Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

  • Joshua P. Nixon
  • Catherine M. Kotz
  • Colleen M. Novak
  • Charles J. Billington
  • Jennifer A. Teske
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 209)


In this chapter, we review the feeding and energy expenditure effects of orexin (also known as hypocretin) and neuromedin. Orexins are multifunctional neuropeptides that affect energy balance by participating in regulation of appetite, arousal, and spontaneous physical activity. Central orexin signaling for all functions originates in the lateral hypothalamus–perifornical area and is likely functionally differentiated based on site of action and on interacting neural influences. The effect of orexin on feeding is likely related to arousal in some ways but is nonetheless a separate neural process that depends on interactions with other feeding-related neuropeptides. In a pattern distinct from other neuropeptides, orexin stimulates both feeding and energy expenditure. Orexin increases in energy expenditure are mainly by increasing spontaneous physical activity, and this energy expenditure effect is more potent than the effect on feeding. Global orexin manipulations, such as in transgenic models, produce energy balance changes consistent with a dominant energy expenditure effect of orexin. Neuromedins are gut–brain peptides that reduce appetite. There are gut sources of neuromedin, but likely the key appetite-related neuromedin-producing neurons are in the hypothalamus and parallel other key anorectic neuropeptide expression in the arcuate to paraventricular hypothalamic projection. As with other hypothalamic feeding-related peptides, hindbrain sites are likely also important sources and targets of neuromedin anorectic action. Neuromedin increases physical activity in addition to reducing appetite, thus producing a consistent negative energy balance effect. Together with the other various neuropeptides, neurotransmitters, neuromodulators, and neurohormones, neuromedin and orexin act in the appetite network to produce changes in food intake and energy expenditure, which ultimately influences the regulation of body weight.


Brain Feeding Obesity Physical activity 


  1. Abrahamson EE, Leak RK, Moore RY (2001) The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12(2):435–440PubMedGoogle Scholar
  2. Ahnaou A, Drinkenburg WH (2011) Neuromedin U(2) receptor signaling mediates alteration of sleep-wake architecture in rats. Neuropeptides 45(2):165–174PubMedGoogle Scholar
  3. Alvarez CE, Sutcliffe JG (2002) Hypocretin is an early member of the incretin gene family. Neurosci Lett 324(3):169–172PubMedGoogle Scholar
  4. Antunes VR, Brailoiu GC, Kwok EH, Scruggs P, Dun NJ (2001) Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am J Physiol Regul Integr Comp Physiol 281(6):R1801–R1807PubMedGoogle Scholar
  5. Asakawa A, Inui A, Goto K, Yuzuriha H, Takimoto Y, Inui T et al (2002) Effects of agouti-related protein, orexin and melanin-concentrating hormone on oxygen consumption in mice. Int J Mol Med 10(4):523–525PubMedGoogle Scholar
  6. Bader R, Colomb J, Pankratz B, Schrock A, Stocker RF, Pankratz MJ (2007) Genetic dissection of neural circuit anatomy underlying feeding behavior in Drosophila: distinct classes of hugin-expressing neurons. J Comp Neurol 502(5):848–856PubMedGoogle Scholar
  7. Baldo BA, Kelley AE (2001) Amylin infusion into rat nucleus accumbens potently depresses motor activity and ingestive behavior. Am J Physiol Regul Integr Comp Physiol 281(4):R1232–R1242PubMedGoogle Scholar
  8. Ballesta J, Carlei F, Bishop AE, Steel JH, Gibson SJ, Fahey M et al (1988) Occurrence and developmental pattern of neuromedin U-immunoreactive nerves in the gastrointestinal tract and brain of the rat. Neuroscience 25(3):797–816PubMedGoogle Scholar
  9. Baumann CR, Clark EL, Pedersen NP, Hecht JL, Scammell TE (2008) Do enteric neurons make hypocretin? Regul Pept 147(1–3):1–3PubMedGoogle Scholar
  10. Bergman JM, Roecker AJ, Mercer SP, Bednar RA, Reiss DR, Ransom RW et al (2008) Proline bis-amides as potent dual orexin receptor antagonists. Bioorg Med Chem Lett 18(4):1425–1430PubMedGoogle Scholar
  11. Berthoud HR, Patterson LM, Sutton GM, Morrison C, Zheng H (2005) Orexin inputs to caudal raphe neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem Cell Biol 123(2):147–156PubMedGoogle Scholar
  12. Biello SM, Janik D, Mrosovsky N (1994) Neuropeptide Y and behaviorally induced phase shifts. Neuroscience 62(1):273–279PubMedGoogle Scholar
  13. Blanco M, Lopez M, Garcia-Caballero T, Gallego R, Vazquez-Boquete A, Morel G et al (2001) Cellular localization of orexin receptors in human pituitary. J Clin Endocrinol Metab 86(4):1616–1619Google Scholar
  14. Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR et al (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20(20):7760–7765PubMedGoogle Scholar
  15. Bray GA (2000) Reciprocal relation of food intake and sympathetic activity: experimental observations and clinical implications. Int J Obes Relat Metab Disord 24(Suppl 2):S8–S17PubMedGoogle Scholar
  16. Brighton PJ, Szekeres PG, Willars GB (2004) Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev 56(2):231–248PubMedGoogle Scholar
  17. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S et al (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13(2):150–155PubMedGoogle Scholar
  18. Broberger C, De Lecea L, Sutcliffe JG, Hokfelt T (1998) Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 402(4):460–474PubMedGoogle Scholar
  19. Campbell RE, Smith MS, Allen SE, Grayson BE, Ffrench-Mullen JM, Grove KL (2003a) Orexin neurons express a functional pancreatic polypeptide Y4 receptor. J Neurosci 23(4):1487–1497PubMedGoogle Scholar
  20. Campbell RE, Grove KL, Smith MS (2003b) Gonadotropin-releasing hormone neurons coexpress orexin 1 receptor immunoreactivity and receive direct contacts by orexin fibers. Endocrinology 144(4):1542–1548PubMedGoogle Scholar
  21. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98(4):437–451PubMedGoogle Scholar
  22. Chen CT, Dun SL, Kwok EH, Dun NJ, Chang JK (1999) Orexin A-like immunoreactivity in the rat brain. Neurosci Lett 260(3):161–164PubMedGoogle Scholar
  23. Chen CT, Hwang LL, Chang JK, Dun NJ (2000) Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats. Am J Physiol Regul Integr Comp Physiol 278(3):R692–R697PubMedGoogle Scholar
  24. Ciriello J, Rosas-Arellano MP, Solano-Flores LP, de Oliveira CV (2003a) Identification of neurons containing orexin-B (hypocretin-2) immunoreactivity in limbic structures. Brain Res 967(1–2):123–131PubMedGoogle Scholar
  25. Ciriello J, Li Z, de Oliveira CV (2003b) Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla. Brain Res 991(1–2):84–95PubMedGoogle Scholar
  26. Cutler DJ, Morris R, Sheridhar V, Wattam TA, Holmes S, Patel S et al (1999) Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides 20(12):1455–1470PubMedGoogle Scholar
  27. Dall’Aglio C, Pascucci L, Mercati F, Giontella A, Pedini V, Scocco P et al (2008) Identification of orexin A- and orexin type 2 receptor-positive cells in the gastrointestinal tract of neonatal dogs. Eur J Histochem 52(4):229–235PubMedGoogle Scholar
  28. Dall’aglio C, Pascucci L, Mercati F, Giontella A, Pedini V, Ceccarelli P (2009) Immunohistochemical identification and localization of orexin A and orexin type 2 receptor in the horse gastrointestinal tract. Res Vet Sci 86(2):189–193PubMedGoogle Scholar
  29. Dall’aglio C, Pascucci L, Mercati F, Boiti C, Ceccarelli P (2011) Localization of the orexin system in the gastrointestinal tract of fallow deer. Acta Histochem. 2011 March 11 [Epub ahead of print]Google Scholar
  30. Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K et al (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96(2):748–753PubMedGoogle Scholar
  31. Date Y, Mondal MS, Matsukura S, Nakazato M (2000) Distribution of orexin-A and orexin-B (hypocretins) in the rat spinal cord. Neurosci Lett 288(2):87–90PubMedGoogle Scholar
  32. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95(1):322–327PubMedGoogle Scholar
  33. de Miguel MJ, Burrell MA (2002) Immunocytochemical detection of orexin A in endocrine cells of the developing mouse gut. J Histochem Cytochem 50(1):63–69PubMedGoogle Scholar
  34. de Oliveira CV, Ciriello J (2003) Cardiovascular responses to hypocretin-1 in nucleus ambiguus of the ovariectomized female rat. Brain Res 986(1–2):148–156PubMedGoogle Scholar
  35. de Oliveira CV, Rosas-Arellano MP, Solano-Flores LP, Ciriello J (2003) Cardiovascular effects of hypocretin-1 in nucleus of the solitary tract. Am J Physiol Heart Circ Physiol 284(4):H1369–H1377PubMedGoogle Scholar
  36. Deurveilher S, Semba K (2005) Indirect projections from the suprachiasmatic nucleus to major arousal-promoting cell groups in rat: implications for the circadian control of behavioural state. Neuroscience 130(1):165–183PubMedGoogle Scholar
  37. Dugovic C, Shelton JE, Aluisio LE, Fraser IC, Jiang X, Sutton SW et al (2009) Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther 330(1):142–151PubMedGoogle Scholar
  38. Duxon MS, Stretton J, Starr K, Jones DN, Holland V, Riley G et al (2001) Evidence that orexin-A-evoked grooming in the rat is mediated by orexin- 1 (OX1) receptors, with downstream 5-HT2C receptor involvement. Psychopharmacology (Berl) 153(2):203–209Google Scholar
  39. Edwards CM, Abusnana S, Sunter D, Murphy KG, Ghatei MA, Bloom SR (1999) The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J Endocrinol 160(3):R7–R12PubMedGoogle Scholar
  40. Egecioglu E, Ploj K, Xu X, Bjursell M, Salome N, Andersson N et al (2009) Central NMU signaling in body weight and energy balance regulation: evidence from NMUR2 deletion and chronic central NMU treatment in mice. Am J Physiol Endocrinol Metab 297(3):E708–E716PubMedGoogle Scholar
  41. Ehrstrom M, Gustafsson T, Finn A, Kirchgessner A, Gryback P, Jacobsson H et al (2005) Inhibitory effect of exogenous orexin A on gastric emptying, plasma leptin and the distribution of orexin and orexin receptors in the gut and pancreas in man. J Clin Endocrinol Metab 90(4):2370–2377PubMedGoogle Scholar
  42. Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J et al (1998) Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 402(4):442–459PubMedGoogle Scholar
  43. España RA, Baldo BA, Kelley AE, Berridge CW (2001) Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 106(4):699–715PubMedGoogle Scholar
  44. España RA, Valentino RJ, Berridge CW (2003) Fos immunoreactivity in hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons: effects of diurnal and nocturnal spontaneous waking, stress and hypocretin-1 administration. Neuroscience 121(1):201–217PubMedGoogle Scholar
  45. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M et al (2001) Fos expression in orexin neurons varies with behavioral state. J Neurosci 21(5):1656–1662PubMedGoogle Scholar
  46. Farrell WJ, Delville Y, Wilczynski W (2003) Immunocytochemical localization of orexin in the brain of the green anole lizard (Anolis carolinensis). Soc Neurosci Abs 33:828Google Scholar
  47. Ferguson AV, Samson WK (2003) The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 24(3):141–150PubMedGoogle Scholar
  48. Fu LY, Acuna-Goycolea C, van den Pol AN (2004) Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system. J Neurosci 24(40):8741–8751PubMedGoogle Scholar
  49. Fukue Y, Sato T, Teranishi H, Hanada R, Takahashi T, Nakashima Y et al (2006) Regulation of gonadotropin secretion and puberty onset by neuromedin U. FEBS Lett 580(14):3485–3488PubMedGoogle Scholar
  50. Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T et al (2009) Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 9(1):64–76, PMCID: 2630400PubMedGoogle Scholar
  51. Gartlon J, Szekeres P, Pullen M, Sarau HM, Aiyar N, Shabon U et al (2004) Localisation of NMU1R and NMU2R in human and rat central nervous system and effects of neuromedin-U following central administration in rats. Psychopharmacology (Berl) 177(1–2):1–14Google Scholar
  52. Gautvik KM, de Lecea L, Gautvik VT, Danielson PE, Tranque P, Dopazo A et al (1996) Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction. Proc Natl Acad Sci USA 93(16):8733–8738PubMedGoogle Scholar
  53. Graham ES, Turnbull Y, Fotheringham P, Nilaweera K, Mercer JG, Morgan PJ et al (2003) Neuromedin U and Neuromedin U receptor-2 expression in the mouse and rat hypothalamus: effects of nutritional status. J Neurochem 87(5):1165–1173PubMedGoogle Scholar
  54. Guan XM, Yu H, Jiang Q, Van Der Ploeg LH, Liu Q (2001) Distribution of neuromedin U receptor subtype 2 mRNA in the rat brain. Brain Res Gene Expr Patterns 1(1):1–4PubMedGoogle Scholar
  55. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S et al (1999) Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 96(19):10911–10916PubMedGoogle Scholar
  56. Hainerova I, Torekov SS, Ek J, Finkova M, Borch-Johnsen K, Jorgensen T et al (2006) Association between neuromedin U gene variants and overweight and obesity. J Clin Endocrinol Metab 91(12):5057–5063PubMedGoogle Scholar
  57. Hanada R, Nakazato M, Murakami N, Sakihara S, Yoshimatsu H, Toshinai K et al (2001) A role for neuromedin U in stress response. Biochem Biophys Res Commun 289(1):225–228PubMedGoogle Scholar
  58. Hanada T, Date Y, Shimbara T, Sakihara S, Murakami N, Hayashi Y et al (2003) Central actions of neuromedin U via corticotropin-releasing hormone. Biochem Biophys Res Commun 311(4):954–958PubMedGoogle Scholar
  59. Hanada R, Teranishi H, Pearson JT, Kurokawa M, Hosoda H, Fukushima N et al (2004) Neuromedin U has a novel anorexigenic effect independent of the leptin signaling pathway. Nat Med 10(10):1067–1073PubMedGoogle Scholar
  60. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM et al (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30(2):345–354PubMedGoogle Scholar
  61. Harrington ME (1997) The ventral lateral geniculate nucleus and the intergeniculate leaflet: interrelated structures in the visual and circadian systems. Neurosci Biobehav Rev 21(5):705–727PubMedGoogle Scholar
  62. Harrington ME, Nance DM, Rusak B (1987) Double-labeling of neuropeptide Y-immunoreactive neurons which project from the geniculate to the suprachiasmatic nuclei. Brain Res 410(2):275–282PubMedGoogle Scholar
  63. Haynes AC, Jackson B, Overend P, Buckingham RE, Wilson S, Tadayyon M et al (1999) Effects of single and chronic intracerebroventricular administration of the orexins on feeding in the rat. Peptides 20(9):1099–1105PubMedGoogle Scholar
  64. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA et al (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 96(1–2):45–51PubMedGoogle Scholar
  65. Hirota K, Kushikata T, Kudo M, Kudo T, Lambert DG, Matsuki A (2001) Orexin A and B evoke noradrenaline release from rat cerebrocortical slices. Br J Pharmacol 134(7):1461–1466PubMedGoogle Scholar
  66. Hirota K, Kushikata T, Kudo M, Kudo T, Smart D, Matsuki A (2003) Effects of central hypocretin-1 administration on hemodynamic responses in young-adult and middle-aged rats. Brain Res 981(1–2):143–150PubMedGoogle Scholar
  67. Hoch M, Hoever P, Haschke M, Krahenbuhl S, Dingemanse J (2011) Food effect and biocomparison of two formulations of the dual orexin receptor antagonist almorexant in healthy male subjects. J Clin Pharmacol 51(7):1116–1121PubMedGoogle Scholar
  68. Hoever P, de Haas S, Winkler J, Schoemaker RC, Chiossi E, van Gerven J et al (2010) Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther 87(5):593–600PubMedGoogle Scholar
  69. Honda Y, Doi Y, Ninomiya R, Ninomiya C (1986) Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 9(1):254–259PubMedGoogle Scholar
  70. Honzawa M, Sudoh T, Minamino N, Tohyama M, Matsuo H (1987) Topographic localization of neuromedin U-like structures in the rat brain: an immunohistochemical study. Neuroscience 23(3):1103–1122PubMedGoogle Scholar
  71. Honzawa M, Sudoh T, Minamino N, Kangawa K, Matsuo H (1990) Neuromedin U-like immunoreactivity in rat intestine: regional distribution and immunohistochemical study. Neuropeptides 15(1):1–9PubMedGoogle Scholar
  72. Horvath TL (2005) The hardship of obesity: a soft-wired hypothalamus. Nat Neurosci 8(5):561–565PubMedGoogle Scholar
  73. Horvath TL, Diano S, van den Pol AN (1999a) Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. J Neurosci 19(3):1072–1087PubMedGoogle Scholar
  74. Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS et al (1999b) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415(2):145–159PubMedGoogle Scholar
  75. Howard AD, Wang R, Pong SS, Mellin TN, Strack A, Guan XM et al (2000) Identification of receptors for neuromedin U and its role in feeding. Nature 406(6791):70–74PubMedGoogle Scholar
  76. Huesa G, van den Pol AN, Finger TE (2005) Differential distribution of hypocretin (orexin) and melanin-concentrating hormone in the goldfish brain. J Comp Neurol 488(4):476–491PubMedGoogle Scholar
  77. Huhman KL, Albers HE (1994) Neuropeptide Y microinjected into the suprachiasmatic region phase shifts circadian rhythms in constant darkness. Peptides 15(8):1475–1478PubMedGoogle Scholar
  78. Hungs M, Mignot E (2001) Hypocretin/orexin, sleep and narcolepsy. Bioessays 23(5):397–408PubMedGoogle Scholar
  79. Hungs M, Fan J, Lin L, Lin X, Maki RA, Mignot E (2001) Identification and functional analysis of mutations in the hypocretin (orexin) genes of narcoleptic canines. Genome Res 11(4):531–539PubMedGoogle Scholar
  80. Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M (1999) Effect of lateral cerebroventricular injection of the appetite- stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 821(2):526–529PubMedGoogle Scholar
  81. Ida T, Nakahara K, Kuroiwa T, Fukui K, Nakazato M, Murakami T et al (2000a) Both corticotropin releasing factor and neuropeptide Y are involved in the effect of orexin (hypocretin) on the food intake in rats. Neurosci Lett 293(2):119–122PubMedGoogle Scholar
  82. Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N (2000b) Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun 270(1):318–323PubMedGoogle Scholar
  83. Iqbal J, Pompolo S, Sakurai T, Clarke IJ (2001) Evidence that orexin-containing neurones provide direct input to gonadotropin-releasing hormone neurones in the ovine hypothalamus. J Neuroendocrinol 13(12):1033–1041PubMedGoogle Scholar
  84. Ivanov TR, Lawrence CB, Stanley PJ, Luckman SM (2002) Evaluation of neuromedin U actions in energy homeostasis and pituitary function. Endocrinology 143(10):3813–3821PubMedGoogle Scholar
  85. Ivanov TR, Le Rouzic P, Stanley PJ, Ling WY, Parello R, Luckman SM (2004) Neuromedin U neurones in the rat nucleus of the tractus solitarius are catecholaminergic and respond to peripheral cholecystokinin. J Neuroendocrinol 16(7):612–619PubMedGoogle Scholar
  86. Iwai T, Iinuma Y, Kodani R, Oka J (2008) Neuromedin U inhibits inflammation-mediated memory impairment and neuronal cell-death in rodents. Neurosci Res 61(1):113–119PubMedGoogle Scholar
  87. Janik D, Mikkelsen JD, Mrosovsky N (1995) Cellular colocalization of Fos and neuropeptide Y in the intergeniculate leaflet after nonphotic phase-shifting events. Brain Res 698(1–2):137–145PubMedGoogle Scholar
  88. Jaszberenyi M, Bagosi Z, Thurzo B, Foldesi I, Telegdy G (2007) Endocrine and behavioral effects of neuromedin S. Horm Behav 52(5):631–639PubMedGoogle Scholar
  89. Jászberényi M, Bujdosó E, Pataki I, Telegdy G (2000) Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol 12(12):1174–1178PubMedGoogle Scholar
  90. Jethwa PH, Small CJ, Smith KL, Seth A, Darch SJ, Abbott CR et al (2005) Neuromedin U has a physiological role in the regulation of food intake and partially mediates the effects of leptin. Am J Physiol Endocrinol Metab 289(2):E301–E305PubMedGoogle Scholar
  91. Jethwa PH, Smith KL, Small CJ, Abbott CR, Darch SJ, Murphy KG et al (2006) Neuromedin U partially mediates leptin-induced hypothalamo-pituitary adrenal (HPA) stimulation and has a physiological role in the regulation of the HPA axis in the rat. Endocrinology 147(6):2886–2892PubMedGoogle Scholar
  92. John J, Wu MF, Siegel JM (2000) Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 3(1):23–28PubMedGoogle Scholar
  93. Johnson RF, Moore RY, Morin LP (1989) Lateral geniculate lesions alter circadian activity rhythms in the hamster. Brain Res Bull 22(2):411–422PubMedGoogle Scholar
  94. Johren O, Neidert SJ, Kummer M, Dendorfer A, Dominiak P (2001) Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats. Endocrinology 142(8):3324–3331PubMedGoogle Scholar
  95. Jones DN, Gartlon J, Parker F, Taylor SG, Routledge C, Hemmati P et al (2001) Effects of centrally administered orexin-B and orexin-A: a role for orexin-1 receptors in orexin-B-induced hyperactivity. Psychopharmacology (Berl) 153(2):210–218Google Scholar
  96. Kamisoyama H, Honda K, Saneyasu T, Sugahara K, Hasegawa S (2007) Central administration of neuromedin U suppresses food intake in chicks. Neurosci Lett 420(1):1–5PubMedGoogle Scholar
  97. Kaslin J, Nystedt JM, Ostergard M, Peitsaro N, Panula P (2004) The orexin/hypocretin system in zebrafish is connected to the aminergic and cholinergic systems. J Neurosci 24(11):2678–2689PubMedGoogle Scholar
  98. Kirchgessner AL, Liu M (1999) Orexin synthesis and response in the gut. Neuron 24(4):941–951PubMedGoogle Scholar
  99. Kiwaki K, Kotz CM, Wang C, Lanningham-Foster L, Levine JA (2004) Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats. Am J Physiol Endocrinol Metab 286(4):E551–E559PubMedGoogle Scholar
  100. Kiyashchenko LI, Mileykovskiy BY, Lai YY, Siegel JM (2001) Increased and decreased muscle tone with orexin (hypocretin) microinjections in the locus coeruleus and pontine inhibitory area. J Neurophysiol 85(5):2008–2016PubMedGoogle Scholar
  101. Kotz CM (2006) Integration of feeding and spontaneous physical activity: role for orexin. Physiol Behav 88(3):294–301PubMedGoogle Scholar
  102. Kotz CM, Glass MJ, Levine AS, Billington CJ (2000) Regional effect of naltrexone in the nucleus of the solitary tract in blockade of NPY-induced feeding. Am J Physiol Regul Integr Comp Physiol 278(2):R499–R503PubMedGoogle Scholar
  103. Kotz CM, Teske JA, Levine JA, Wang C (2002) Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 104(1–3):27–32PubMedGoogle Scholar
  104. Kotz CM, Wang C, Teske JA, Thorpe AJ, Novak CM, Kiwaki K et al (2006) Orexin A mediation of time spent moving in rats: neural mechanisms. Neuroscience 142(1):29–36PubMedGoogle Scholar
  105. Kotz CM, Teske JA, Billington CJ (2008) Neuroregulation of nonexercise activity thermogenesis and obesity resistance. Am J Physiol Regul Integr Comp Physiol 294(3):R699–R710PubMedGoogle Scholar
  106. Kowalski TJ, Spar BD, Markowitz L, Maguire M, Golovko A, Yang S et al (2005) Transgenic overexpression of neuromedin U promotes leanness and hypophagia in mice. J Endocrinol 185(1):151–164PubMedGoogle Scholar
  107. Kummer M, Neidert SJ, Johren O, Dominiak P (2001) Orexin (hypocretin) gene expression in rat ependymal cells. Neuroreport 12(10):2117–2120PubMedGoogle Scholar
  108. Kunii K, Yamanaka A, Nambu T, Matsuzaki I, Goto K, Sakurai T (1999) Orexins/hypocretins regulate drinking behaviour. Brain Res 842(1):256–261PubMedGoogle Scholar
  109. Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (2004) Characterisation of the binding of [3 H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol 141(2):340–346, PMCID: 1574197PubMedGoogle Scholar
  110. Li A, Nattie E (2010) Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. J Physiol 588(Pt 15):2935–2944, PMCID: 2956908PubMedGoogle Scholar
  111. Li Y, Li S, Sui N, Kirouac GJ (2009) Orexin-A acts on the paraventricular nucleus of the midline thalamus to inhibit locomotor activity in rats. Pharmacol Biochemand Behav 93(4):506–514Google Scholar
  112. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X et al (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98(3):365–376PubMedGoogle Scholar
  113. Liu JJ, Payza K, Huang J, Liu R, Chen T, Coupal M et al (2009) Discovery and pharmacological characterization of a small-molecule antagonist at neuromedin U receptor NMUR2. J Pharmacol Exp Ther 330(1):268–275PubMedGoogle Scholar
  114. Lu XY, Bagnol D, Burke S, Akil H, Watson SJ (2000) Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav 37(4):335–344PubMedGoogle Scholar
  115. Lubkin M, Stricker-Krongrad A (1998) Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 253(2):241–245PubMedGoogle Scholar
  116. Malherbe P, Borroni E, Gobbi L, Knust H, Nettekoven M, Pinard E et al (2009) Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol 156(8):1326–1341PubMedGoogle Scholar
  117. Mangold C, Ksiazek I, Yun SW, Berger E, Binkert C (2008) Distribution of neuromedin U binding sites in the rat CNS revealed by in vitro receptor autoradiography. Neuropeptides 42(4):377–386PubMedGoogle Scholar
  118. Martinez GS, Smale L, Nuñez AA (2002) Diurnal and nocturnal rodents show rhythms in orexinergic neurons. Brain Res 955(1–2):1–7PubMedGoogle Scholar
  119. Maruyama K, Konno N, Ishiguro K, Wakasugi T, Uchiyama M, Shioda S et al (2008) Isolation and characterisation of four cDNAs encoding neuromedin U (NMU) from the brain and gut of goldfish, and the inhibitory effect of a deduced NMU on food intake and locomotor activity. J Neuroendocrinol 20(1):71–78PubMedGoogle Scholar
  120. Maruyama K, Kaiya H, Miyazato M, Konno N, Wakasugi T, Uchiyama M et al (2011) Isolation and characterisation of two cDNAs encoding the neuromedin U receptor from goldfish brain. J Neuroendocrinol 23(3):282–291PubMedGoogle Scholar
  121. Matsumura K, Tsuchihashi T, Abe I (2001) Central orexin-A augments sympathoadrenal outflow in conscious rabbits. Hypertension 37(6):1382–1387PubMedGoogle Scholar
  122. Matsuzaki I, Sakurai T, Kunii K, Nakamura T, Yanagisawa M, Goto K (2002) Involvement of the serotonergic system in orexin-induced behavioral alterations in rats. Regul Pept 104(1–3):119–123PubMedGoogle Scholar
  123. McGranaghan PA, Piggins HD (2001) Orexin A-like immunoreactivity in the hypothalamus and thalamus of the Syrian hamster (Mesocricetus auratus) and Siberian hamster (Phodopus sungorus), with special reference to circadian structures. Brain Res 904(2):234–244PubMedGoogle Scholar
  124. Meister B (2000) Control of food intake via leptin receptors in the hypothalamus. Vitam Horm 59:265–304PubMedGoogle Scholar
  125. Methippara MM, Alam MN, Szymusiak R, McGinty D (2000) Effects of lateral preoptic area application of orexin-A on sleep- wakefulness. Neuroreport 11(16):3423–3426PubMedGoogle Scholar
  126. Mileykovskiy BY, Kiyashchenko LI, Siegel JM (2002) Muscle tone facilitation and inhibition after orexin-a (hypocretin-1) microinjections into the medial medulla. J Neurophysiol 87(5):2480–2489PubMedGoogle Scholar
  127. Minamino N, Kangawa K, Matsuo H (1985a) Neuromedin U-8 and U-25: novel uterus stimulating and hypertensive peptides identified in porcine spinal cord. Biochem Biophys Res Commun 130(3):1078–1085PubMedGoogle Scholar
  128. Minamino N, Sudoh T, Kangawa K, Matsuo H (1985b) Neuromedins: novel smooth-muscle stimulating peptides identified in porcine spinal cord. Peptides 6(Suppl 3):245–248PubMedGoogle Scholar
  129. Mintz EM, van den Pol AN, Casano AA, Albers HE (2001) Distribution of hypocretin-(orexin) immunoreactivity in the central nervous system of Syrian hamsters (Mesocricetus auratus). J Chem Neuroanat 21(3):225–238PubMedGoogle Scholar
  130. Mitchell JD, Maguire JJ, Davenport AP (2009) Emerging pharmacology and physiology of neuromedin U and the structurally related peptide neuromedin S. Br J Pharmacol 158(1):87–103, PMCID: 2795236PubMedGoogle Scholar
  131. Miyazato M, Mori K, Ida T, Kojima M, Murakami N, Kangawa K (2008) Identification and functional analysis of a novel ligand for G protein-coupled receptor, Neuromedin S. Regul Pept 145(1–3):37–41PubMedGoogle Scholar
  132. Monda M, Viggiano A, Mondola P, De Luca V (2001) Inhibition of prostaglandin synthesis reduces hyperthermic reactions induced by hypocretin-1/orexin A. Brain Res 909(1–2):68–74PubMedGoogle Scholar
  133. Monda M, Viggiano A, De Luca V (2003) Paradoxical [correction of parodoxical] effect of orexin A: hypophagia induced by hyperthermia. Brain Res 961(2):220–228PubMedGoogle Scholar
  134. Monda M, Viggiano AN, Viggiano AL, Fuccio F, De Luca V (2004a) Cortical spreading depression blocks the hyperthermic reaction induced by orexin A. Neuroscience 123(2):567–574PubMedGoogle Scholar
  135. Monda M, Viggiano A, Viggiano A, Fuccio F, De Luca V (2004b) Injection of orexin A into the diagonal band of Broca induces sympathetic and hyperthermic reactions. Brain Res 1018(2):265–271PubMedGoogle Scholar
  136. Mondal MS, Nakazato M, Date Y, Murakami N, Yanagisawa M, Matsukura S (1999) Widespread distribution of orexin in rat brain and its regulation upon fasting. Biochem Biophys Res Commun 256(3):495–499PubMedGoogle Scholar
  137. Moore RY, Card JP (1994) Intergeniculate leaflet: an anatomically and functionally distinct subdivision of the lateral geniculate complex. J Comp Neurol 344(3):403–430PubMedGoogle Scholar
  138. Moore RY, Abrahamson EA, Van Den Pol A (2001) The hypocretin neuron system: an arousal system in the human brain. Arch Ital Biol 139(3):195–205PubMedGoogle Scholar
  139. Mori K, Miyazato M, Kangawa K (2008) Neuromedin S: discovery and functions. Results Probl Cell Differ 46:201–212PubMedGoogle Scholar
  140. Moriguchi T, Sakurai T, Nambu T, Yanagisawa M, Goto K (1999) Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia. Neurosci Lett 264(1–3):101–104PubMedGoogle Scholar
  141. Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M et al (2000) Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 873(1):181–187PubMedGoogle Scholar
  142. Nakazato M, Hanada R, Murakami N, Date Y, Mondal MS, Kojima M et al (2000) Central effects of neuromedin U in the regulation of energy homeostasis. Biochem Biophys Res Commun 277(1):191–194PubMedGoogle Scholar
  143. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827(1–2):243–260PubMedGoogle Scholar
  144. Nevsimalova S, Vankova J, Stepanova I, Seemanova E, Mignot E, Nishino S (2005) Hypocretin deficiency in Prader-Willi syndrome. Eur J Neurol 12(1):70–72PubMedGoogle Scholar
  145. Niimi M, Sato M, Taminato T (2001a) Neuropeptide Y in central control of feeding and interactions with orexin and leptin. Endocrine 14(2):269–273PubMedGoogle Scholar
  146. Niimi M, Murao K, Taminato T (2001b) Central administration of neuromedin U activates neurons in ventrobasal hypothalamus and brainstem. Endocrine 16(3):201–206PubMedGoogle Scholar
  147. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355(9197):39–40PubMedGoogle Scholar
  148. Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J et al (2001) Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 50(3):381–388PubMedGoogle Scholar
  149. Nixon JP, Smale L (2004) Individual differences in wheel-running rhythms are related to temporal and spatial patterns of activation of orexin A and B cells in a diurnal rodent (Arvicanthis niloticus). Neuroscience 127(1):25–34PubMedGoogle Scholar
  150. Nixon JP, Smale L (2005) Orexin fibers form appositions with Fos expressing neuropeptide-Y cells in the grass rat intergeniculate leaflet. Brain Res 1053(1–2):33–37PubMedGoogle Scholar
  151. Nixon JP, Smale L (2007) A comparative analysis of the distribution of immunoreactive orexin A and B in the brains of nocturnal and diurnal rodents. Behav Brain Funct 3:28, PMCID: 1913054PubMedGoogle Scholar
  152. Nogueiras R, Tovar S, Mitchell SE, Barrett P, Rayner DV, Dieguez C et al (2006) Negative energy balance and leptin regulate neuromedin-U expression in the rat pars tuberalis. J Endocrinol 190(2):545–553PubMedGoogle Scholar
  153. Novak CM, Levine JA (2007) Central neural and endocrine mechanisms of non-exercise activity thermogenesis and their potential impact on obesity. J Neuroendocrinol 19(12):923–940PubMedGoogle Scholar
  154. Novak CM, Levine JA (2009) Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obesity (Silver Spring) 7(8):1493–1498Google Scholar
  155. Novak CM, Kotz CM, Levine JA (2006a) Central orexin sensitivity, physical activity, and obesity in diet-induced obese and diet-resistant rats. Am J Physiol Endocrinol Metab 290(2):E396–E403PubMedGoogle Scholar
  156. Novak CM, Zhang M, Levine JA (2006b) Neuromedin U in the paraventricular and arcuate hypothalamic nuclei increases non-exercise activity thermogenesis. J Neuroendocrinol 18(8):594–601PubMedGoogle Scholar
  157. Novak CM, Zhang M, Levine JA (2007) Sensitivity of the hypothalamic paraventricular nucleus to the locomotor-activating effects of neuromedin U in obesity. Brain Res 1169:57–68PubMedGoogle Scholar
  158. Novak CM, Escande C, Burghardt PR, Zhang M, Barbosa MT, Chini EN et al (2010) Spontaneous activity, economy of activity, and resistance to diet-induced obesity in rats bred for high intrinsic aerobic capacity. Horm Behav 58(3):355–367, PMCID: 2923555PubMedGoogle Scholar
  159. Nunez A, Rodrigo-Angulo ML, Andres ID, Garzon M (2009) Hypocretin/Orexin neuropeptides: participation in the control of sleep-wakefulness cycle and energy homeostasis. Curr Neuropharmacol 7(1):50–59, PMCID: 2724663PubMedGoogle Scholar
  160. Ohkubo T, Boswell T, Lumineau S (2002) Molecular cloning of chicken prepro-orexin cDNA and preferential expression in the chicken hypothalamus. Biochim Biophys Acta 1577(3):476–480PubMedGoogle Scholar
  161. Overeem S, Mignot E, Gert van Dijk J, Lammers GJ (2001) Narcolepsy: clinical features, new pathophysiologic insights, and future perspectives. J Clin Neurophysiol 18(2):78–105PubMedGoogle Scholar
  162. Peever JH, Lai YY, Siegel JM (2003) Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism. J Neurophysiol 89(5):2591–2600PubMedGoogle Scholar
  163. Peier A, Kosinski J, Cox-York K, Qian Y, Desai K, Feng Y et al (2009) The antiobesity effects of centrally administered neuromedin U and neuromedin S are mediated predominantly by the neuromedin U receptor 2 (NMUR2). Endocrinology 150(7):3101–3109, PMCID: 2703546PubMedGoogle Scholar
  164. Perrey DA, Gilmour BP, Runyon SP, Thomas BF, Zhang Y (2011) Diaryl urea analogues of SB-334867 as orexin-1 receptor antagonists. Bioorg Med Chem Lett 21(10):2980–2985, PMCID: 3085582PubMedGoogle Scholar
  165. Petersén Å, Gil J, Maat-Schieman ML, Björkqvist M, Tanila H, Araújo IM et al (2005) Orexin loss in Huntington’s disease. Hum Mol Genet 14(1):39–47PubMedGoogle Scholar
  166. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015PubMedGoogle Scholar
  167. Piper DC, Upton N, Smith MI, Hunter AJ (2000) The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. Eur J Neurosci 12(2):726–730PubMedGoogle Scholar
  168. Qiu DL, Chu CP, Shirasaka T, Nabekura T, Kunitake T, Kato K et al (2003) Neuromedin U depolarizes rat hypothalamic paraventricular nucleus neurons in vitro by enhancing IH channel activity. J Neurophysiol 90(2):843–850PubMedGoogle Scholar
  169. Qiu DL, Chu CP, Tsukino H, Shirasaka T, Nakao H, Kato K et al (2005) Neuromedin U receptor-2 mRNA and HCN channels mRNA expression in NMU-sensitive neurons in rat hypothalamic paraventricular nucleus. Neurosci Lett 374(1):69–72PubMedGoogle Scholar
  170. Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ et al (1996) A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380(6571):243–247PubMedGoogle Scholar
  171. Raddatz R, Wilson AE, Artymyshyn R, Bonini JA, Borowsky B, Boteju LW et al (2000) Identification and characterization of two neuromedin U receptors differentially expressed in peripheral tissues and the central nervous system. J Biol Chem 275(42):32452–32459PubMedGoogle Scholar
  172. Rauch M, Riediger T, Schmid HA, Simon E (2000) Orexin A activates leptin-responsive neurons in the arcuate nucleus. Pflugers Arch 440(5):699–703PubMedGoogle Scholar
  173. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR et al (2000) Dose-response effects of orexin-A on food intake and the behavioural satiety sequence in rats. Regul Pept 96(1–2):71–84PubMedGoogle Scholar
  174. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR et al (2001) SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neurosci 13(7):1444–1452PubMedGoogle Scholar
  175. Rucinski M, Ziolkowska A, Neri G, Trejter M, Zemleduch T, Tyczewska M et al (2007) Expression of neuromedins S and U and their receptors in the hypothalamus and endocrine glands of the rat. Int J Mol Med 20(2):255–259PubMedGoogle Scholar
  176. Rusak B, Meijer JH, Harrington ME (1989) Hamster circadian rhythms are phase-shifted by electrical stimulation of the geniculo-hypothalamic tract. Brain Res 493(2):283–291PubMedGoogle Scholar
  177. Russell SH, Small CJ, Kennedy AR, Stanley SA, Seth A, Murphy KG et al (2001) Orexin A interactions in the hypothalamo-pituitary gonadal axis. Endocrinology 142(12):5294–5302PubMedGoogle Scholar
  178. Sakamoto T, Mori K, Nakahara K, Miyazato M, Kangawa K, Sameshima H et al (2007) Neuromedin S exerts an antidiuretic action in rats. Biochem Biophys Res Commun 361(2):457–461PubMedGoogle Scholar
  179. Sakamoto T, Mori K, Miyazato M, Kangawa K, Sameshima H, Nakahara K et al (2008) Involvement of neuromedin S in the oxytocin release response to suckling stimulus. Biochem Biophys Res Commun 375(1):49–53PubMedGoogle Scholar
  180. Sakurai T (2003) Orexin: a link between energy homeostasis and adaptive behaviour. Curr Opin Clin Nutr Metab Care 6(4):353–360PubMedGoogle Scholar
  181. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92(4):573–585PubMedGoogle Scholar
  182. Sakurai T, Moriguchi T, Furuya K, Kajiwara N, Nakamura T, Yanagisawa M et al (1999) Structure and function of human prepro-orexin gene. J Biol Rhythms 274(25):17771–17776Google Scholar
  183. Samson WK, Gosnell B, Chang JK, Resch ZT, Murphy TC (1999) Cardiovascular regulatory actions of the hypocretins in brain. Brain Res 831(1–2):248–253PubMedGoogle Scholar
  184. Samson WK, Taylor MM, Ferguson AV (2005) Non-sleep effects of hypocretin/orexin. Sleep Med Rev 9(4):243–252PubMedGoogle Scholar
  185. Samson WK, Bagley SL, Ferguson AV, White MM (2010) Orexin receptor subtype activation and locomotor behaviour in the rat. Acta Physiol (Oxf) 198(3):313–324Google Scholar
  186. Sato S, Hanada R, Kimura A, Abe T, Matsumoto T, Iwasaki M et al (2007) Central control of bone remodeling by neuromedin U. Nat Med 13(10):1234–1240PubMedGoogle Scholar
  187. Sato-Suzuki I, Kita I, Seki Y, Oguri M, Arita H (2002) Cortical arousal induced by microinjection of orexins into the paraventricular nucleus of the rat. Behav Brain Res 128(2):169–177PubMedGoogle Scholar
  188. Scammell TE, Winrow CJ (2011) Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51:243–266PubMedGoogle Scholar
  189. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671PubMedGoogle Scholar
  190. Semjonous NM, Smith KL, Parkinson JR, Gunner DJ, Liu YL, Murphy KG et al (2009) Coordinated changes in energy intake and expenditure following hypothalamic administration of neuropeptides involved in energy balance. Int J Obes (Lond) 33(7):775–785, PMCID: 2711051Google Scholar
  191. Shan L, Qiao X, Crona JH, Behan J, Wang S, Laz T et al (2000) Identification of a novel neuromedin U receptor subtype expressed in the central nervous system. J Biol Chem 275(50):39482–39486PubMedGoogle Scholar
  192. Shibahara M, Sakurai T, Nambu T, Takenouchi T, Iwaasa H, Egashira SI et al (1999) Structure, tissue distribution, and pharmacological characterization of Xenopus orexins. Peptides 20(10):1169–1176PubMedGoogle Scholar
  193. Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277(6 Pt 2):R1780–R1785PubMedGoogle Scholar
  194. Shirasaka T, Kunitake T, Takasaki M, Kannan H (2002) Neuronal effects of orexins: relevant to sympathetic and cardiovascular functions. Regul Pept 104(1–3):91–95PubMedGoogle Scholar
  195. Siegel JM (1999) Narcolepsy: a key role for hypocretins (orexins). Cell 98(4):409–412PubMedGoogle Scholar
  196. Singletary KG, Delville Y, Farrell WJ, Wilczynski W (2005) Distribution of orexin/hypocretin immunoreactivity in the nervous system of the green Treefrog, Hyla cinerea. Brain Res 1041(2):231–236PubMedGoogle Scholar
  197. Smale L, McElhinny T, Nixon J, Gubik B, Rose S (2001) Patterns of wheel running are related to Fos expression in neuropeptide- Y-containing neurons in the intergeniculate leaflet of Arvicanthis niloticus. J Biol Rhythms 16(2):163–172PubMedGoogle Scholar
  198. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F et al (1999) Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br J Pharmacol 128(1):1–3PubMedGoogle Scholar
  199. Smith PM, Connolly BC, Ferguson AV (2002) Microinjection of orexin into the rat nucleus tractus solitarius causes increases in blood pressure. Brain Res 950(1–2):261–267PubMedGoogle Scholar
  200. Smith MI, Piper DC, Duxon MS, Upton N (2003) Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in the rat. Neurosci Lett 341(3):256–258PubMedGoogle Scholar
  201. Smith PM, Samson WK, Ferguson AV (2007) Cardiovascular actions of orexin-A in the rat subfornical organ. J Neuroendocrinol 19(1):7–13PubMedGoogle Scholar
  202. Stanley BG, Thomas WJ (1993) Feeding responses to perifornical hypothalamic injection of neuropeptide Y in relation to circadian rhythms of eating behavior. Peptides 14(3):475–481PubMedGoogle Scholar
  203. Stanley BG, Magdalin W, Seirafi A, Thomas WJ, Leibowitz SF (1993) The perifornical area: the major focus of (a) patchily distributed hypothalamic neuropeptide Y-sensitive feeding system(s). Brain Res 604(1–2):304–317PubMedGoogle Scholar
  204. Sunter D, Morgan I, Edwards CM, Dakin CL, Murphy KG, Gardiner J et al (2001) Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res 907(1–2):27–34PubMedGoogle Scholar
  205. Sutcliffe JG, de Lecea L (2000) The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 62(2):161–168PubMedGoogle Scholar
  206. Sutton RE, Koob GF, Le Moal M, Rivier J, Vale W (1982) Corticotropin releasing factor produces behavioural activation in rats. Nature 297(5864):331–333PubMedGoogle Scholar
  207. Sweet DC, Levine AS, Billington CJ, Kotz CM (1999) Feeding response to central orexins. Brain Res 821(2):535–538PubMedGoogle Scholar
  208. Szekely M (2006) Orexins, energy balance, temperature, sleep-wake cycle. Am J Physiol Regul Integr Comp Physiol 291(3):R530–R532PubMedGoogle Scholar
  209. Szekely M, Petervari E, Balasko M, Hernadi I, Uzsoki B (2002) Effects of orexins on energy balance and thermoregulation. Regul Pept 104(1–3):47–53PubMedGoogle Scholar
  210. Szekely M, Petervari E, Balasko M (2010) Thermoregulation, energy balance, regulatory peptides: recent developments. Front Biosci (Schol Ed) 2:1009–1046Google Scholar
  211. Tachibana T, Matsuda K, Khan MS, Ueda H, Cline MA (2010a) Feeding and drinking response following central administration of neuromedin S in chicks. Comp Biochem Physiol A Mol Integr Physiol 157(1):63–67PubMedGoogle Scholar
  212. Tachibana T, Matsuda K, Khan SI, Ueda H, Cline MA (2010b) Feeding and drinking response following central administrations of bombesin-like peptides in chicks. Comp Biochem Physiol A Mol Integr Physiol 156(4):394–399PubMedGoogle Scholar
  213. Takenoya F, Hirayama M, Kageyama H, Funahashi H, Kita T, Matsumoto H et al (2005) Neuronal interactions between galanin-like-peptide- and orexin- or melanin-concentrating hormone-containing neurons. Regul Pept 126(1–2):79–83PubMedGoogle Scholar
  214. Tanida M, Satomi J, Shen J, Nagai K (2009) Autonomic and cardiovascular effects of central neuromedin U in rats. Physiol Behav 96(2):282–288PubMedGoogle Scholar
  215. Teske JA, Levine AS, Kuskowski M, Levine JA, Kotz CM (2006) Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats. Am J Physiol Regul Integr Comp Physiol 291(4):R889–R899PubMedGoogle Scholar
  216. Teske JA, Billington CJ, Kotz CM (2010) Hypocretin/Orexin and Energy Expenditure. Acta Physiol (Oxf) 198:303–312Google Scholar
  217. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M et al (2000) Reduced number of hypocretin neurons in human narcolepsy. Neuron 27(3):469–474PubMedGoogle Scholar
  218. Thompson EL, Murphy KG, Todd JF, Martin NM, Small CJ, Ghatei MA et al (2004) Chronic administration of NMU into the paraventricular nucleus stimulates the HPA axis but does not influence food intake or body weight. Biochem Biophys Res Commun 323(1):65–71PubMedGoogle Scholar
  219. Thorpe AJ, Kotz CM (2005) Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res 1050(1–2):156–162PubMedGoogle Scholar
  220. Thorpe AJ, Mullett MA, Wang C, Kotz CM (2003) Peptides that regulate food intake: regional, metabolic, and circadian specificity of lateral hypothalamic orexin A feeding stimulation. Am J Physiol Regul Integr Comp Physiol 284(6):R1409–R1417PubMedGoogle Scholar
  221. Tsujino N, Sakurai T (2009) Orexin/Hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 61(2):162–176PubMedGoogle Scholar
  222. van den Pol AN (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 19(8):3171–3182PubMedGoogle Scholar
  223. van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB (1998) Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 18(19):7962–7971PubMedGoogle Scholar
  224. van den Top M, Nolan MF, Lee K, Richardson PJ, Buijs RM, Davies CH et al (2003) Orexins induce increased excitability and synchronisation of rat sympathetic preganglionic neurones. J Physiol 549(Pt 3):809–821PubMedGoogle Scholar
  225. Verty AN, Allen AM, Oldfield BJ (2010) The endogenous actions of hypothalamic peptides on brown adipose tissue thermogenesis in the rat. Endocrinology 151(9):4236–4246PubMedGoogle Scholar
  226. Volgin DV, Saghir M, Kubin L (2002) Developmental changes in the orexin 2 receptor mRNA in hypoglossal motoneurons. Neuroreport 13(4):433–436PubMedGoogle Scholar
  227. Volkoff H, Peter RE (2000) Effects of CART peptides on food consumption, feeding and associated behaviors in the goldfish, Carassius auratus: actions on neuropeptide Y- and orexin A-induced feeding. Brain Res 887(1):125–133PubMedGoogle Scholar
  228. Wang C, Kotz C (2002) Urocortin in the lateral septal area modulates feeding induced by orexin A in the lateral hypothalamus. Am J Physiol Regul Integr Comp Physiol 283(2):R358–R367PubMedGoogle Scholar
  229. Wang J, Osaka T, Inoue S (2001) Energy expenditure by intracerebroventricular administration of orexin to anesthetized rats. Neurosci Lett 315(1–2):49–52PubMedGoogle Scholar
  230. Wang JB, Murata T, Narita K, Honda K, Higuchi T (2003a) Variation in the expression of orexin and orexin receptors in the rat hypothalamus during the estrous cycle, pregnancy, parturition, and lactation. Endocrine 22(2):127–134PubMedGoogle Scholar
  231. Wang J, Osaka T, Inoue S (2003b) Orexin-A-sensitive site for energy expenditure localized in the arcuate nucleus of the hypothalamus. Brain Res 971(1):128–134PubMedGoogle Scholar
  232. Weaver DR (1998) The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms 13(2):100–112PubMedGoogle Scholar
  233. Webb P, Annis JF, Troutman SJ Jr (1980) Energy balance in man measured by direct and indirect calorimetry. Am J Clin Nutr 33(6):1287–1298PubMedGoogle Scholar
  234. Webb IC, Patton DF, Hamson DK, Mistlberger RE (2008) Neural correlates of arousal-induced circadian clock resetting: hypocretin/orexin and the intergeniculate leaflet. Eur J Neurosci 27(4):828–835PubMedGoogle Scholar
  235. Whitman DB, Cox CD, Breslin MJ, Brashear KM, Schreier JD, Bogusky MJ et al (2009) Discovery of a potent, CNS-penetrant orexin receptor antagonist based on an n, n-disubstituted-1,4-diazepane scaffold that promotes sleep in rats. ChemMedChem 4(7):1069–1074PubMedGoogle Scholar
  236. Wickland C, Turek FW (1994) Lesions of the thalamic intergeniculate leaflet block activity-induced phase shifts in the circadian activity rhythm of the golden hamster. Brain Res 660(2):293–300PubMedGoogle Scholar
  237. Winrow CJ, Tanis KQ, Reiss DR, Rigby AM, Uslaner JM, Uebele VN et al (2010) Orexin receptor antagonism prevents transcriptional and behavioral plasticity resulting from stimulant exposure. Neuropharmacology 58(1):185–194PubMedGoogle Scholar
  238. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ et al (2011) Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J Neurogenet 25(1–2):52–61PubMedGoogle Scholar
  239. Wren AM, Small CJ, Abbott CR, Jethwa PH, Kennedy AR, Murphy KG et al (2002) Hypothalamic actions of neuromedin U. Endocrinology 143(11):4227–4234PubMedGoogle Scholar
  240. Wu MF, John J, Maidment N, Lam HA, Siegel JM (2002) Hypocretin release in normal and narcoleptic dogs after food and sleep deprivation, eating, and movement. Am J Physiol Regul Integr Comp Physiol 283(5):R1079–R1086PubMedGoogle Scholar
  241. Yamamoto T, Suzuki H, Uemura H, Yamamoto K, Kikuyama S (2004) Localization of orexin-A-like immunoreactivity in prolactin cells in the bullfrog (Rana catesbeiana) pituitary. Gen Comp Endocrinol 135(2):186–192PubMedGoogle Scholar
  242. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I et al (2000) Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 859(2):404–409PubMedGoogle Scholar
  243. Yang G, Su J, Yao Y, Lei Z, Zhang G, Li X (2010) The regulatory mechanism of neuromedin S on luteinizing hormone in pigs. Anim Reprod Sci 122(3–4):367–374PubMedGoogle Scholar
  244. Yayou K, Kitagawa S, Ito S, Kasuya E, Sutoh M (2009) Effects of intracerebroventricular administration of neuromedin U or neuromedin S in steers. Gen Comp Endocrinol 163(3):324–328PubMedGoogle Scholar
  245. Yokota M, Ozaki Y, Sakamoto F, Yamada S, Saito J, Fujihara H et al (2004) Fos expression in CRF-containing neurons in the rat paraventricular nucleus after central administration of neuromedin U. Stress 7(2):109–112PubMedGoogle Scholar
  246. Yoshimichi G, Yoshimatsu H, Masaki T, Sakata T (2001) Orexin-A regulates body temperature in coordination with arousal status. Exp Biol Med (Maywood) 226(5):468–476Google Scholar
  247. Zeng H, Gragerov A, Hohmann JG, Pavlova MN, Schimpf BA, Xu H et al (2006) Neuromedin U receptor 2-deficient mice display differential responses in sensory perception, stress, and feeding. Mol Cell Biol 26(24):9352–9363PubMedGoogle Scholar
  248. Zhang J, Luo P (2002) Orexin B immunoreactive fibers and terminals innervate the sensory and motor neurons of jaw-elevator muscles in the rat. Synapse 44(2):106–110PubMedGoogle Scholar
  249. Zhang W, Fukuda Y, Kuwaki T (2005a) Respiratory and cardiovascular actions of orexin-A in mice. Neurosci Lett 385(2):131–136PubMedGoogle Scholar
  250. Zhang S, Blache D, Vercoe PE, Adam CL, Blackberry MA, Findlay PA et al (2005b) Expression of orexin receptors in the brain and peripheral tissues of the male sheep. Regul Pept 124(1–3):81–87PubMedGoogle Scholar
  251. Zhang Y, Jiang D, Zhang J, Wang F, Jiang X, Tao J (2010) Activation of neuromedin U type 1 receptor inhibits L-type Ca2+ channel currents via phosphatidylinositol 3-kinase-dependent protein kinase C epsilon pathway in mouse hippocampal neurons. Cell Signal 22(11):1660–1668PubMedGoogle Scholar
  252. Zheng H, Patterson LM, Berthoud HR (2005) Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function. J Comp Neurol 485(2):127–142PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Joshua P. Nixon
    • 1
    • 2
    • 3
  • Catherine M. Kotz
    • 4
    • 1
    • 2
    • 3
  • Colleen M. Novak
    • 5
  • Charles J. Billington
    • 1
    • 6
    • 2
    • 3
  • Jennifer A. Teske
    • 1
    • 2
    • 3
  1. 1.Veterans Affairs Medical Center, Research Service (151)MinneapolisUSA
  2. 2.Department of Food Science and NutritionUniversity of MinnesotaSt. PaulUSA
  3. 3.Minnesota Obesity CenterUniversity of MinnesotaSt. PaulUSA
  4. 4.Veterans Affairs Medical Center, GRECC (11 G)MinneapolisUSA
  5. 5.Department of Biological SciencesKent State UniversityKentUSA
  6. 6.Veterans Affairs Medical Center, Endocrine Unit (111 G)MinneapolisUSA

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