the opioid reward pathway stimulation. Ghrelin immunoreactive terminals make contact with Orexin neurones in the lateral hypothalamus. Endocrinology. 2003 Apr;144(4):1506-12. Ghrelin administration centrally has been shown to activate orexin neurons. Endocrinology. 2002 Jan;143(1):155-62. and blockade of Orexin A and B receptors by injection of antisera can attenuate the effect of centrally administered Ghrelin on food intake. |
Orexins and Glucose
Fasting, Biochem Biophys Res Commun. 1999 Mar 24;256(3):495-9 as well as insulin induced hypoglycaemia Neurosci Lett. 1999 Mar 5;262(2):77-80. increases hypothalamic prepro-orexin mRNA levels, suggesting that a fall in blood glucose may stimulate orexin neurons. Hypoglycaemia has also been shown to increase activity in orexin-immunoreactive neurons. Endogenous Orexin A release from the isolated pancreas of rat is stimulated by low glucose (2.8 mmol/l) and inhibited by high glucose (16.7 mmol/l), a manner akin to glucagon release. Diabetes. 2003 Jan;52(1):111-7. Thus the glucose mediated orexin stimulation may in turn regulate short term feeding. As a corollary, Orexin A administration has been shown to increase the discharge in the glucose sensitive neurons of the Lateral Hypothalamus (LHA). Physiol Behav. 2000 Nov 1-15;71(3-4):251-61 which might reflect the physiological response elicited by increased orexin A levels during hypoglycaemia, leading onto feeding. Feeding results in a reduction in orexin expression which might partly be mediated by the gastric distension with vagal signalling, rising glucose levels, as well as falling Ghrelin levels post prandially. Orexins and the Pancreas OX1R like immunoreactivity and OX1R mRNA have been detected in rat islets. Neuron. 1999 Dec;24(4):941-51. Pancreatic alpha cells also demonstrate Orexin receptors. Subcutaneous injection of Orexin A stimulates insulin secretion from the rat pancreas both in vivo and in vitro. Life Sci. 2000;66(5):449-54. It was considered a possibility that orexin may stimulate hunger through insulin secretion, but it remains to be known whether this action is mediated through direct beta cell stimulation. Jan;52(1):111-7. A study in isolated rat pancreas demonstrated that incubation with Orexin A , in the presence of hypoglycaemia, stimulated glucagon release with no effect on insulin. Fasted rats infused with Orexin A intravenously also demonstrated a rise in glucagon with concomitant fall in insulin levels. Diabetes. 2003 Jan;52(1):111-7 |
Orexins and the Gut
The enteric nervous system consists of ganglia in two plexuses- myenteric and submucosal plexuses. The CNS controls the gut motility and secretions via the enteric plexus. Prepro orexin and orexin receptor mRNA have been shown in rat myenteric plexus. In the submucosal ganglia Orexin neurons of two types have been described; non-cholinergic neurons containing VIP (presumably secretory in function in view of the ability of VIP-ergic neurones to facilitate chloride secretion) News Physiol Sci. 1998 Dec;13:269-274. and, cholinergic neurons with substance P. Fasting results in increased orexin positive submucosal neurons suggesting orexin synthesis in response to hunger. Neuron. 1999 Dec;24(4):941-51. Orexin A administration increases activity in these submucosal neurons in keeping with the presence of OX1R receptors at this location. Orexin nerve fibres have been identified all along the gut, especially marked in the duodenum. Orexin neurons in the myenteric and submucosal plexuses also show leptin receptor immunoreactivity, possibly facilitating feed back signalling from adipose tissue to the gut. Endocr Rev. 2002 Feb;23(1):1-15. Orexin fibres in the circular muscle contain VIP which mediates muscle relaxation, implying the role of orexin in intestinal motility. Peripheral administration of Orexins results in inhibition of intestinal motility. Orexin receptors are widely distributed in the enteric nervous system with OX1R being found in the circular muscle of stomach and small intestine as well as submucosal and myenteric neurons, ganglia and mucosa. Neuron. 1999 Dec;24(4):941-51. OX2R is localized to enteroendocrine cells in the intestinal mucosa raising the possibility of endocrine control of or synergism with gut hormones by orexins. |
Orexins and Wakefulness
Orexinergic neurones from the lateral hypothalamus radiate widely but the locus coeruleus receives the most dense innervation with these fibres, which in turn increases cell firing of intrinsic noradrenergic neurones facilitating arousal. Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10911-6 OXR2 receptors have been demonstrated in the tuberomammillary nucleus of the hypothalamus. J Comp Neurol. 2001 Jun 18;435(1):6-25. The tuberomammillary nucleus is the only source of histamine in the central nervous system. Considering the fact that histamine is crucial in the maintenance of wakefulness, Neuropharmacology. 1988 Feb;27(2):111-22. the presence of OX2R implicates orexins in modulating the wakeful state. Orexin administration suppresses REM sleep while blockade of OX1R prevents this effect of orexins. J Neurosci. 2000 Oct 15;20(20):7760-5. Orexin knock-out mice Cell. 1999 Aug 20;98(4):437-51 as well as OX2R mutant dogs Cell. 1999 Aug 6;98(3):365-76. show narcoleptic symptoms. In rats, chronic intra-cerebroventricular injection of Orexin disrupts the diurnal feeding pattern, with rats showing increased daytime feeding than the night time Brain Res. 1999 Dec 4;849(1-2):248-52 suggesting that a prolonged wakeful state may contribute to the increased food intake. Narcoleptic humans have been shown to have low CSF concentrations of Orexin A. Lancet. 2000 Jan 1;355(9197):39-40.Orexin mRNA has been identified in the testes Cell. 1998 Feb 20;92(4):573-85 and OX1R and OX2R expression in the adrenal medulla of rats.Endocrinology. 1999 Dec;140(12):5991-4. The significance of these remain to be elucidated. |