Orexins/Hypocretins

A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior

	Orexin (Hypocretin) Related Products
	Orexin in Narcolepsy

Orexin-A and B were identified as endogenous ligands for the orexin-1 (HCRT1) and orexin-2 (HCRT2) G-protein coupled receptors (Sakurai et al, 1998). These peptides are identical to two hypothalamic peptides that share a high degree of homology with secretin, designated hypocretin-1 and hypocretin-2 (De Lecea et al, 1998). ICV administration of orexin-A and B stimulated food intake in rats. Additionally, prepro-orexin mRNA levels were upregulated in fasting rats. Recent reports suggest a role in the sleep-wake cycle.

Sakurai, T.et al. Cell 92: 573-585,1998.

The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity.

de Lecea, L.et al. Proc. Nat. Acad. Sci. 95: 322-327, 1998.

Roles of orexins in regulation of feeding and wakefulness.

Maintenance of energy homeostasis requires the coordination of systems that regulate feeding, body temperature, autonomic and endocrine functions with those that govern an appropriate state of arousal (wakefulness). Historically, the hypothalamus has been recognized to play a critical role in maintaining energy homeostasis by integrating these factors and coordinating metabolic, neuroendocrine and behavioral responses and arousal states. Recent studies have suggested that orexin-containing neurons in the lateral hypothalamic area (LHA) constitute an important central pathway that promotes adaptive behavioral and arousal responses to metabolic and environmental signals. Orexins, also called hypocretins, are neuropeptides originally identified as endogenous ligands for two orphan G-protein-coupled receptors termed orexin receptors -1 and -2. Orexin-A and -B are expressed by a specific population of neurons in the LHA. These neurons project to numerous brain regions, with monoaminergic and cholinergic nuclei of the hypothalamus, midbrain, and pons receiving particularly strong innervations. The orexinergic system is anatomically well-placed to coordinate the metabolic, motivational, motor, autonomic, and arousal processes necessary to elicit environmentally appropriate behaviors. Recent studies on orexin suggest that the orexinergic system plays a significant role in feeding and sleep-wakefulness regulation, possibly by coordinating the complex behavioral and physiological responses of these complementary homeostatic functions. Orexin neurons may provide an integrative link between peripheral metabolism and central regulation of behaviors required for an adaptive response to homeostatic challenges. <

Sakurai T. Neuroreport 2002 Jun 12;13(8):987-95

Sleep, feeding, and neuropeptides: roles of orexins and orexin receptors.

RECENT STUDIES USING MOLECULAR GENETICS IN MICE AND DOGS, AS WELL AS HISTOPATHOLOGICAL ANALYSES OF HUMAN DISEASE, HAVE COME TO THE SAME CONCLUSION: the human sleep disorder narcolepsy is caused by failure of signaling mediated by orexin (hypocretin) neuropeptides. These and other findings strongly suggest that the orexin system plays a critical role in sleep/wake regulation. In addition, the orexin system may link energy homeostasis to the regulation of sleep/wake cycles.

Mieda M, Yanagisawa M. Curr Opin Neurobiol 2002 Jun;12(3):339-45

Orexin-A and -B stimulate appetite and food intake in rats. Orexins and orexin receptors are present in the hypothalamus as well as the enteric nervous system, the pancreas and the gut. The presence of orexins in peripheral blood, however, has not yet been reported. To determine whether orexin-A is present in human plasma and is related to body weight, we measured plasma orexin-A and leptin levels in a population with a body mass index (BMI) range from 19.8 to 59 kg/m(2). Plasma orexin-A levels correlated negatively and plasma leptin levels correlated positively with BMI. In obese and morbidly obese individuals, orexin-A levels were significantly lower and leptin levels were significantly higher when compared to normal. Our results support previous data suggesting that orexin-A acts also in a peripheral manner. The fact that lower levels of plasma orexin-A are present in obese individuals suggests that it is involved in the regulation of human energy metabolism.

Adam JA, Menheere PP, van Dielen FM, Soeters PB, Buurman WA, Greve JW. Int J Obes Relat Metab Disord 2002 Feb;26(2):274-6

Pressor effects of orexins injected intracisternally and to rostral
ventrolateral medulla of anesthetized rats. Chen CT, Hwang LL, Chang JK, Dun NJ. Am J Physiol Regul Integr Comp Physiol 2000 Mar;278(3):R692-7
Orexin A-like immunoreactivity in the rat brain. Chen CT, Dun SL, Kwok EH, Dun NJ, Chang JK. Neurosci Lett 1999 Feb 5;260(3):161-4
Orexins: a role in medullary sympathetic outflow. Dun NJ, Le Dun S, Chen CT, Hwang LL, Kwok EH, Chang JK. Regul Pept 2000 Dec 22;96(1-2):65-70
Hypothalamic orexin A-immunoreactive neurons project to the rat dorsal medulla. Harrison TA, Chen CT, Dun NJ, Chang JK. Neurosci Lett 1999 Sep 24;273(1):17-20
Cardiovascular regulatory actions of the hypocretins in brain. Samson WK, Gosnell B, Chang JK, Resch ZT, Murphy TC. Brain Res 1999 Jun 12;831(1-2):248-53

Slides courtesy Dr. Nae Dun, James H. Quillen College of Medicine East Tennessee State University.
Orexin A-like Immunoreactivity in the Rat Brain
C.-T Chen et al., Neuroscience Letters 260, 161-164 (1999)

Immunohistochemical prodedures employed in this study were similar to those described previously. Sprague-Dawley rats (Harlan, Indianapolis, IN) of either sex, weighing 200-250 g, were anesthetized with urethane (1.2 g/kg, IP) and intracardially perfused with chilled phosphate-buffered saline (PBS) followed by freshly prepared 4% paraformaldehyde in PBS. Brains were removed, post-fixed in the same fixative for 2 h, and cryoprotected in 30% sucrose/PBS overnight. Sections of 40 µm were prepared using a Vibratome and processed for ORX-LI by the standard avidin-biotin complex methods as described. Orexin-A antisera (lot no. 262-3) were a rabbit polyclonal directed against the human orexin A peptide (Phoenix Pharmaceuticals, Mountain View, CA). The antisera, which were used at a dilution of 1: 1250-1500 with 0.4% Triton X-100 and 1% bovine serum albumin in PBS, exhibit 100% cross-reactivity with human orxin A, and no cross reactivity with human neuropeptide Y, alpha-melanocyte stimulating hormone, human leptin, human orexin B, orexin A (16-33) and human agouti-related protein fragment (83-132)-NH2 (data supplied by Phoenix Pharmaceuticals). In addition, Western blot assay showed that the antisera interact with the peptide orexin A but not with the peptide orexin B (unpublished data). Two sets of control experiments were performed. First, orexin A antisera were replaced with normal rabbit IgG at the corresponding dilution in the staining procedures from randomly selected sections. Second, randomly selected sections from each brain were processed with orexin A antisera pre-absorbed with human orexin A peptide or human orexin B peptide (10 µg/ml, PHoenix Pharmaceuticals) overnight.

Orexin A-like Immunoreactivity in the Rat Brain
C.-T Chen, et al., Neuroscience Letters 260, 161-164 (1999)