The orexin peptides and their two receptors are involved in multiple physiological processes, including energy homeostasis, arousal, stress and reward. Higher signaling of the orexin peptides at the orexin receptors (OXR) protects against obesity, but it is less clear how their activation in different brain regions contributes to this behavioral output. This review summarizes the evidence available for a role of central OXR in energy homeostasis and their contribution to obesity. A detailed analysis of anatomical, cellular and behavioral evidence shows that modulation of energy homeostasis by the OXR is largely dependent upon anatomical and cellular context. It also shows that obesity resistance provided by activation of the OXR is distributed across multiple brain sites with site-specific actions. We suggest that understanding the role of the OXR in the development of obesity requires considering both specific mechanisms within brain regions and interactions of orexinergic input between multiple sites.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Reproductive Biology and Endocrinology Open Access 11 September 2018
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Rent or buy this article
Prices vary by article type
Prices may be subject to local taxes which are calculated during checkout
Date Y, Ueta Y, Yamashita H, Yamaguchi H, Matsukura S, Kangawa K et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 1999; 96: 748–753.
Iqbal J, Pompolo S, Sakurai T, Clarke IJ . Evidence that orexin-containing neurones provide direct input to gonadotropin-releasing hormone neurones in the ovine hypothalamus. J Neuroendocrinol 2001; 13: 1033–1041.
Mintz EM, van den Pol AN, Casano AA, Albers HE . Distribution of hypocretin-(orexin) immunoreactivity in the central nervous system of Syrian hamsters (Mesocricetus auratus). J Chem Neuroanat 2001; 21: 225–238.
Moore RY, Abrahamson EA, Van Den Pol A . The hypocretin neuron system: an arousal system in the human brain. Arch Ital Biol 2001; 139: 195–205.
Nixon JP, Smale L . A comparative analysis of the distribution of immunoreactive orexin A and B in the brains of nocturnal and diurnal rodents. Behav Brain Funct 2007; 3: 28.
Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998; 18: 9996–10015.
Zhang JH, Sampogna S, Morales FR, Chase MH . Orexin (hypocretin)-like immunoreactivity in the cat hypothalamus: a light and electron microscopic study. Sleep 2001; 24: 67–76.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998; 95: 322–327.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998; 92: 573–585.
Ammoun S, Holmqvist T, Shariatmadari R, Oonk HB, Detheux M, Parmentier M et al. Distinct recognition of OX1 and OX2 receptors by orexin peptides. J Pharmacol Exp Ther 2003; 305: 507–514.
Lubkin M, Stricker-Krongrad A . Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 1998; 253: 241–245.
Horvath TL, Diano S, van den Pol AN . 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 1999; 19: 1072–1087.
Sweet DC, Levine AS, Billington CJ, Kotz CM . Feeding response to central orexins. Brain Res 1999; 821: 535–538.
Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA et al. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 2000; 96: 45–51.
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999; 98: 365–376.
Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999; 98: 437–451.
Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci USA 1999; 96: 10911–10916.
Willie JT, Chemelli RM, Sinton CM, Yanagisawa M . To eat or to sleep? Orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 2001; 24: 429–458.
Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001; 30: 345–354.
Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M . Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci 2010; 30: 12642–12652.
Cluderay JE, Harrison DC, Hervieu GJ . Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 2002; 104: 131–144.
Greco MA, Shiromani PJ . Hypocretin receptor protein and mRNA expression in the dorsolateral pons of rats. Brain Res Mol Brain Res 2001; 88: 176–182.
Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA . Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 2001; 103: 777–797.
Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001; 435: 6–25.
Sunter D, Morgan I, Edwards CM, Dakin CL, Murphy KG, Gardiner J et al. Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res 2001; 907: 27–34.
Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM . Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998; 438: 71–75.
Backberg M, Hervieu G, Wilson S, Meister B . Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Eur J Neurosci 2002; 15: 315–328.
Suzuki R, Shimojima H, Funahashi H, Nakajo S, Yamada S, Guan JL et al. Orexin-1 receptor immunoreactivity in chemically identified target neurons in the rat hypothalamus. Neurosci Lett 2002; 324: 5–8.
Espana RA, Reis KM, Valentino RJ, Berridge CW . Organization of hypocretin/orexin efferents to locus coeruleus and basal forebrain arousal-related structures. J Comp Neurol 2005; 481: 160–178.
Ciriello J, McMurray JC, Babic T, de Oliveira CV . Collateral axonal projections from hypothalamic hypocretin neurons to cardiovascular sites in nucleus ambiguus and nucleus tractus solitarius. Brain Res 2003; 991: 133–141.
Krout KE, Mettenleiter TC, Loewy AD . Single CNS neurons link both central motor and cardiosympathetic systems: a double-virus tracing study. Neuroscience 2003; 118: 853–866.
Geerling JC, Mettenleiter TC, Loewy AD . Orexin neurons project to diverse sympathetic outflow systems. Neuroscience 2003; 122: 541–550.
Oldfield BJ, Allen AM, Davern P, Giles ME, Owens NC . Lateral hypothalamic ‘command neurons’ with axonal projections to regions involved in both feeding and thermogenesis. Eur J Neurosci 2007; 25: 2404–2412.
Olszewski PK, Cedernaes J, Olsson F, Levine AS, Schioth HB . Analysis of the network of feeding neuroregulators using the Allen Brain Atlas. Neurosci Biobehav Rev 2008; 32: 945–956.
Berthoud HR, Morrison C . The brain, appetite, and obesity. Annu Rev Psychol 2008; 59: 55–92.
Ammoun S, Johansson L, Ekholm ME, Holmqvist T, Danis AS, Korhonen L et al. OX1 orexin receptors activate extracellular signal-regulated kinase in Chinese hamster ovary cells via multiple mechanisms: the role of Ca2+ influx in OX1 receptor signaling. Mol Endocrinol 2006; 20: 80–99.
Ekholm ME, Johansson L, Kukkonen JP . IP3-independent signalling of OX1 orexin/hypocretin receptors to Ca2+ influx and ERK. Biochem Biophys Res Commun 2007; 353: 475–480.
Johansson L, Ekholm ME, Kukkonen JP . Regulation of OX1 orexin/hypocretin receptor-coupling to phospholipase C by Ca2+ influx. Br J Pharmacol 2007; 150: 97–104.
Johansson L, Ekholm ME, Kukkonen JP . Multiple phospholipase activation by OX(1) orexin/hypocretin receptors. Cell Mol Life Sci 2008; 65: 1948–1956.
Kukkonen JP, Akerman KE . Orexin receptors couple to Ca2+ channels different from store-operated Ca2+ channels. Neuroreport 2001; 12: 2017–2020.
Lund PE, Shariatmadari R, Uustare A, Detheux M, Parmentier M, Kukkonen JP et al. The orexin OX1 receptor activates a novel Ca2+ influx pathway necessary for coupling to phospholipase C. J Biol Chem 2000; 275: 30806–30812.
Magga J, Bart G, Oker-Blom C, Kukkonen JP, Akerman KE, Nasman J . Agonist potency differentiates G protein activation and Ca2+ signalling by the orexin receptor type 1. Biochem Pharmacol 2006; 71: 827–836.
Larsson KP, Peltonen HM, Bart G, Louhivuori LM, Penttonen A, Antikainen M et al. Orexin-A-induced Ca2+ entry: evidence for involvement of trpc channels and protein kinase C regulation. J Biol Chem 2005; 280: 1771–1781.
Nasman J, Bart G, Larsson K, Louhivuori L, Peltonen H, Akerman KE . The orexin OX1 receptor regulates Ca2+ entry via diacylglycerol-activated channels in differentiated neuroblastoma cells. J Neurosci 2006; 26: 10658–10666.
Peltonen HM, Magga JM, Bart G, Turunen PM, Antikainen MS, Kukkonen JP et al. Involvement of TRPC3 channels in calcium oscillations mediated by OX orexin receptors. Biochem Biophys Res Commun 2009; 385: 408–412.
Tang J, Chen J, Ramanjaneya M, Punn A, Conner AC, Randeva HS . The signalling profile of recombinant human orexin-2 receptor. Cell Signal 2008; 20: 1651–1661.
Holmqvist T, Johansson L, Ostman M, Ammoun S, Akerman KE, Kukkonen JP . OX1 orexin receptors couple to adenylyl cyclase regulation via multiple mechanisms. J Biol Chem 2005; 280: 6570–6579.
Karteris E, Machado RJ, Chen J, Zervou S, Hillhouse EW, Randeva HS . Food deprivation differentially modulates orexin receptor expression and signaling in rat hypothalamus and adrenal cortex. Am J Physiol Endocrinol Metab 2005; 288: E1089–E1100.
Hoang QV, Bajic D, Yanagisawa M, Nakajima S, Nakajima Y . Effects of orexin (hypocretin) on GIRK channels. J Neurophysiol 2003; 90: 693–702.
Hoang QV, Zhao P, Nakajima S, Nakajima Y . Orexin (hypocretin) effects on constitutively active inward rectifier K+ channels in cultured nucleus basalis neurons. J Neurophysiol 2004; 92: 3183–3191.
Mukai K, Kim J, Nakajima K, Oomura Y, Wayner MJ, Sasaki K . Electrophysiological effects of orexin/hypocretin on nucleus accumbens shell neurons in rats: an in vitro study. Peptides 2009; 30: 1487–1496.
van den Pol AN, Ghosh PK, Liu RJ, Li Y, Aghajanian GK, Gao XB . Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol 2002; 541 (Pt 1): 169–185.
Follwell MJ, Ferguson AV . Cellular mechanisms of orexin actions on paraventricular nucleus neurones in rat hypothalamus. J Physiol 2002; 545 (Pt 3): 855–867.
van den Pol AN, Gao XB, Obrietan K, Kilduff TS, Belousov AB . Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 1998; 18: 7962–7971.
Samson WK, Taylor MM, Follwell M, Ferguson AV . Orexin actions in hypothalamic paraventricular nucleus: physiological consequences and cellular correlates. Regul Pept 2002; 104: 97–103.
Burlet S, Tyler CJ, Leonard CS . Direct and indirect excitation of laterodorsal tegmental neurons by Hypocretin/Orexin peptides: implications for wakefulness and narcolepsy. J Neurosci 2002; 22: 2862–2872.
Bayer L, Eggermann E, Saint-Mleux B, Machard D, Jones BE, Muhlethaler M et al. Selective action of orexin (hypocretin) on nonspecific thalamocortical projection neurons. J Neurosci 2002; 22: 7835–7839.
Bisetti A, Cvetkovic V, Serafin M, Bayer L, Machard D, Jones BE et al. Excitatory action of hypocretin/orexin on neurons of the central medial amygdala. Neuroscience 2006; 142: 999–1004.
Liu RJ, van den Pol AN, Aghajanian GK . Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002; 22: 9453–9464.
Yang B, Ferguson AV . Orexin-A depolarizes nucleus tractus solitarius neurons through effects on nonselective cationic and K+ conductances. J Neurophysiol 2003; 89: 2167–2175.
Burdakov D, Liss B, Ashcroft FM . Orexin excites GABAergic neurons of the arcuate nucleus by activating the sodium--calcium exchanger. J Neurosci 2003; 23: 4951–4957.
Uramura K, Funahashi H, Muroya S, Shioda S, Takigawa M, Yada T . Orexin-a activates phospholipase C- and protein kinase C-mediated Ca2+ signaling in dopamine neurons of the ventral tegmental area. Neuroreport 2001; 12: 1885–1889.
Kohlmeier KA, Inoue T, Leonard CS . Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol 2004; 92: 221–235.
Jones DN, Gartlon J, Parker F, Taylor SG, Routledge C, Hemmati P et al. Effects of centrally administered orexin-B and orexin-A: a role for orexin-1 receptors in orexin-B-induced hyperactivity. Psychopharmacology (Berl) 2001; 153: 210–218.
Akiyama M, Yuasa T, Hayasaka N, Horikawa K, Sakurai T, Shibata S . Reduced food anticipatory activity in genetically orexin (hypocretin) neuron-ablated mice. Eur J Neurosci 2004; 20: 3054–3062.
Novak CM, Levine JA . Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obesity (Silver Spring) 2009; 17: 1493–1498.
Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K . Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 1999; 849: 248–252.
Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M . Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA 2004; 101: 4649–4654.
Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T et al. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 2009; 9: 64–76.
Hara J, Yanagisawa M, Sakurai T . Difference in obesity phenotype between orexin-knockout mice and orexin neuron-deficient mice with same genetic background and environmental conditions. Neurosci Lett 2005; 380: 239–242.
Fujiki N, Yoshida Y, Zhang S, Sakurai T, Yanagisawa M, Nishino S . Sex difference in body weight gain and leptin signaling in hypocretin/orexin deficient mouse models. Peptides 2006; 27: 2326–2331.
Tupone D, Madden CJ, Cano G, Morrison SF . An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis. J Neurosci 2011; 31: 15944–15955.
Cerri M, Morrison SF . Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis. Neuroscience 2005; 135: 627–638.
Espana RA, Baldo BA, Kelley AE, Berridge CW . Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action. Neuroscience 2001; 106: 699–715.
Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M . Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 1999; 821: 526–529.
Matsuzaki I, Sakurai T, Kunii K, Nakamura T, Yanagisawa M, Goto K . Involvement of the serotonergic system in orexin-induced behavioral alterations in rats. Regul Pept 2002; 104: 119–123.
Kotz CM, Teske JA, Levine JA, Wang C . Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 2002; 104: 27–32.
Dube MG, Kalra SP, Kalra PS . Food intake elicited by central administration of orexins/hypocretins: identification of hypothalamic sites of action. Brain Res 1999; 842: 473–477.
Thorpe AJ, Teske JA, Kotz CM . Orexin A-induced feeding is augmented by caloric challenge. Am J Physiol Regul Integr Comp Physiol 2005; 289: R367–R372.
Kotz CM, Teske JA, Billington CJ . Neuroregulation of nonexercise activity thermogenesis and obesity resistance. Am J Physiol Regul Integr Comp Physiol 2008; 294: R699–R710.
Li Y, Gao XB, Sakurai T, van den Pol AN . Hypocretin/Orexin excites hypocretin neurons via a local glutamate neuron-A potential mechanism for orchestrating the hypothalamic arousal system. Neuron 2002; 36: 1169–1181.
Thorpe AJ, Mullett MA, Wang C, Kotz CM . Peptides that regulate food intake: regional, metabolic, and circadian specificity of lateral hypothalamic orexin A feeding stimulation. Am J Physiol Regul Integr Comp Physiol 2003; 284: R1409–R1417.
Kiwaki K, Kotz CM, Wang C, Lanningham-Foster L, Levine JA . Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats. Am J Physiol Endocrinol Metab 2004; 286: E551–E559.
Thorpe AJ, Kotz CM . Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res 2005; 1050: 156–162.
Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE . Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am J Physiol 1997; 273 (2 Pt 2): R725–R730.
Teske JA, Levine AS, Kuskowski M, Levine JA, Kotz CM . Elevated hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous physical activity in obesity-resistant rats. Am J Physiol Regul Integr Comp Physiol 2006; 291: R889–R899.
Teske JA, Billington CJ, Kuskowski MA, Kotz CM . Spontaneous physical activity protects against fat mass gain. Int J Obes 2011; e-pub ahead of print 24 May 2011; doi:10.1038/ijo.2011.108.
Akbari E, Motamedi F, Davoodi FG, Noorbakhshnia M, Ghanbarian E . Orexin-1 receptor mediates long-term potentiation in the dentate gyrus area of freely moving rats. Behav Brain Res 2010; 216: 375–380.
Walling SG, Nutt DJ, Lalies MD, Harley CW . Orexin-A infusion in the locus ceruleus triggers norepinephrine (NE) release and NE-induced long-term potentiation in the dentate gyrus. J Neurosci 2004; 24: 7421–7426.
Wayner MJ, Armstrong DL, Phelix CF, Oomura Y . Orexin-A (Hypocretin-1) and leptin enhance LTP in the dentate gyrus of rats in vivo. Peptides 2004; 25: 991–996.
Hanlon EC, Van Cauter E . Quantification of sleep behavior and of its impact on the cross-talk between the brain and peripheral metabolism. Proc Natl Acad Sci USA 2011; 108 (Suppl 3): 15609–15016.
Van Cauter E, Knutson KL . Sleep and the epidemic of obesity in children and adults. Eur J Endocrinol 2008; 159 (Suppl 1): S59–S66.
Sakurai T . Roles of orexin/hypocretin in regulation of sleep/wakefulness and energy homeostasis. Sleep Med Rev 2005; 9: 231–241.
Tsujino N, Sakurai T . Orexin/Hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 2009; 61: 162–176.
Kisanuki YY, Chemelli RM, Tokita S, Willie JT, Sinton CM, Yanagisawa M . Behavioral and polysomnographic characterization of orexin-1 receptor and orexin-2 receptor double knockout mice. Sleep 2001; 24: A22–A22.
Zhang S, Zeitzer JM, Sakurai T, Nishino S, Mignot E . Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy. J Physiol 2007; 581 (Pt 2): 649–663.
Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M et al. Fos expression in orexin neurons varies with behavioral state. J Neurosci 2001; 21: 1656–1662.
Kiyashchenko LI, Mileykovskiy BY, Maidment N, Lam HA, Wu MF, John J et al. Release of hypocretin (orexin) during waking and sleep states. J Neurosci 2002; 22: 5282–5286.
Mileykovskiy BY, Kiyashchenko LI, Siegel JM . Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005; 46: 787–798.
Lee MG, Hassani OK, Jones BE . Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 2005; 25: 6716–6720.
Takahashi K, Lin JS, Sakai K . Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience 2008; 153: 860–870.
Adamantidis AR, Zhang F, Aravanis AM, Deisseroth K, de Lecea L . Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 2007; 450: 420–424.
Bourgin P, Huitron-Resendiz S, Spier AD, Fabre V, Morte B, Criado JR et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000; 20: 7760–7765.
Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci USA 2001; 98: 9965–9970.
Methippara MM, Alam MN, Szymusiak R, McGinty D . Effects of lateral preoptic area application of orexin-A on sleep-wakefulness. Neuroreport 2000; 11: 3423–3426.
Xi MC, Morales FR, Chase MH . Effects on sleep and wakefulness of the injection of hypocretin-1 (orexin-A) into the laterodorsal tegmental nucleus of the cat. Brain Res 2001; 901: 259–264.
Eriksson KS, Sergeeva O, Brown RE, Haas HL . Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001; 21: 9273–9279.
Brown RE, Sergeeva O, Eriksson KS, Haas HL . Orexin A excites serotonergic neurons in the dorsal raphe nucleus of the rat. Neuropharmacology 2001; 40: 457–459.
Bayer L, Eggermann E, Serafin M, Saint-Mleux B, Machard D, Jones B et al. Orexins (hypocretins) directly excite tuberomammillary neurons. Eur J Neurosci 2001; 14: 1571–1575.
Eggermann E, Serafin M, Bayer L, Machard D, Saint-Mleux B, Jones BE et al. Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience 2001; 108: 177–181.
Beccuti G, Pannain S . Sleep and obesity. Curr Opin Clin Nutr Metab Care 2011; 14: 402–412.
Spiegel K, Tasali E, Leproult R, Van Cauter E . Effects of poor and short sleep on glucose metabolism and obesity risk. Nat Rev Endocrinol 2009; 5: 253–261.
Nishino S, Ripley B, Overeem S, Nevsimalova S, Lammers GJ, Vankova J et al. Low cerebrospinal fluid hypocretin (Orexin) and altered energy homeostasis in human narcolepsy. Ann Neurol 2001; 50: 381–388.
Nishino S, Mignot E . Article reviewed: plasma orexin-A is lower in patients with narcolepsy. Sleep Med 2002; 3: 377–378.
Willie JT, Chemelli RM, Sinston CM, Tokita H, Williams SC, Kisanuki YY et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 2003; 38: 715–730.
Mavanji V, Teske JA, Billington CJ, Kotz CM . Elevated sleep quality and orexin receptor mRNA in obesity-resistant rats. Int J Obes 2010; 34: 1576–1588.
Horvath TL . The hardship of obesity: a soft-wired hypothalamus. Nat Neurosci 2005; 8: 561–565.
Morton GJ, Cummings DE, Baskin DG, Barsh GS, Schwartz MW . Central nervous system control of food intake and body weight. Nature 2006; 443: 289–295.
Stranahan AM, Mattson MP . Impact of energy intake and expenditure on neuronal plasticity. Neuromol Med 2008; 10: 209–218.
Noble EE, Billington CJ, Kotz CM, Wang C . The lighter side of BDNF. Am J Physiol Regul Integr Comp Physiol 2011; 300: R1053–R1069.
We thank Dr Joshua Nixon, Dr Jennifer Teske and Dr Vijaya Mavanji for valuable discussions and suggestions to this article. This study was supported by funding from the National Institute of Health, NIDDK, DK078985.
The authors declare no conflict of interest.
About this article
Cite this article
Perez-Leighton, C., Butterick-Peterson, T., Billington, C. et al. Role of orexin receptors in obesity: from cellular to behavioral evidence. Int J Obes 37, 167–174 (2013). https://doi.org/10.1038/ijo.2012.30
This article is cited by
Reproductive Biology and Endocrinology (2018)
Current Obesity Reports (2017)