Skip to main content
SpringerLink
Log in

Neuropeptides Controlling Energy Balance: Orexins and Neuromedins

  • Chapter
  • First Online:
Appetite Control

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 209))

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abrahamson EE, Leak RK, Moore RY (2001) The suprachiasmatic nucleus projects to posterior hypothalamic arousal systems. Neuroreport 12(2):435–440

    PubMed  CAS  Google Scholar 

  • Ahnaou A, Drinkenburg WH (2011) Neuromedin U(2) receptor signaling mediates alteration of sleep-wake architecture in rats. Neuropeptides 45(2):165–174

    PubMed  CAS  Google Scholar 

  • Alvarez CE, Sutcliffe JG (2002) Hypocretin is an early member of the incretin gene family. Neurosci Lett 324(3):169–172

    PubMed  CAS  Google Scholar 

  • 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–R1807

    PubMed  CAS  Google Scholar 

  • 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):523–525

    PubMed  CAS  Google Scholar 

  • 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):848–856

    PubMed  Google Scholar 

  • 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–R1242

    PubMed  CAS  Google Scholar 

  • 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):797–816

    PubMed  CAS  Google Scholar 

  • Baumann CR, Clark EL, Pedersen NP, Hecht JL, Scammell TE (2008) Do enteric neurons make hypocretin? Regul Pept 147(1–3):1–3

    PubMed  CAS  Google Scholar 

  • 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):1425–1430

    PubMed  CAS  Google Scholar 

  • 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):147–156

    PubMed  CAS  Google Scholar 

  • Biello SM, Janik D, Mrosovsky N (1994) Neuropeptide Y and behaviorally induced phase shifts. Neuroscience 62(1):273–279

    PubMed  CAS  Google Scholar 

  • 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):1616–1619

    CAS  Google Scholar 

  • 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):7760–7765

    PubMed  CAS  Google Scholar 

  • 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–S17

    PubMed  CAS  Google Scholar 

  • Brighton PJ, Szekeres PG, Willars GB (2004) Neuromedin U and its receptors: structure, function, and physiological roles. Pharmacol Rev 56(2):231–248

    PubMed  CAS  Google Scholar 

  • 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):150–155

    PubMed  CAS  Google Scholar 

  • 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):460–474

    PubMed  CAS  Google Scholar 

  • 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):1487–1497

    PubMed  CAS  Google Scholar 

  • 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):1542–1548

    PubMed  CAS  Google Scholar 

  • 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):437–451

    PubMed  CAS  Google Scholar 

  • Chen CT, Dun SL, Kwok EH, Dun NJ, Chang JK (1999) Orexin A-like immunoreactivity in the rat brain. Neurosci Lett 260(3):161–164

    PubMed  CAS  Google Scholar 

  • 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–R697

    PubMed  CAS  Google Scholar 

  • 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):123–131

    PubMed  CAS  Google Scholar 

  • Ciriello J, Li Z, de Oliveira CV (2003b) Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla. Brain Res 991(1–2):84–95

    PubMed  CAS  Google Scholar 

  • 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):1455–1470

    PubMed  CAS  Google Scholar 

  • 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):229–235

    PubMed  Google Scholar 

  • 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):189–193

    PubMed  Google Scholar 

  • 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 

  • 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):748–753

    PubMed  CAS  Google Scholar 

  • 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):87–90

    PubMed  CAS  Google Scholar 

  • 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):322–327

    PubMed  Google Scholar 

  • de Miguel MJ, Burrell MA (2002) Immunocytochemical detection of orexin A in endocrine cells of the developing mouse gut. J Histochem Cytochem 50(1):63–69

    PubMed  Google Scholar 

  • de Oliveira CV, Ciriello J (2003) Cardiovascular responses to hypocretin-1 in nucleus ambiguus of the ovariectomized female rat. Brain Res 986(1–2):148–156

    PubMed  Google Scholar 

  • 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–H1377

    PubMed  Google Scholar 

  • 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):165–183

    PubMed  CAS  Google Scholar 

  • 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):142–151

    PubMed  CAS  Google Scholar 

  • 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):203–209

    CAS  Google Scholar 

  • 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–R12

    PubMed  CAS  Google Scholar 

  • 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–E716

    PubMed  CAS  Google Scholar 

  • 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):2370–2377

    PubMed  CAS  Google Scholar 

  • 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):442–459

    PubMed  CAS  Google Scholar 

  • 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):699–715

    PubMed  Google Scholar 

  • 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):201–217

    PubMed  Google Scholar 

  • 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):1656–1662

    PubMed  CAS  Google Scholar 

  • Farrell WJ, Delville Y, Wilczynski W (2003) Immunocytochemical localization of orexin in the brain of the green anole lizard (Anolis carolinensis). Soc Neurosci Abs 33:828

    Google Scholar 

  • Ferguson AV, Samson WK (2003) The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function. Front Neuroendocrinol 24(3):141–150

    PubMed  CAS  Google Scholar 

  • 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):8741–8751

    PubMed  CAS  Google Scholar 

  • 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):3485–3488

    PubMed  CAS  Google Scholar 

  • 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: 2630400

    PubMed  CAS  Google Scholar 

  • 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):1–14

    CAS  Google Scholar 

  • 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):8733–8738

    PubMed  CAS  Google Scholar 

  • 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):1165–1173

    PubMed  CAS  Google Scholar 

  • 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):1–4

    PubMed  CAS  Google Scholar 

  • 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):10911–10916

    PubMed  CAS  Google Scholar 

  • 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):5057–5063

    PubMed  CAS  Google Scholar 

  • 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):225–228

    PubMed  CAS  Google Scholar 

  • 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):954–958

    PubMed  CAS  Google Scholar 

  • 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):1067–1073

    PubMed  CAS  Google Scholar 

  • 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):345–354

    PubMed  CAS  Google Scholar 

  • 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):705–727

    PubMed  CAS  Google Scholar 

  • 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):275–282

    PubMed  CAS  Google Scholar 

  • 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):1099–1105

    PubMed  CAS  Google Scholar 

  • 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):45–51

    PubMed  CAS  Google Scholar 

  • 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):1461–1466

    PubMed  CAS  Google Scholar 

  • 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):143–150

    PubMed  CAS  Google Scholar 

  • 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):1116–1121

    PubMed  CAS  Google Scholar 

  • 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):593–600

    PubMed  CAS  Google Scholar 

  • Honda Y, Doi Y, Ninomiya R, Ninomiya C (1986) Increased frequency of non-insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 9(1):254–259

    PubMed  CAS  Google Scholar 

  • 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):1103–1122

    PubMed  CAS  Google Scholar 

  • 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):1–9

    PubMed  CAS  Google Scholar 

  • Horvath TL (2005) The hardship of obesity: a soft-wired hypothalamus. Nat Neurosci 8(5):561–565

    PubMed  CAS  Google Scholar 

  • 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):1072–1087

    PubMed  CAS  Google Scholar 

  • 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):145–159

    PubMed  CAS  Google Scholar 

  • 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):70–74

    PubMed  CAS  Google Scholar 

  • 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):476–491

    PubMed  CAS  Google Scholar 

  • Huhman KL, Albers HE (1994) Neuropeptide Y microinjected into the suprachiasmatic region phase shifts circadian rhythms in constant darkness. Peptides 15(8):1475–1478

    PubMed  CAS  Google Scholar 

  • Hungs M, Mignot E (2001) Hypocretin/orexin, sleep and narcolepsy. Bioessays 23(5):397–408

    PubMed  CAS  Google Scholar 

  • 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):531–539

    PubMed  CAS  Google Scholar 

  • 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):526–529

    PubMed  CAS  Google Scholar 

  • 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):119–122

    PubMed  CAS  Google Scholar 

  • 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):318–323

    PubMed  CAS  Google Scholar 

  • 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):1033–1041

    PubMed  CAS  Google Scholar 

  • Ivanov TR, Lawrence CB, Stanley PJ, Luckman SM (2002) Evaluation of neuromedin U actions in energy homeostasis and pituitary function. Endocrinology 143(10):3813–3821

    PubMed  CAS  Google Scholar 

  • 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):612–619

    PubMed  CAS  Google Scholar 

  • 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):113–119

    PubMed  CAS  Google Scholar 

  • 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):137–145

    PubMed  CAS  Google Scholar 

  • Jaszberenyi M, Bagosi Z, Thurzo B, Foldesi I, Telegdy G (2007) Endocrine and behavioral effects of neuromedin S. Horm Behav 52(5):631–639

    PubMed  CAS  Google Scholar 

  • JászberĂ©nyi M, BujdosĂł E, Pataki I, Telegdy G (2000) Effects of orexins on the hypothalamic-pituitary-adrenal system. J Neuroendocrinol 12(12):1174–1178

    PubMed  Google Scholar 

  • 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–E305

    PubMed  CAS  Google Scholar 

  • 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):2886–2892

    PubMed  CAS  Google Scholar 

  • 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):23–28

    PubMed  CAS  Google Scholar 

  • Johnson RF, Moore RY, Morin LP (1989) Lateral geniculate lesions alter circadian activity rhythms in the hamster. Brain Res Bull 22(2):411–422

    PubMed  CAS  Google Scholar 

  • 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):3324–3331

    PubMed  CAS  Google Scholar 

  • 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):210–218

    CAS  Google Scholar 

  • 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):1–5

    PubMed  CAS  Google Scholar 

  • 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):2678–2689

    PubMed  CAS  Google Scholar 

  • Kirchgessner AL, Liu M (1999) Orexin synthesis and response in the gut. Neuron 24(4):941–951

    PubMed  CAS  Google Scholar 

  • 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–E559

    PubMed  CAS  Google Scholar 

  • 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):2008–2016

    PubMed  CAS  Google Scholar 

  • Kotz CM (2006) Integration of feeding and spontaneous physical activity: role for orexin. Physiol Behav 88(3):294–301

    PubMed  CAS  Google Scholar 

  • 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–R503

    PubMed  CAS  Google Scholar 

  • 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):27–32

    PubMed  CAS  Google Scholar 

  • 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):29–36

    PubMed  CAS  Google Scholar 

  • 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–R710

    PubMed  CAS  Google Scholar 

  • 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):151–164

    PubMed  CAS  Google Scholar 

  • Kummer M, Neidert SJ, Johren O, Dominiak P (2001) Orexin (hypocretin) gene expression in rat ependymal cells. Neuroreport 12(10):2117–2120

    PubMed  CAS  Google Scholar 

  • Kunii K, Yamanaka A, Nambu T, Matsuzaki I, Goto K, Sakurai T (1999) Orexins/hypocretins regulate drinking behaviour. Brain Res 842(1):256–261

    PubMed  CAS  Google Scholar 

  • 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: 1574197

    PubMed  CAS  Google Scholar 

  • 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: 2956908

    PubMed  CAS  Google Scholar 

  • 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):506–514

    CAS  Google Scholar 

  • 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):365–376

    PubMed  CAS  Google Scholar 

  • 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):268–275

    PubMed  CAS  Google Scholar 

  • 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):335–344

    PubMed  CAS  Google Scholar 

  • Lubkin M, Stricker-Krongrad A (1998) Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 253(2):241–245

    PubMed  CAS  Google Scholar 

  • 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):1326–1341

    PubMed  CAS  Google Scholar 

  • 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):377–386

    PubMed  CAS  Google Scholar 

  • Martinez GS, Smale L, Nuñez AA (2002) Diurnal and nocturnal rodents show rhythms in orexinergic neurons. Brain Res 955(1–2):1–7

    PubMed  CAS  Google Scholar 

  • 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):71–78

    PubMed  CAS  Google Scholar 

  • 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):282–291

    PubMed  CAS  Google Scholar 

  • Matsumura K, Tsuchihashi T, Abe I (2001) Central orexin-A augments sympathoadrenal outflow in conscious rabbits. Hypertension 37(6):1382–1387

    PubMed  CAS  Google Scholar 

  • 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):119–123

    PubMed  CAS  Google Scholar 

  • 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):234–244

    PubMed  CAS  Google Scholar 

  • Meister B (2000) Control of food intake via leptin receptors in the hypothalamus. Vitam Horm 59:265–304

    PubMed  CAS  Google Scholar 

  • Methippara MM, Alam MN, Szymusiak R, McGinty D (2000) Effects of lateral preoptic area application of orexin-A on sleep- wakefulness. Neuroreport 11(16):3423–3426

    PubMed  CAS  Google Scholar 

  • 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):2480–2489

    PubMed  CAS  Google Scholar 

  • 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):1078–1085

    PubMed  CAS  Google Scholar 

  • Minamino N, Sudoh T, Kangawa K, Matsuo H (1985b) Neuromedins: novel smooth-muscle stimulating peptides identified in porcine spinal cord. Peptides 6(Suppl 3):245–248

    PubMed  CAS  Google Scholar 

  • 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):225–238

    PubMed  CAS  Google Scholar 

  • 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: 2795236

    PubMed  CAS  Google Scholar 

  • 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):37–41

    PubMed  CAS  Google Scholar 

  • 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):68–74

    PubMed  CAS  Google Scholar 

  • Monda M, Viggiano A, De Luca V (2003) Paradoxical [correction of parodoxical] effect of orexin A: hypophagia induced by hyperthermia. Brain Res 961(2):220–228

    PubMed  CAS  Google Scholar 

  • 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):567–574

    PubMed  CAS  Google Scholar 

  • 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):265–271

    PubMed  CAS  Google Scholar 

  • 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):495–499

    PubMed  CAS  Google Scholar 

  • Moore RY, Card JP (1994) Intergeniculate leaflet: an anatomically and functionally distinct subdivision of the lateral geniculate complex. J Comp Neurol 344(3):403–430

    PubMed  CAS  Google Scholar 

  • 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):195–205

    PubMed  CAS  Google Scholar 

  • Mori K, Miyazato M, Kangawa K (2008) Neuromedin S: discovery and functions. Results Probl Cell Differ 46:201–212

    PubMed  CAS  Google Scholar 

  • 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):101–104

    PubMed  CAS  Google Scholar 

  • 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):181–187

    PubMed  CAS  Google Scholar 

  • 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):191–194

    PubMed  CAS  Google Scholar 

  • 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):243–260

    PubMed  CAS  Google Scholar 

  • Nevsimalova S, Vankova J, Stepanova I, Seemanova E, Mignot E, Nishino S (2005) Hypocretin deficiency in Prader-Willi syndrome. Eur J Neurol 12(1):70–72

    PubMed  CAS  Google Scholar 

  • Niimi M, Sato M, Taminato T (2001a) Neuropeptide Y in central control of feeding and interactions with orexin and leptin. Endocrine 14(2):269–273

    PubMed  CAS  Google Scholar 

  • Niimi M, Murao K, Taminato T (2001b) Central administration of neuromedin U activates neurons in ventrobasal hypothalamus and brainstem. Endocrine 16(3):201–206

    PubMed  CAS  Google Scholar 

  • Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355(9197):39–40

    PubMed  CAS  Google Scholar 

  • 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):381–388

    PubMed  CAS  Google Scholar 

  • 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):25–34

    PubMed  CAS  Google Scholar 

  • 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):33–37

    PubMed  CAS  Google Scholar 

  • 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: 1913054

    PubMed  Google Scholar 

  • 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):545–553

    PubMed  CAS  Google Scholar 

  • 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):923–940

    PubMed  CAS  Google Scholar 

  • Novak CM, Levine JA (2009) Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obesity (Silver Spring) 7(8):1493–1498

    Google Scholar 

  • 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–E403

    PubMed  CAS  Google Scholar 

  • 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):594–601

    PubMed  CAS  Google Scholar 

  • 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 1169:57–68

    PubMed  CAS  Google Scholar 

  • 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: 2923555

    PubMed  Google Scholar 

  • 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: 2724663

    PubMed  CAS  Google Scholar 

  • 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):476–480

    PubMed  CAS  Google Scholar 

  • 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):78–105

    PubMed  CAS  Google Scholar 

  • 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):2591–2600

    PubMed  CAS  Google Scholar 

  • 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: 2703546

    PubMed  CAS  Google Scholar 

  • 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: 3085582

    PubMed  CAS  Google Scholar 

  • PetersĂ©n Ă…, Gil J, Maat-Schieman ML, Björkqvist M, Tanila H, AraĂşjo IM et al (2005) Orexin loss in Huntington’s disease. Hum Mol Genet 14(1):39–47

    PubMed  Google Scholar 

  • 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):9996–10015

    PubMed  CAS  Google Scholar 

  • 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):726–730

    PubMed  CAS  Google Scholar 

  • 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):843–850

    PubMed  CAS  Google Scholar 

  • 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):69–72

    PubMed  CAS  Google Scholar 

  • 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):243–247

    PubMed  CAS  Google Scholar 

  • 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):32452–32459

    PubMed  CAS  Google Scholar 

  • Rauch M, Riediger T, Schmid HA, Simon E (2000) Orexin A activates leptin-responsive neurons in the arcuate nucleus. Pflugers Arch 440(5):699–703

    PubMed  CAS  Google Scholar 

  • 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):71–84

    PubMed  CAS  Google Scholar 

  • 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):1444–1452

    PubMed  CAS  Google Scholar 

  • 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):255–259

    PubMed  CAS  Google Scholar 

  • 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):283–291

    PubMed  CAS  Google Scholar 

  • 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):5294–5302

    PubMed  CAS  Google Scholar 

  • 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):457–461

    PubMed  CAS  Google Scholar 

  • 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):49–53

    PubMed  CAS  Google Scholar 

  • Sakurai T (2003) Orexin: a link between energy homeostasis and adaptive behaviour. Curr Opin Clin Nutr Metab Care 6(4):353–360

    PubMed  CAS  Google Scholar 

  • 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):573–585

    PubMed  CAS  Google Scholar 

  • 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):17771–17776

    CAS  Google Scholar 

  • Samson WK, Gosnell B, Chang JK, Resch ZT, Murphy TC (1999) Cardiovascular regulatory actions of the hypocretins in brain. Brain Res 831(1–2):248–253

    PubMed  CAS  Google Scholar 

  • Samson WK, Taylor MM, Ferguson AV (2005) Non-sleep effects of hypocretin/orexin. Sleep Med Rev 9(4):243–252

    PubMed  Google Scholar 

  • Samson WK, Bagley SL, Ferguson AV, White MM (2010) Orexin receptor subtype activation and locomotor behaviour in the rat. Acta Physiol (Oxf) 198(3):313–324

    CAS  Google Scholar 

  • 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):1234–1240

    PubMed  CAS  Google Scholar 

  • 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):169–177

    PubMed  CAS  Google Scholar 

  • Scammell TE, Winrow CJ (2011) Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51:243–266

    PubMed  CAS  Google Scholar 

  • Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671

    PubMed  CAS  Google Scholar 

  • 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: 2711051

    CAS  Google Scholar 

  • 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):39482–39486

    PubMed  CAS  Google Scholar 

  • 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):1169–1176

    PubMed  CAS  Google Scholar 

  • 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–R1785

    PubMed  CAS  Google Scholar 

  • Shirasaka T, Kunitake T, Takasaki M, Kannan H (2002) Neuronal effects of orexins: relevant to sympathetic and cardiovascular functions. Regul Pept 104(1–3):91–95

    PubMed  CAS  Google Scholar 

  • Siegel JM (1999) Narcolepsy: a key role for hypocretins (orexins). Cell 98(4):409–412

    PubMed  CAS  Google Scholar 

  • 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):231–236

    PubMed  CAS  Google Scholar 

  • 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):163–172

    PubMed  CAS  Google Scholar 

  • 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):1–3

    PubMed  CAS  Google Scholar 

  • 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):261–267

    PubMed  CAS  Google Scholar 

  • 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):256–258

    PubMed  CAS  Google Scholar 

  • Smith PM, Samson WK, Ferguson AV (2007) Cardiovascular actions of orexin-A in the rat subfornical organ. J Neuroendocrinol 19(1):7–13

    PubMed  CAS  Google Scholar 

  • 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):475–481

    PubMed  CAS  Google Scholar 

  • 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):304–317

    PubMed  CAS  Google Scholar 

  • 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):27–34

    PubMed  CAS  Google Scholar 

  • Sutcliffe JG, de Lecea L (2000) The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding. J Neurosci Res 62(2):161–168

    PubMed  CAS  Google Scholar 

  • Sutton RE, Koob GF, Le Moal M, Rivier J, Vale W (1982) Corticotropin releasing factor produces behavioural activation in rats. Nature 297(5864):331–333

    PubMed  CAS  Google Scholar 

  • Sweet DC, Levine AS, Billington CJ, Kotz CM (1999) Feeding response to central orexins. Brain Res 821(2):535–538

    PubMed  CAS  Google Scholar 

  • Szekely M (2006) Orexins, energy balance, temperature, sleep-wake cycle. Am J Physiol Regul Integr Comp Physiol 291(3):R530–R532

    PubMed  CAS  Google Scholar 

  • Szekely M, Petervari E, Balasko M, Hernadi I, Uzsoki B (2002) Effects of orexins on energy balance and thermoregulation. Regul Pept 104(1–3):47–53

    PubMed  CAS  Google Scholar 

  • Szekely M, Petervari E, Balasko M (2010) Thermoregulation, energy balance, regulatory peptides: recent developments. Front Biosci (Schol Ed) 2:1009–1046

    Google Scholar 

  • 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):63–67

    PubMed  Google Scholar 

  • 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):394–399

    PubMed  Google Scholar 

  • 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):79–83

    PubMed  CAS  Google Scholar 

  • Tanida M, Satomi J, Shen J, Nagai K (2009) Autonomic and cardiovascular effects of central neuromedin U in rats. Physiol Behav 96(2):282–288

    PubMed  CAS  Google Scholar 

  • 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–R899

    PubMed  CAS  Google Scholar 

  • Teske JA, Billington CJ, Kotz CM (2010) Hypocretin/Orexin and Energy Expenditure. Acta Physiol (Oxf) 198:303–312

    CAS  Google Scholar 

  • 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):469–474

    PubMed  CAS  Google Scholar 

  • 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):65–71

    PubMed  CAS  Google Scholar 

  • Thorpe AJ, Kotz CM (2005) Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res 1050(1–2):156–162

    PubMed  CAS  Google Scholar 

  • 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–R1417

    PubMed  CAS  Google Scholar 

  • Tsujino N, Sakurai T (2009) Orexin/Hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 61(2):162–176

    PubMed  CAS  Google Scholar 

  • van den Pol AN (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 19(8):3171–3182

    PubMed  Google Scholar 

  • 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):7962–7971

    PubMed  Google Scholar 

  • 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):809–821

    PubMed  Google Scholar 

  • Verty AN, Allen AM, Oldfield BJ (2010) The endogenous actions of hypothalamic peptides on brown adipose tissue thermogenesis in the rat. Endocrinology 151(9):4236–4246

    PubMed  CAS  Google Scholar 

  • Volgin DV, Saghir M, Kubin L (2002) Developmental changes in the orexin 2 receptor mRNA in hypoglossal motoneurons. Neuroreport 13(4):433–436

    PubMed  CAS  Google Scholar 

  • 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):125–133

    PubMed  CAS  Google Scholar 

  • 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–R367

    PubMed  CAS  Google Scholar 

  • Wang J, Osaka T, Inoue S (2001) Energy expenditure by intracerebroventricular administration of orexin to anesthetized rats. Neurosci Lett 315(1–2):49–52

    PubMed  CAS  Google Scholar 

  • 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):127–134

    PubMed  CAS  Google Scholar 

  • 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):128–134

    PubMed  CAS  Google Scholar 

  • Weaver DR (1998) The suprachiasmatic nucleus: a 25-year retrospective. J Biol Rhythms 13(2):100–112

    PubMed  CAS  Google Scholar 

  • Webb P, Annis JF, Troutman SJ Jr (1980) Energy balance in man measured by direct and indirect calorimetry. Am J Clin Nutr 33(6):1287–1298

    PubMed  CAS  Google Scholar 

  • 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):828–835

    PubMed  Google Scholar 

  • 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):1069–1074

    PubMed  CAS  Google Scholar 

  • 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):293–300

    PubMed  CAS  Google Scholar 

  • 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):185–194

    PubMed  CAS  Google Scholar 

  • 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):52–61

    PubMed  CAS  Google Scholar 

  • Wren AM, Small CJ, Abbott CR, Jethwa PH, Kennedy AR, Murphy KG et al (2002) Hypothalamic actions of neuromedin U. Endocrinology 143(11):4227–4234

    PubMed  CAS  Google Scholar 

  • 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–R1086

    PubMed  Google Scholar 

  • 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):186–192

    PubMed  CAS  Google Scholar 

  • 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):404–409

    PubMed  CAS  Google Scholar 

  • 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):367–374

    PubMed  CAS  Google Scholar 

  • 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):324–328

    PubMed  CAS  Google Scholar 

  • 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):109–112

    PubMed  CAS  Google Scholar 

  • 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):468–476

    CAS  Google Scholar 

  • 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):9352–9363

    PubMed  CAS  Google Scholar 

  • 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):106–110

    PubMed  CAS  Google Scholar 

  • Zhang W, Fukuda Y, Kuwaki T (2005a) Respiratory and cardiovascular actions of orexin-A in mice. Neurosci Lett 385(2):131–136

    PubMed  CAS  Google Scholar 

  • 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):81–87

    PubMed  CAS  Google Scholar 

  • 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):1660–1668

    PubMed  CAS  Google Scholar 

  • 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):127–142

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Veterans Affairs Medical Center, Research Service (151), Minneapolis, MN, USA

    Joshua P. Nixon, Catherine M. Kotz, Charles J. Billington & Jennifer A. Teske

  2. Department of Food Science and Nutrition, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN, 55108, USA

    Joshua P. Nixon, Catherine M. Kotz, Charles J. Billington & Jennifer A. Teske

  3. Minnesota Obesity Center, University of Minnesota, 1334 Eckles Avenue, St. Paul, MN, 55108, USA

    Joshua P. Nixon, Catherine M. Kotz, Charles J. Billington & Jennifer A. Teske

  4. Veterans Affairs Medical Center, GRECC (11 G), Minneapolis, MN, USA

    Catherine M. Kotz

  5. Department of Biological Sciences, Kent State University, Kent, OH, USA

    Colleen M. Novak

  6. Veterans Affairs Medical Center, Endocrine Unit (111 G), Minneapolis, MN, USA

    Charles J. Billington

Authors
  1. Joshua P. Nixon
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Catherine M. Kotz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Colleen M. Novak
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles J. Billington
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jennifer A. Teske
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine M. Kotz .

Editor information

Editors and Affiliations

  1. , Department of Pharmacology, German Institute of Human Nutrition, Arthur-Scheunert-Allee 114-116, Nuthetal, 14558, Germany

    Hans-Georg Joost

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Nixon, J.P., Kotz, C.M., Novak, C.M., Billington, C.J., Teske, J.A. (2012). Neuropeptides Controlling Energy Balance: Orexins and Neuromedins. In: Joost, HG. (eds) Appetite Control. Handbook of Experimental Pharmacology, vol 209. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-24716-3_4

Download citation

Publish with us

Policies and ethics

Search

Navigation