Advertisement

The Ghrelin Receptor: A Novel Therapeutic Target for Obesity

  • Harriët Schellekens
  • Timothy G. Dinan
  • John F. CryanEmail author
Chapter
Part of the The Receptors book series (REC, volume 25)

Abstract

The obesity epidemic has evolved into an ever expanding serious global health concern. Several physiological as well as environmental factors have contributed to the rise in obesity incidence. Obesity or being overweight results from an energy imbalance characterized by an excess of caloric intake more often than not combined with a reduced energy expenditure, for example, due to physical inactivity. Nutrient status is communicated via circulating gut hormones, which all act on the brain to regulate short-and long-term appetite and the body’s metabolism and this brain-gut axis communication is dysregulated under metabolic conditions, such as obesity. Ghrelin is the only peripheral-derived hormone, which exerts an orexigenic effect via the modulation of central circuitries, and has therefore received considerable focus in the pharmaceutical industry for the development of anti-obesity therapeutics. Two subtypes of the ghrelin receptor have been reported to date, the growth hormone secretagogue (GHS-R1a) receptor 1a isoform, which is activated by acylated ghrelin, and the truncated isoform GHS-R1b, which is functionally inactive. Interestingly, the GHS-R1b receptor has been shown to exert a dominant-negative effect on GHS-R1a receptor functioning via the formation of a GHS-R1a/1b dimer. The GHS-R1a is expressed in multiple brain regions with ghrelin’s orexigenic effect on homeostatic food intake being mainly mediated in the arcuate nucleus of the hypothalamus and hedonic aspects being mediated via GHS-R1a receptors in the mesolimbic dopaminergic circuitry. In this review, we discuss the role of ghrelin in the hypothalamic regulation of appetite and highlight the additional dimension of the ghrelin/GHS-R1a receptor axis as a target in obesity via manipulation of the ghrelin-mediated nonhomeostatic rewarding aspect of food intake behavior. In addition, we review the current understanding of the role of the ghrelin receptor isoforms as targets in obesity and discuss the potential of heterodimers in the development of more specific anti-obesity therapeutics.

Keywords

Obesity Ghrelin Growth hormone secretagogue receptor Food intake behavior Heterodimerization 

Notes

Acknowledgements

The work was supported by Enterprise Ireland under Grant Number CC20080001. JFC and TGD are also supported in part by Science Foundation Ireland (SFI) in the form of a center grant (Alimentary Pharmabiotic Center) through the Irish Government’s National Development Plan. The authors and their work were supported by SFI (grant no.s 02/CE/B124 and 07/CE/B1368). JFC is funded by European Community’s Seventh Framework Program; Grant Number: FP7/2007-2013, Grant Agreement 201714.

References

  1. Abizaid A (2009) Ghrelin and dopamine: new insights on the peripheral regulation of appetite. J Neuroendocrinol 21(9):787–793PubMedGoogle Scholar
  2. Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD, Roth RH, Sleeman MW, Picciotto MR, Tschop MH, Gao XB, Horvath TL (2006) Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin Invest 116(12):3229–3239PubMedCentralPubMedGoogle Scholar
  3. Adan RA, Tiesjema B, Hillebrand JJ, La Fleur SE, Kas MJ, Krom M de (2006) The MC4 receptor and control of appetite. Br J Pharmacol 149(7): 815–27Google Scholar
  4. Ahima RS, Antwi DA (2008) Brain regulation of appetite and satiety. Endocrinol Metab Clin North Am 37(4):811–823PubMedCentralPubMedGoogle Scholar
  5. Ahima RS, Lazar MA (2008) Adipokines and the peripheral and neural control of energy balance. Mol Endocrinol 22(5):1023–1031PubMedCentralPubMedGoogle Scholar
  6. Andrews ZB (2011) Central mechanisms involved in the orexigenic actions of ghrelin. Peptides 32(11):2248–2255PubMedGoogle Scholar
  7. Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, Tschop MH, Shanabrough M, Cline G, Shulman GI, Coppola A, Gao XB, Horvath TL, Diano S (2008) UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature 454(7206):846–851PubMedGoogle Scholar
  8. Arnold M, Mura A, Langhans W, Geary N (2006) Gut vagal afferents are not necessary for the eating-stimulatory effect of intraperitoneally injected ghrelin in the rat. J Neurosci 26(43):11052–11060PubMedGoogle Scholar
  9. Asakawa A, Inui A, Kaga T, Katsuura G, Fujimiya M, Fujino MA, Kasuga M (2003) Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 52(7):947–952PubMedCentralPubMedGoogle Scholar
  10. Atalayer D, Gibson C, Konopacka A, Geliebter A (2013) Ghrelin and eating disorders. Prog Neuropsychopharmacol Biol Psychiatry 40:70–82PubMedCentralPubMedGoogle Scholar
  11. Banks WA, Tschop M, Robinson SM, Heiman ML (2002) Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 302(2):822–827PubMedGoogle Scholar
  12. Banks WA, Burney BO, Robinson SM (2008) Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier. Peptides 29(11):2061–2065PubMedCentralPubMedGoogle Scholar
  13. Bassareo V, Di Chiara G (1999) Differential responsiveness of dopamine transmission to food-stimuli in nucleus accumbens shell/core compartments. Neuroscience 89(3):637–641PubMedGoogle Scholar
  14. Beck B, Richy S, Stricker-Krongrad A (2004) Feeding response to ghrelin agonist and antagonist in lean and obese Zucker rats. Life Sci 76(4):473–478PubMedGoogle Scholar
  15. Bednarek MA, Feighner SD, Pong SS, McKee KK, Hreniuk DL, Silva MV, Warren VA, Howard AD, Van Der Ploeg LH, Heck JV (2000) Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J Med Chem 43(23):4370–4376PubMedGoogle Scholar
  16. Bing C, Ambye L, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, Urhammer SA (2005) Large-scale studies of the Leu72Met polymorphism of the ghrelin gene in relation to the metabolic syndrome and associated quantitative traits. Diabet Med 22(9):1157–1160PubMedGoogle Scholar
  17. Blevins JE, Baskin DG (2010) Hypothalamic-brainstem circuits controlling eating. Forum Nutr 63:133–140PubMedGoogle Scholar
  18. Bloom SR, Kuhajda FP, Laher I, Pi-Sunyer X, Ronnett GV, Tan TM, Weigle DS (2008) The obesity epidemic: pharmacological challenges. Mol Interv 8(2):82–98PubMedGoogle Scholar
  19. Briggs DI, Enriori PJ, Lemus MB, Cowley MA, Andrews ZB (2010) Diet-Induced Obesity Causes Ghrelin Resistance in Arcuate NPY/AgRP Neurons. Endocrinology 151(10):4745–4755PubMedGoogle Scholar
  20. Briggs DI, Lockie SH, Wu Q, Lemus MB, Stark R, Andrews ZB (2013) Calorie-restricted weight loss reverses high-fat diet-induced ghrelin resistance, which contributes to rebound weight gain in a ghrelin-dependent manner. Endocrinology 154(2):709–717PubMedGoogle Scholar
  21. Camina JP (2006) Cell biology of the ghrelin receptor. J Neuroendocrinol 18(1):65–76PubMedGoogle Scholar
  22. Caminos JE, Gualillo O, Lago F, Otero M, Blanco M, Gallego R, Garcia-Caballero T, Goldring MB, Casanueva FF, Gomez-Reino JJ, Dieguez C (2005) The endogenous growth hormone secretagogue (ghrelin) is synthesized and secreted by chondrocytes. Endocrinology 146(3):1285–1292PubMedGoogle Scholar
  23. Casanueva FF, Camina JP, Carreira MC, Pazos Y, Varga JL, Schally AV (2008) Growth hormone-releasing hormone as an agonist of the ghrelin receptor GHS-R1a. Proc Natl Acad Sci USA 105(51):20452–20457PubMedCentralPubMedGoogle Scholar
  24. Castaneda TR, Tong J, Datta R, Culler M, Tschop MH (2010) Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol 31(1):44–60PubMedGoogle Scholar
  25. Center_for_Disease_Control (2013) “http://www.cdc.gov/obesity/data/databases.html
  26. Chakrabarti R (2009) Pharmacotherapy of obesity: emerging drugs and targets. Expert Opin Ther Targets 13(2):195–207PubMedGoogle Scholar
  27. Chan CB, Cheng CH (2004) Identification and functional characterization of two alternatively spliced growth hormone secretagogue receptor transcripts from the pituitary of black seabream Acanthopagrus schlegeli. Mol Cell Endocrinol 214(1–2):81–95PubMedGoogle Scholar
  28. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, Shen Z, Marsh DJ, Feighner SD, Guan XM, Ye Z, Nargund RP, Smith RG, Ploeg LH Van der, Howard AD, MacNeil DJ, Qian S (2004) Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology 145(6): 2607–2612Google Scholar
  29. Cheng AY, Leiter LA (2006) Metabolic syndrome under fire: weighing in on the truth. Can J Cardiol 22(5):379–382PubMedCentralPubMedGoogle Scholar
  30. Chollet C, Meyer K, Beck-Sickinger AG (2009) Ghrelin–a novel generation of anti-obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues. J Pept Sci 15(11):711–730PubMedGoogle Scholar
  31. Chuang JC, Zigman JM (2010) Ghrelin’s roles in stress, mood, and anxiety regulation. Int J Pept Google Scholar
  32. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV (1997) Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 337(9):581–588PubMedGoogle Scholar
  33. Costantino L (2012) Growth hormone secretagogue receptor antagonists. Expert Opin Ther Pat 22(6):697–700PubMedGoogle Scholar
  34. Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37(4):649–661PubMedGoogle Scholar
  35. Cummings DE, Shannon MH (2003) Roles for ghrelin in the regulation of appetite and body weight. Arch Surg 138(4):389–396PubMedGoogle Scholar
  36. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (2001) A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50(8):1714–1719PubMedGoogle Scholar
  37. Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS (2002a) Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 8(7):643–644PubMedGoogle Scholar
  38. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (2002b) Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 346(21):1623–1630PubMedGoogle Scholar
  39. Currie PJ, Mirza A, Fuld R, Park D, Vasselli JR (2005) Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular nuclei. Am J Physiol Regul Integr Comp Physiol 289(2):R353–R358PubMedGoogle Scholar
  40. Date Y, Kojima M, Hosoda H, Sawaguchi A, Mondal MS, Suganuma T, Matsukura S, Kangawa K, Nakazato M (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141(11):4255–4261PubMedGoogle Scholar
  41. DelParigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, Sell SM, Bunt JC, Tataranni PA (2002) High circulating ghrelin: a potential cause for hyperphagia and obesity in prader-willi syndrome. J Clin Endocrinol Metab 87(12):5461–5464PubMedGoogle Scholar
  42. Delporte C (2012) Recent advances in potential clinical application of ghrelin in obesity. J Obes 2012:535624PubMedCentralPubMedGoogle Scholar
  43. Demange L, Boeglin D, Moulin A, Mousseaux D, Ryan J, Berge G, Gagne D, Heitz A, Perrissoud D, Locatelli V, Torsello A, Galleyrand JC, Fehrentz JA, Martinez J (2007) Synthesis and pharmacological in vitro and in vivo evaluations of novel triazole derivatives as ligands of the ghrelin receptor. 1. J Med Chem 50(8):1939–1957PubMedGoogle Scholar
  44. Depoortere I (2009) Targeting the ghrelin receptor to regulate food intake. Regul Pept 156(1–3):13–23PubMedGoogle Scholar
  45. Derosa G, Maffioli P (2012) Anti-obesity drugs: a review about their effects and their safety. Expert Opin Drug Saf 11(3):459–471PubMedGoogle Scholar
  46. Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (2011) The role of the central ghrelin system in reward from food and chemical drugs. Mol Cell Endocrinol 340(1):80–87PubMedGoogle Scholar
  47. Disse E, Bussier AL, Veyrat-Durebex C, Deblon N, Pfluger PT, Tschop MH, Laville M, Rohner-Jeanrenaud F (2010) Peripheral ghrelin enhances sweet taste food consumption and preference, regardless of its caloric content. Physiol Behav 101(2):277–281PubMedGoogle Scholar
  48. Disse E, Bussier AL, Deblon N, Pfluger PT, Tschop MH, Laville M, Rohner-Jeanrenaud F (2011) Systemic ghrelin and reward: effect of cholinergic blockade. Physiol Behav 102(5):481–484PubMedGoogle Scholar
  49. Dostalova I, Haluzik M (2009) The role of ghrelin in the regulation of food intake in patients with obesity and anorexia nervosa. Physiol Res 58(2):159–170PubMedGoogle Scholar
  50. Douglas A, Douglas JG, Robertson CE, Munro JF (1983) Plasma phentermine levels, weight loss and side-effects. Int J Obes 7(6):591–595PubMedGoogle Scholar
  51. Druce MR, Wren AM, Park AJ, Milton JE, Patterson M, Frost G, Ghatei MA, Small C, Bloom SR (2005) Ghrelin increases food intake in obese as well as lean subjects. Int J Obes (Lond) 29(9):1130–1136Google Scholar
  52. Egecioglu E, Jerlhag E, Salome N, Skibicka KP, Haage D, Bohlooly YM, Andersson D, Bjursell M, Perrissoud D, Engel JA, Dickson SL (2010) Ghrelin increases intake of rewarding food in rodents. Addict Biol 15(3):304–311PubMedCentralPubMedGoogle Scholar
  53. Egecioglu E, Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA, Jerlhag E, Engel JA, Dickson SL (2011) Hedonic and incentive signals for body weight control. Rev Endocr Metab Disord 12(3):141–151PubMedCentralPubMedGoogle Scholar
  54. Eknoyan G (2008) Adolphe Quetelet (1796-1874)–the average man and indices of obesity. Nephrol Dial Transplant 23(1):47–51PubMedGoogle Scholar
  55. Esler WP, Rudolph J, Claus TH, Tang W, Barucci N, Brown SE, Bullock W, Daly M, Decarr L, Li Y, Milardo L, Molstad D, Zhu J, Gardell SJ, Livingston JN, Sweet LJ (2007) Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology 148(11):5175–5185PubMedGoogle Scholar
  56. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Rossi Fanelli F, Schambelan M, Schols A, Schuster M, Thomas D, Wolfe R, Anker SD (2008) Cachexia: a new definition. Clin Nutr 27(6):793–799PubMedGoogle Scholar
  57. Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ (2003) Hyperphagic effects of brainstem ghrelin administration. Diabetes 52(9):2260–2265PubMedGoogle Scholar
  58. Finger BC, Schellekens H, Dinan TG, Cryan JF (2011) Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day. Psychopharmacology 216(3):421–429PubMedGoogle Scholar
  59. Finger BC, Dinan TG, Cryan JF (2012) Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task. Psychopharmacology 220(1):173–181PubMedGoogle Scholar
  60. Flegal KM, Carroll MD, Kit BK, Ogden CL (2012) Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA 307(5):491–497PubMedGoogle Scholar
  61. Funahashi H, Takenoya F, Guan JL, Kageyama H, Yada T, Shioda S (2003) Hypothalamic neuronal networks and feeding-related peptides involved in the regulation of feeding. Anat Sci Int 78(3):123–138PubMedGoogle Scholar
  62. Furness JB, Hunne B, Matsuda N, Yin L, Russo D, Kato I, Fujimiya M, Patterson M, McLeod J, Andrews ZB, Bron R (2011) Investigation of the presence of ghrelin in the central nervous system of the rat and mouse. Neuroscience 193:1–9PubMedGoogle Scholar
  63. George SR, O’Dowd BF, Lee SP (2002) G-protein-coupled receptor oligomerization and its potential for drug discovery. Nat Rev Drug Discov 1(10):808–820PubMedGoogle Scholar
  64. Gibbs J, Young RC, Smith GP (1973) Cholecystokinin elicits satiety in rats with open gastric fistulas. Nature 245(5424):323–325PubMedGoogle Scholar
  65. Gualillo O, Lago F, Dieguez C (2008) Introducing GOAT: a target for obesity and anti-diabetic drugs? Trends Pharmacol Sci 29(8):398–401PubMedGoogle Scholar
  66. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Ploeg LH Van der, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48(1):23–29Google Scholar
  67. Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, Witcher DR, Luo S, Onyia JE, Hale JE (2008) Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci U S A 105(17):6320–6325PubMedCentralPubMedGoogle Scholar
  68. Halford JC, Boyland EJ, Blundell JE, Kirkham TC, Harrold JA (2010) Pharmacological management of appetite expression in obesity. Nat Rev Endocrinol 6(5):255–269PubMedGoogle Scholar
  69. Haqq AM, Grambow SC, Muehlbauer M, Newgard CB, Svetkey LP, Carrel AL, Yanovski JA, Purnell JQ, Freemark M (2008) Ghrelin concentrations in Prader-Willi syndrome (PWS) infants and children: changes during development. Clin Endocrinol (Oxf) 69(6):911–920Google Scholar
  70. Hebert TE, Bouvier M (1998) Structural and functional aspects of G protein-coupled receptor oligomerization. Biochem Cell Biol 76(1):1–11PubMedGoogle Scholar
  71. Hinney A, Hoch A, Geller F, Schafer H, Siegfried W, Goldschmidt H, Remschmidt H, Hebebrand J (2002) Ghrelin gene: identification of missense variants and a frameshift mutation in extremely obese children and adolescents and healthy normal weight students. J Clin Endocrinol Metab 87(6):2716PubMedGoogle Scholar
  72. Hoebel BG (1985) Brain neurotransmitters in food and drug reward. Am J Clin Nutr 42(5 Suppl):1133–1150PubMedGoogle Scholar
  73. Holliday ND, Holst B, Rodionova EA, Schwartz TW, Cox HM (2007) Importance of constitutive activity and arrestin-independent mechanisms for intracellular trafficking of the ghrelin receptor. Mol Endocrinol 21(12):3100–3112PubMedGoogle Scholar
  74. Holst B, Schwartz TW (2004) Constitutive ghrelin receptor activity as a signaling set-point in appetite regulation. Trends Pharmacol Sci 25(3):113–117PubMedGoogle Scholar
  75. Holst B, Cygankiewicz A, Jensen TH, Ankersen M, Schwartz TW (2003) High constitutive signaling of the ghrelin receptor–identification of a potent inverse agonist. Mol Endocrinol 17(11):2201–2210PubMedGoogle Scholar
  76. Holst B, Brandt E, Bach A, Heding A, Schwartz TW (2005) Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling. Mol Endocrinol 19(9):2400–2411PubMedGoogle Scholar
  77. Hosoda H, Kojima M, Matsuo H, Kangawa K (2000) Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 275(29):21995–22000PubMedGoogle Scholar
  78. Hosoda H, Kojima M, Mizushima T, Shimizu S, Kangawa K (2003) Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem 278(1):64–70PubMedGoogle Scholar
  79. Hou Z, Miao Y, Gao L, Pan H, Zhu S (2006) Ghrelin-containing neuron in cerebral cortex and hypothalamus linked with the DVC of brainstem in rat. Regul Pept 134(2–3):126–131PubMedGoogle Scholar
  80. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273(5277):974–977PubMedGoogle Scholar
  81. Inhoff T, Monnikes H, Noetzel S, Stengel A, Goebel M, Dinh QT, Riedl A, Bannert N, Wisser AS, Wiedenmann B, Klapp BF, Tache Y, Kobelt P (2008) Desacyl ghrelin inhibits the orexigenic effect of peripherally injected ghrelin in rats. Peptides 29(12):2159–2168PubMedCentralPubMedGoogle Scholar
  82. Inui A (2004) Ghrelin, obesity and anorexia nervosa. J Pediatr 145(6):862; author reply 862–823Google Scholar
  83. Jeffery PL, Duncan RP, Yeh AH, Jaskolski RA, Hammond DS, Herington AC, Chopin LK (2005) Expression of the ghrelin axis in the mouse: an exon 4-deleted mouse proghrelin variant encodes a novel C terminal peptide. Endocrinology 146(1):432–440PubMedGoogle Scholar
  84. Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA (2007) Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens. Addict Biol 12(1):6–16PubMedGoogle Scholar
  85. Jiang H, Betancourt L, Smith RG (2006) Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol 20(8):1772–1785PubMedGoogle Scholar
  86. Kadowaki T, Yamauchi T, Kubota N (2008) The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett 582(1):74–80PubMedGoogle Scholar
  87. Kageyama H, Kitamura Y, Hosono T, Kintaka Y, Seki M, Takenoya F, Hori Y, Nonaka N, Arata S, Shioda S (2008) Visualization of ghrelin-producing neurons in the hypothalamic arcuate nucleus using ghrelin-EGFP transgenic mice. Regul Pept 145(1–3):116–121PubMedGoogle Scholar
  88. Kageyama K, Akimoto K, Yamagata S, Sugiyama A, Murasawa S, Watanuki Y, Tamasawa N, Suda T (2012) Dexamethasone stimulates the expression of ghrelin and its receptor in rat hypothalamic 4B cells. Regul Pept 174(1–3):12–17PubMedGoogle Scholar
  89. Kang JG, Park CY (2012) Anti-Obesity drugs: a review about their effects and safety. Diabetes Metab J 36(1):13–25PubMedCentralPubMedGoogle Scholar
  90. Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, Mosbacher J, Bischoff S, Kulik A, Shigemoto R, Karschin A, Bettler B (1998) GABA(B)-receptor subtypes assemble into functional heteromeric complexes. Nature 396(6712):683–687PubMedGoogle Scholar
  91. Kaye WH, Wierenga CE, Bailer UF, Simmons AN, Bischoff-Grethe A (2013) Nothing tastes as good as skinny feels: the neurobiology of anorexia nervosa. Trends Neurosci 36(2):110–120PubMedGoogle Scholar
  92. Kent T, McAlpine C, Sabetnia S, Presland J (2007) G-protein-coupled receptor heterodimerization: assay technologies to clinical significance. Curr Opin Drug Discov Devel 10(5):580–589PubMedGoogle Scholar
  93. Kern A, Albarran-Zeckler R, Walsh HE, Smith RG (2012) Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73(2):317–332PubMedCentralPubMedGoogle Scholar
  94. Kineman RD, Gahete MD, Luque RM (2007) Identification of a mouse ghrelin gene transcript that contains intron 2 and is regulated in the pituitary and hypothalamus in response to metabolic stress. J Mol Endocrinol 38(5):511–521PubMedGoogle Scholar
  95. Kohno D, Gao HZ, Muroya S, Kikuyama S, Yada T (2003) Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52(4):948–956PubMedGoogle Scholar
  96. Kojima M, Kangawa K (2002) Ghrelin, an orexigenic signaling molecule from the gastrointestinal tract. Curr Opin Pharmacol 2(6):665–668PubMedGoogle Scholar
  97. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402(6762):656–660PubMedGoogle Scholar
  98. Kojima M, Hosoda H, Kangawa K (2001) Purification and distribution of ghrelin: the natural endogenous ligand for the growth hormone secretagogue receptor. Horm Res 56(Suppl 1):93–97PubMedGoogle Scholar
  99. Kojima M, Hosoda H, Kangawa K (2004) Clinical endocrinology and metabolism. Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach. Best Pract Res Clin Endocrinol Metab 18(4):517–530PubMedGoogle Scholar
  100. Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, Williams LM, Hawley SA, Hardie DG, Grossman AB, Korbonits M (2005) Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem 280(26):25196–25201PubMedGoogle Scholar
  101. Konturek SJ, Konturek JW, Pawlik T, Brzozowski T (2004) Brain-gut axis and its role in the control of food intake. J Physiol Pharmacol 55(1 Pt 2):137–154PubMedGoogle Scholar
  102. Korbonits M, Gueorguiev M, O’Grady E, Lecoeur C, Swan DC, Mein CA, Weill J, Grossman AB, Froguel P (2002) A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J Clin Endocrinol Metab 87(8):4005–4008PubMedGoogle Scholar
  103. Koyama KI, Yasuhara D, Nakahara T, Harada T, Uehara M, Ushikai M, Asakawa A, Inui A (2010) Changes in acyl ghrelin, des-acyl ghrelin, and ratio of acyl ghrelin to total ghrelin with short-term refeeding in female inpatients with restricting-type anorexia nervosa. Horm Metab Res 42(8):595–598PubMedGoogle Scholar
  104. Krsek M, Rosicka M, Papezova H, Krizova J, Kotrlikova E, Haluz’k M, Justova V, Lacinova Z, Jarkovska Z (2003) Plasma ghrelin levels and malnutrition: a comparison of two etiologies. Eat Weight Disord 8(3):207–211PubMedGoogle Scholar
  105. Kurose Y, Iqbal J, Rao A, Murata Y, Hasegawa Y, Terashima Y, Kojima M, Kangawa K, Clarke IJ (2005) Changes in expression of the genes for the leptin receptor and the growth hormone-releasing peptide/ghrelin receptor in the hypothalamic arcuate nucleus with long-term manipulation of adiposity by dietary means. J Neuroendocrinol 17(6):331–340PubMedGoogle Scholar
  106. Larsen LH, Gjesing AP, Sorensen TI, Hamid YH, Echwald SM, Toubro S, Black E, Astrup A, Hansen T, Pedersen O (2005) Mutation analysis of the preproghrelin gene: no association with obesity and type 2 diabetes. Clin Biochem 38(5):420–424PubMedGoogle Scholar
  107. Lawrence CB, Snape AC, Baudoin FM, Luckman SM (2002) Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 143(1):155–162PubMedGoogle Scholar
  108. le Roux CW, Patterson M, Vincent RP, Hunt C, Ghatei MA, Bloom SR (2005) Postprandial plasma ghrelin is suppressed proportional to meal calorie content in normal-weight but not obese subjects. J Clin Endocrinol Metab 90(2):1068–1071PubMedGoogle Scholar
  109. Leite-Moreira AF, Soares JB (2007) Physiological, pathological and potential therapeutic roles of ghrelin. Drug Discov Today 12(7–8):276–288PubMedGoogle Scholar
  110. Leung PK, Chow KB, Lau PN, Chu KM, Chan CB, Cheng CH, Wise H (2007) The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19(5):1011–1022PubMedGoogle Scholar
  111. Liu G, Fortin JP, Beinborn M, Kopin AS (2007) Four missense mutations in the ghrelin receptor result in distinct pharmacological abnormalities. J Pharmacol Exp Ther 322(3):1036–1043PubMedGoogle Scholar
  112. Lu S, Guan JL, Wang QP, Uehara K, Yamada S, Goto N, Date Y, Nakazato M, Kojima M, Kangawa K, Shioda S (2002) Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus. Neurosci Lett 321(3):157–160PubMedGoogle Scholar
  113. Lu SC, Xu J, Chinookoswong N, Liu S, Steavenson S, Gegg C, Brankow D, Lindberg R, Veniant M, Gu W (2009) An acyl-ghrelin-specific neutralizing antibody inhibits the acute ghrelin-mediated orexigenic effects in mice. Mol Pharmacol 75(4):901–907PubMedGoogle Scholar
  114. Luttrell LM (2008) Reviews in molecular biology and biotechnology: transmembrane signaling by G protein-coupled receptors. Mol Biotechnol 39(3):239–264PubMedGoogle Scholar
  115. Lutz TA (2006) Amylinergic control of food intake. Physiol Behav 89(4):465–471PubMedGoogle Scholar
  116. Mager U, Degenhardt T, Pulkkinen L, Kolehmainen M, Tolppanen AM, Lindstrom J, Eriksson JG, Carlberg C, Tuomilehto J, Uusitupa M (2008) Variations in the ghrelin receptor gene associate with obesity and glucose metabolism in individuals with impaired glucose tolerance. PLoS ONE 3(8):e2941PubMedCentralPubMedGoogle Scholar
  117. Marston OJ, Garfield AS, Heisler LK (2011) Role of central serotonin and melanocortin systems in the control of energy balance. Eur J Pharmacol 660(1):70–79PubMedGoogle Scholar
  118. Marzullo P, Verti B, Savia G, Walker GE, Guzzaloni G, Tagliaferri M, Di Blasio A, Liuzzi A (2004) The relationship between active ghrelin levels and human obesity involves alterations in resting energy expenditure. J Clin Endocrinol Metab 89(2):936–939PubMedGoogle Scholar
  119. Matsumoto M, Hosoda H, Kitajima Y, Morozumi N, Minamitake Y, Tanaka S, Matsuo H, Kojima M, Hayashi Y, Kangawa K (2001a) Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun 287(1):142–146PubMedGoogle Scholar
  120. Matsumoto M, Kitajima Y, Iwanami T, Hayashi Y, Tanaka S, Minamitake Y, Hosoda H, Kojima M, Matsuo H, Kangawa K (2001b) Structural similarity of ghrelin derivatives to peptidyl growth hormone secretagogues. Biochem Biophys Res Commun 284(3):655–659PubMedGoogle Scholar
  121. Melis MR, Mascia MS, Succu S, Torsello A, Muller EE, Deghenghi R, Argiolas A (2002) Ghrelin injected into the paraventricular nucleus of the hypothalamus of male rats induces feeding but not penile erection. Neurosci Lett 329(3):339–343PubMedGoogle Scholar
  122. Mikhail N (2009) The metabolic syndrome: insulin resistance. Curr Hypertens Rep 11(2):156–158PubMedGoogle Scholar
  123. Miwa H, Koseki J, Oshima T, Kondo T, Tomita T, Watari J, Matsumoto T, Hattori T, Kubota K, Iizuka S (2010) Rikkunshito, a traditional Japanese medicine, may relieve abdominal symptoms in rats with experimental esophagitis by improving the barrier function of epithelial cells in esophageal mucosa. J Gastroenterol 45(5):478–487PubMedGoogle Scholar
  124. Montoya-Flores D, Mora O, Tamariz E, Gonzalez-Davalos L, Gonzalez-Gallardo A, Antaramian A, Shimada A, Varela-Echavarria A, Romano-Munoz JL (2012) Ghrelin stimulates myogenic differentiation in a mouse muscle satellite cell line and in primary cultures of bovine myoblasts. J Anim Physiol Anim Nutr (Berl) 96(4):725–738Google Scholar
  125. Moreira FA, Crippa JA (2009) The psychiatric side-effects of rimonabant. Rev Bras Psiquiatr 31(2):145–153PubMedGoogle Scholar
  126. Moulin A, Ryan J, Martinez J, Fehrentz JA (2007) Recent developments in ghrelin receptor ligands. ChemMedChem 2(9):1242–1259PubMedGoogle Scholar
  127. Moulin A, Demange L, Ryan J, M’Kadmi C, Galleyrand JC, Martinez J, Fehrentz JA (2008a) Trisubstituted 1, 2, 4-triazoles as ligands for the ghrelin receptor: on the significance of the orientation and substitution at position 3. Bioorg Med Chem Lett 18(1):164–168PubMedGoogle Scholar
  128. Moulin A, Demange L, Ryan J, Mousseaux D, Sanchez P, Berge G, Gagne D, Perrissoud D, Locatelli V, Torsello A, Galleyrand JC, Fehrentz JA, Martinez J (2008b) New trisubstituted 1, 2, 4-triazole derivatives as potent ghrelin receptor antagonists 3. Synthesis and pharmacological in vitro and in vivo evaluations. J Med Chem 51(3):689–693PubMedGoogle Scholar
  129. Muccioli G, Baragli A, Granata R, Papotti M, Ghigo E (2007) Heterogeneity of ghrelin/growth hormone secretagogue receptors. Toward the understanding of the molecular identity of novel ghrelin/GHS receptors. Neuroendocrinology 86(3):147–164PubMedGoogle Scholar
  130. Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, Matsukura S (2001) A role for ghrelin in the central regulation of feeding. Nature 409(6817):194–198PubMedGoogle Scholar
  131. Naleid AM, Grace MK, Cummings DE, Levine AS (2005) Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens. Peptides 26(11):2274–2279PubMedGoogle Scholar
  132. Narayanan NS, Guarnieri DJ, DiLeone RJ (2010) Metabolic hormones, dopamine circuits, and feeding. Front Neuroendocrinol 31(1):104–112PubMedCentralPubMedGoogle Scholar
  133. Nass R, Gaylinn BD, Thorner MO (2011) The ghrelin axis in disease: potential therapeutic indications. Mol Cell Endocrinol 340(1):106–110PubMedCentralPubMedGoogle Scholar
  134. Nathan PJ, O’Neill BV, Napolitano A, Bullmore ET (2011) Neuropsychiatric adverse effects of centrally acting antiobesity drugs. CNS Neurosci Ther 17(5):490–505PubMedGoogle Scholar
  135. Nguyen N, Champion JK, Ponce J, Quebbemann B, Patterson E, Pham B, Raum W, Buchwald JN, Segato G, Favretti F (2012) A review of unmet needs in obesity management. Obes Surg 22(6):956–966PubMedGoogle Scholar
  136. Nishi Y, Hiejima H, Hosoda H, Kaiya H, Mori K, Fukue Y, Yanase T, Nawata H, Kangawa K, Kojima M (2005) Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin. Endocrinology 146(5):2255–2264PubMedGoogle Scholar
  137. Ogden CL, Carroll MD, Kit BK, Flegal KM (2012) Prevalence of obesity and trends in body mass index among US children and adolescents, 1999–2010. JAMA 307(5):483–490PubMedGoogle Scholar
  138. Ogiso K, Asakawa A, Amitani H, Inui A (2011) Ghrelin and anorexia nervosa: a psychosomatic perspective. Nutrition 27(10):988–993PubMedGoogle Scholar
  139. Ohgusu H, Shirouzu K, Nakamura Y, Nakashima Y, Ida T, Sato T, Kojima M (2009) Ghrelin O-acyltransferase (GOAT) has a preference for n-hexanoyl-CoA over n-octanoyl-CoA as an acyl donor. Biochem Biophys Res Commun 386(1):153–158PubMedGoogle Scholar
  140. Olszewski PK, Grace MK, Billington CJ, Levine AS (2003a) Hypothalamic paraventricular injections of ghrelin: effect on feeding and c-Fos immunoreactivity. Peptides 24(6):919–923PubMedGoogle Scholar
  141. Olszewski PK, Li D, Grace MK, Billington CJ, Kotz CM, Levine AS (2003b) Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus. Peptides 24(4):597–602PubMedGoogle Scholar
  142. Overduin J, Figlewicz DP, Bennett-Jay J, Kittleson S, Cummings DE (2012) Ghrelin increases the motivation to eat, but does not alter food palatability. Am J Physiol Regul Integr Comp Physiol 303(3):R259–R269PubMedCentralPubMedGoogle Scholar
  143. Pandit R, de Jong JW, Vanderschuren LJ, Adan RA (2011) Neurobiology of overeating and obesity: the role of melanocortins and beyond. Eur J Pharmacol 660(1):28–42PubMedGoogle Scholar
  144. Panetta R, Greenwood MT (2008) Physiological relevance of GPCR oligomerization and its impact on drug discovery. Drug Discov Today 13(23–24):1059–1066PubMedGoogle Scholar
  145. Parylak SL, Koob GF, Zorrilla EP (2011) The dark side of food addiction. Physiol Behav 104(1):149–156PubMedCentralPubMedGoogle Scholar
  146. Patterson M, Murphy KG, le Roux CW, Ghatei MA, Bloom SR (2005) Characterization of ghrelin-like immunoreactivity in human plasma. J Clin Endocrinol Metab 90(4):2205–2211PubMedGoogle Scholar
  147. Patterson M, Bloom SR, Gardiner JV (2011) Ghrelin and appetite control in humans–potential application in the treatment of obesity. Peptides 32(11):2290–2294PubMedGoogle Scholar
  148. Perello M, Zigman JM (2012) The role of ghrelin in reward-based eating. Biol Psychiatry 72(5):347–353PubMedCentralPubMedGoogle Scholar
  149. Perello M, Sakata I, Birnbaum S, Chuang JC, Osborne-Lawrence S, Rovinsky SA, Woloszyn J, Yanagisawa M, Lutter M, Zigman JM (2010) Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol Psychiatry 67(9):880–886PubMedCentralPubMedGoogle Scholar
  150. Perreault M, Istrate N, Wang L, Nichols AJ, Tozzo E, Stricker-Krongrad A (2004) Resistance to the orexigenic effect of ghrelin in dietary-induced obesity in mice: reversal upon weight loss. Int J Obes Relat Metab Disord 28(7):879–885PubMedGoogle Scholar
  151. Pfluger PT, Kirchner H, Gunnel S, Schrott B, Perez-Tilve D, Fu S, Benoit SC, Horvath T, Joost HG, Wortley KE, Sleeman MW, Tschop MH (2008) Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure. Am J Physiol Gastrointest Liver Physiol 294(3):G610–G618PubMedGoogle Scholar
  152. Powell AG, Apovian CM, Aronne LJ (2011) New drug targets for the treatment of obesity. Clin Pharmacol Ther 90(1):40–51PubMedGoogle Scholar
  153. Rediger A, Tarnow P, Bickenbach A, Schaefer M, Krude H, Grüters A, Biebermann H (2009) Heterodimerization of Hypothalamic G-Protein-Coupled receptors involved in weight regulation. Obes Facts 2(2):80–86PubMedGoogle Scholar
  154. Rediger A, Piechowski CL, Yi CX, Tarnow P, Strotmann R, Gruters A, Krude H, Schoneberg T, Tschop MH, Kleinau G, Biebermann H (2011) Mutually opposite signal modulation by hypothalamic heterodimerization of ghrelin and melanocortin-3 receptors. J Biol Chem 286(45):39623–39631PubMedCentralPubMedGoogle Scholar
  155. Richardson NR, Gratton A (1998) Changes in medial prefrontal cortical dopamine levels associated with response-contingent food reward: an electrochemical study in rat. J Neurosci 18(21):9130–9138PubMedGoogle Scholar
  156. Rindi G, Necchi V, Savio A, Torsello A, Zoli M, Locatelli V, Raimondo F, Cocchi D, Solcia E (2002) Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem Cell Biol 117(6):511–519PubMedGoogle Scholar
  157. Rodriguez A, Gomez-Ambrosi J, Catalan V, Gil MJ, Becerril S, Sainz N, Silva C, Salvador J, Colina I, Fruhbeck G (2009) Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes (Lond) 33(5):541–552Google Scholar
  158. Rozenfeld R, Devi LA (2010) Receptor heteromerization and drug discovery. Trends Pharmacol Sci 31(3):124–130PubMedCentralPubMedGoogle Scholar
  159. Rozenfeld R, Devi LA (2011) Exploring a role for heteromerization in GPCR signalling specificity. Biochem J 433(1):11–18PubMedGoogle Scholar
  160. Rudolph J, Esler WP, O’Connor S, Coish PD, Wickens PL, Brands M, Bierer DE, Bloomquist BT, Bondar G, Chen L, Chuang CY, Claus TH, Fathi Z, Fu W, Khire UR, Kristie JA, Liu XG, Lowe DB, McClure AC, Michels M, Ortiz AA, Ramsden PD, Schoenleber RW, Shelekhin TE, Vakalopoulos A, Tang W, Wang L, Yi L, Gardell SJ, Livingston JN, Sweet LJ, Bullock WH (2007) Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem 50(21):5202–5216PubMedGoogle Scholar
  161. Sakata I, Nakamura K, Yamazaki M, Matsubara M, Hayashi Y, Kangawa K, Sakai T (2002) Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides 23(3):531–536PubMedGoogle Scholar
  162. Salim K, Fenton T, Bacha J, Urien-Rodriguez H, Bonnert T, Skynner HA, Watts E, Kerby J, Heald A, Beer M, McAllister G, Guest PC (2002) Oligomerization of G-protein-coupled receptors shown by selective co-immunoprecipitation. J Biol Chem 277(18):15482–15485PubMedGoogle Scholar
  163. Sato T, Fukue Y, Teranishi H, Yoshida Y, Kojima M (2005) Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration. Endocrinology 146(6):2510–2516PubMedGoogle Scholar
  164. Schellekens H, Dinan TG, Cryan JF (2009) Lean mean fat reducing “ghrelin” machine: hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology 58(1):2–16PubMedGoogle Scholar
  165. Schellekens H, Finger BC, Dinan TG, Cryan JF (2012) Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther 135(3):316–326PubMedGoogle Scholar
  166. Schellekens H, Dinan TG, Cryan JF (2013a) Ghrelin at the interface of obesity and reward. Vitam Horm 91:285–323PubMedGoogle Scholar
  167. Schellekens H, Dinan TG, Cryan JF (2013b) Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Frontiers Neurosci 7Google Scholar
  168. Schellekens H, van Oeffelen WE, Dinan TG, Cryan JF (2013c) Promiscuous dimerization of the growth hormone secretagogue receptor (GHS-R1a) attenuates ghrelin-mediated signaling. J Biol Chem 288(1):181–191PubMedCentralPubMedGoogle Scholar
  169. Seim I, Collet C, Herington AC, Chopin LK (2007) Revised genomic structure of the human ghrelin gene and identification of novel exons, alternative splice variants and natural antisense transcripts. BMC Genom 8:298Google Scholar
  170. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S (2002) Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab 87(1):240–244PubMedGoogle Scholar
  171. Shimbara T, Mondal MS, Kawagoe T, Toshinai K, Koda S, Yamaguchi H, Date Y, Nakazato M (2004) Central administration of ghrelin preferentially enhances fat ingestion. Neurosci Lett 369(1):75–79PubMedGoogle Scholar
  172. Shrestha YB, Wickwire K, Giraudo S (2009) Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance. Peptides 30(7):1336–1341PubMedCentralPubMedGoogle Scholar
  173. Shuto Y, Shibasaki T, Otagiri A, Kuriyama H, Ohata H, Tamura H, Kamegai J, Sugihara H, Oikawa S, Wakabayashi I (2002) Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J Clin Invest 109(11):1429–1436PubMedCentralPubMedGoogle Scholar
  174. Simpson K, Martin A, Niamh M, Bloom SR (2008) Hypothalamic regulation of appetite. Expert Rev Endocrinol Metab 3(5):577–592Google Scholar
  175. Simpson KA, Martin NM, Bloom SR (2009) Hypothalamic regulation of food intake and clinical therapeutic applications. Arq Bras Endocrinol Metabol 53(2):120–128PubMedGoogle Scholar
  176. Skibicka KP, Dickson SL (2011) Ghrelin and food reward: the story of potential underlying substrates. Peptides 32(11):2265–2273PubMedGoogle Scholar
  177. Skibicka KP, Hansson C, Egecioglu E, Dickson SL (2012) Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addict Biol 17(1):95–107PubMedCentralPubMedGoogle Scholar
  178. Smith NJ, Milligan G (2010) Allostery at G protein-coupled receptor homo-and heteromers: uncharted pharmacological landscapes. Pharmacol Rev 62(4):701–725PubMedCentralPubMedGoogle Scholar
  179. Soares JB, Leite-Moreira AF (2008) Ghrelin, des-acyl ghrelin and obestatin: three pieces of the same puzzle. Peptides 29(7):1255–1270PubMedGoogle Scholar
  180. Soares JB, Roncon-Albuquerque R Jr, Leite-Moreira A (2008) Ghrelin and ghrelin receptor inhibitors: agents in the treatment of obesity. Expert Opin Ther Targets 12(9):1177–1189PubMedGoogle Scholar
  181. Soriano-Guillen L, Barrios V, Campos-Barros A, Argente J (2004) Ghrelin levels in obesity and anorexia nervosa: effect of weight reduction or recuperation. J Pediatr 144(1):36–42PubMedGoogle Scholar
  182. Stanley S, Wynne K, McGowan B, Bloom S (2005) Hormonal regulation of food intake. Physiol Rev 85(4):1131–1158PubMedGoogle Scholar
  183. Stengel A, Goebel M, Wang L, Tache Y (2010) Ghrelin, des-acyl ghrelin and nesfatin-1 in gastric X/A-like cells: role as regulators of food intake and body weight. Peptides 31(2):357–369PubMedCentralPubMedGoogle Scholar
  184. Stricker-Krongrad A, Richy S, Beck B (2002) Orexins/hypocretins in the ob/ob mouse: hypothalamic gene expression, peptide content and metabolic effects. Regul Pept 104(1–3):11–20PubMedGoogle Scholar
  185. Sun Y, Ahmed S, Smith RG (2003) Deletion of ghrelin impairs neither growth nor appetite. Mol Cell Biol 23(22):7973–7981PubMedCentralPubMedGoogle Scholar
  186. Sun Y, Wang P, Zheng H, Smith RG (2004) Ghrelin stimulation of growth hormone release and appetite is mediated through the growth hormone secretagogue receptor. Proc Natl Acad Sci USA 101(13):4679–4684PubMedCentralPubMedGoogle Scholar
  187. Sun Y, Butte NF, Garcia JM, Smith RG (2008) Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance. Endocrinology 149(2):843–850PubMedCentralPubMedGoogle Scholar
  188. Suzuki K, Simpson KA, Minnion JS, Shillito JC, Bloom SR (2010) The role of gut hormones and the hypothalamus in appetite regulation. Endocr J 57(5):359–372PubMedGoogle Scholar
  189. Swinburn BA, Sacks G, Hall KD, McPherson K, Finegood DT, Moodie ML, Gortmaker SL (2011) The global obesity pandemic: shaped by global drivers and local environments. The Lancet 378(9793):804–814Google Scholar
  190. Tamura H, Kamegai J, Shimizu T, Ishii S, Sugihara H, Oikawa S (2002) Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology 143(9):3268–3275PubMedGoogle Scholar
  191. Tanaka M, Hayashida Y, Nakao N, Nakai N, Nakashima K (2001) Testis-specific and developmentally induced expression of a ghrelin gene-derived transcript that encodes a novel polypeptide in the mouse. Biochim Biophys Acta 1522(1):62–65PubMedGoogle Scholar
  192. Teitler M, Klein MT (2012) A new approach for studying GPCR dimers: drug-induced inactivation and reactivation to reveal GPCR dimer function in vitro, in primary culture, and in vivo. Pharmacol Ther 133(2):205–217PubMedCentralPubMedGoogle Scholar
  193. Terrillon S, Bouvier M (2004) Roles of G-protein-coupled receptor dimerization. EMBO Rep 5(1):30–34PubMedCentralPubMedGoogle Scholar
  194. Tisdale MJ (1997) Biology of cachexia. J Natl Cancer Inst 89(23):1763–1773PubMedGoogle Scholar
  195. Tolle V, Low MJ (2008) In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice. Diabetes 57(1):86–94PubMedGoogle Scholar
  196. Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, Guan JL, Wang QP, Funahashi H, Sakurai T, Shioda S, Matsukura S, Kangawa K, Nakazato M (2003) Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 144(4):1506–1512PubMedGoogle Scholar
  197. Tovar S, Nogueiras R, Tung LY, Castaneda TR, Vazquez MJ, Morris A, Williams LM, Dickson SL, Dieguez C (2005) Central administration of resistin promotes short-term satiety in rats. Eur J Endocrinol 153(3):R1–R5PubMedGoogle Scholar
  198. Tschop M, Wawarta R, Riepl RL, Friedrich S, Bidlingmaier M, Landgraf R, Folwaczny C (2001a) Post-prandial decrease of circulating human ghrelin levels. J Endocrinol Invest 24(6):RC19–RC21Google Scholar
  199. Tschop M, Smiley DL, Heiman ML (2000) Ghrelin induces adiposity in rodents. Nature 407(6806):908–913PubMedGoogle Scholar
  200. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML (2001b) Circulating ghrelin levels are decreased in human obesity. Diabetes 50(4):707–709PubMedGoogle Scholar
  201. Ukkola O, Ravussin E, Jacobson P, Snyder EE, Chagnon M, Sjostrom L, Bouchard C (2001) Mutations in the preproghrelin/ghrelin gene associated with obesity in humans. J Clin Endocrinol Metab 86(8):3996–3999PubMedGoogle Scholar
  202. Venkova K, Greenwood-Van Meerveld B (2008) Application of ghrelin to gastrointestinal diseases. Curr Opin Investig Drugs 9(10):1103–1107PubMedGoogle Scholar
  203. Vivenza D, Rapa A, Castellino N, Bellone S, Petri A, Vacca G, Aimaretti G, Broglio F, Bona G (2004) Ghrelin gene polymorphisms and ghrelin, insulin, IGF-I, leptin and anthropometric data in children and adolescents. Eur J Endocrinol 151(1):127–133PubMedGoogle Scholar
  204. Volkow ND, Wang GJ, Baler RD (2010) Reward, dopamine and the control of food intake: implications for obesity. Trends Cogn Sci 15(1):37–46PubMedCentralPubMedGoogle Scholar
  205. Volkow ND, Wang GJ, Fowler JS, Tomasi D, Baler R, Carter CS, Dalley JW (2012) Food and drug reward: overlapping circuits in human obesity and addiction. Brain imaging in behavioral neuroscience; current topics in behavioral neuroscience, vol 11. Springer, Berlin, pp 1–24Google Scholar
  206. Wise RA (2006) Role of brain dopamine in food reward and reinforcement. Philos Trans R Soc Lond B Biol Sci 361(1471):1149–1158PubMedCentralPubMedGoogle Scholar
  207. Wise RA, Rompre PP (1989) Brain dopamine and reward. Annu Rev Psychol 40:191–225PubMedGoogle Scholar
  208. World_Health_Organisation (2013) http://www.who.int/topics/obesity/en/index.html
  209. Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R, Moncrieffe M, Thabet K, Cox HJ, Yancopoulos GD, Wiegand SJ, Sleeman MW (2004) Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference. Proc Natl Acad Sci USA 101(21):8227–8232PubMedCentralPubMedGoogle Scholar
  210. Wortley KE, del Rincon JP, Murray JD, Garcia K, Iida K, Thorner MO, Sleeman MW (2005) Absence of ghrelin protects against early-onset obesity. J Clin Invest 115(12):3573–3578PubMedCentralPubMedGoogle Scholar
  211. Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR (2001) Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86(12):5992–5995PubMedGoogle Scholar
  212. Xu Y, Elmquist JK, Fukuda M (2011) Central nervous control of energy and glucose balance: focus on the central melanocortin system. Ann N Y Acad Sci 1243:1–14PubMedCentralPubMedGoogle Scholar
  213. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T (2003) Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38(5):701–713PubMedGoogle Scholar
  214. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008a) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132(3):387–396PubMedGoogle Scholar
  215. Yang J, Zhao TJ, Goldstein JL, Brown MS (2008b) Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. Proc Natl Acad Sci U S A 105(31):10750–10755PubMedCentralPubMedGoogle Scholar
  216. Yi CX, Heppner K, Tschop MH (2011) Ghrelin in eating disorders. Mol Cell Endocrinol 340(1):29–34PubMedGoogle Scholar
  217. Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J (2004) Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity. Proc Natl Acad Sci USA 101(28):10434–10439PubMedCentralPubMedGoogle Scholar
  218. Yu M, Lizarzaburu M, Beckmann H, Connors R, Dai K, Haller K, Li C, Liang L, Lindstrom M, Ma J, Motani A, Wanska M, Zhang A, Li L, Medina JC (2010) Identification of piperazine-bisamide GHSR antagonists for the treatment of obesity. Bioorg Med Chem Lett 20(5):1758–1762PubMedGoogle Scholar
  219. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372(6505):425–432PubMedGoogle Scholar
  220. Zhi J, Melia AT, Eggers H, Joly R, Patel IH (1995) Review of limited systemic absorption of orlistat, a lipase inhibitor, in healthy human volunteers. J Clin Pharmacol 35(11):1103–1108PubMedGoogle Scholar
  221. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, Jones JE, Deysher AE, Waxman AR, White RD, Williams TD, Lachey JL, Seeley RJ, Lowell BB, Elmquist JK (2005) Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest 115(12):3564–3572PubMedCentralPubMedGoogle Scholar
  222. Zigman JM, Jones JE, Lee CE, Saper CB, Elmquist JK (2006) Expression of ghrelin receptor mRNA in the rat and the mouse brain. J Comp Neurol 494(3):528–548PubMedGoogle Scholar
  223. Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, Meijler MM, Janda KD (2006) Vaccination against weight gain. Proc Natl Acad Sci USA 103(35):13226–13231PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Harriët Schellekens
    • 1
    • 5
  • Timothy G. Dinan
    • 1
    • 2
    • 3
  • John F. Cryan
    • 1
    • 2
    • 4
    Email author
  1. 1.Food for Health IrelandUniversity College CorkCorkIreland
  2. 2.Laboratory of Neurogastroenterology, Alimentary Pharmabiotic CentreUniversity College CorkCorkIreland
  3. 3.Department of PsychiatryUniversity College CorkCorkIreland
  4. 4.Deparment of Anatomy and Neuroscience, Western Gateway BuildingUniversity College CorkCorkIreland
  5. 5.School of PharmacyUniversity College CorkCorkIreland

Personalised recommendations