Reviews in Endocrine and Metabolic Disorders

, Volume 12, Issue 3, pp 173–186 | Cite as

The ghrelin/GOAT/GHS-R system and energy metabolism

  • Chung Thong Lim
  • Blerina Kola
  • Márta Korbonits


Ghrelin is a brain-gut peptide that was discovered through reverse pharmacology and was first isolated from extracts of porcine stomach. Ghrelin binds to growth hormone secretagogue receptor (GHS-R) and is acylated on its serine 3 residue by ghrelin O-acyltransferase (GOAT). Several important biological functions of ghrelin have been identified, which include its growth hormone-releasing and appetite-inducing effects. Ghrelin exerts its central orexigenic effect mainly by acting on the hypothalamic arcuate nucleus via the activation of the GHS-R. Peripherally ghrelin has multiple metabolic effects which include promoting gluconeogenesis and fat deposition. These effects together with the increased food intake lead to an overall body weight gain. AMP-activated protein kinase, which is a key enzyme in energy homeostasis, has been shown to mediate the central and peripheral metabolic effects of ghrelin. The hypothalamic fatty acid pathway, hypothalamic mitochondrial respiration and uncoupling protein 2 have all been shown to act as the downstream targets of AMPK in mediating the orexigenic effects of ghrelin. Abnormal levels of ghrelin are associated with several metabolic conditions such as obesity, type 2 diabetes, Prader-Willi syndrome and anorexia nervosa. The ghrelin/GOAT/GHS-R system is now recognised as a potential target for the development of anti-obesity treatment.


Ghrelin GOAT GHS-R Appetite AMPK Obesity 


Declaration of Interest

The authors have nothing to declare.


  1. 1.
    Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav. 2006;89(1):71–84.PubMedCrossRefGoogle Scholar
  2. 2.
    Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656–60.PubMedCrossRefGoogle Scholar
  3. 3.
    Nakazato M, Murakami N, Date Y, Kojima M, Matsuo H, Kangawa K, et al. A role for ghrelin in the central regulation of feeding. Nature. 2001;409(6817):194–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Soares JB, Roncon-Albuquerque Jr R, Leite-Moreira A. Ghrelin and ghrelin receptor inhibitors: Agents in the treatment of obesity. Expert Opin Ther Targets. 2008;12(9):1177–89.PubMedCrossRefGoogle Scholar
  5. 5.
    Momany FA, Bowers CY, Reynolds GA, Chang D, Hong A, Newlander K. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology. 1981;108(1):31–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Leontiou CA, Franchi G, Korbonits M. Ghrelin in neuroendocrine organs and tumours. Pituitary. 2007;10(3):213–25.PubMedCrossRefGoogle Scholar
  7. 7.
    Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974–7.PubMedCrossRefGoogle Scholar
  8. 8.
    Palyha OC, Feighner SD, Tan CP, McKee KK, Hreniuk DL, Gao YD, et al. Ligand activation domain of human orphan growth hormone (GH) secretagogue receptor (GHS-R) conserved from Pufferfish to humans. Mol Endocrinol. 2000;14(1):160–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Castaneda TR, Tong J, Datta R, Culler M, Tschop MH. Ghrelin in the regulation of body weight and metabolism. Front Neuroendocrinol. 2010;31(1):44–60.PubMedCrossRefGoogle Scholar
  10. 10.
    Chartrel N, Alvear-Perez R, Leprince J, Iturrioz X, Reaux-Le Goazigo A, Audinot V, et al. Comment on “Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin’s effects on food intake”. Science. 2007;315(5813):766. author reply 766.PubMedCrossRefGoogle Scholar
  11. 11.
    Gourcerol G, Coskun T, Craft LS, Mayer JP, Heiman ML, Wang L, et al. Preproghrelin-derived peptide, obestatin, fails to influence food intake in lean or obese rodents. Obes Silver Spring. 2007;15(11):2643–52.CrossRefGoogle Scholar
  12. 12.
    Nogueiras R, Pfluger P, Tovar S, Arnold M, Mitchell S, Morris A, et al. Effects of obestatin on energy balance and growth hormone secretion in rodents. Endocrinology. 2007;148(1):21–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Gnanapavan S, Kola B, Bustin SA, Morris DG, McGee P, Fairclough P, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab. 2002;87(6):2988.PubMedCrossRefGoogle Scholar
  14. 14.
    Korbonits M, Grossman AB. Ghrelin: Update on a novel hormonal system. Eur J Endocrinol. 2004;151 Suppl 1:S67–70.PubMedCrossRefGoogle Scholar
  15. 15.
    Higgins SC, Gueorguiev M, Korbonits M. Ghrelin, the peripheral hunger hormone. Ann Med. 2007;39(2):116–36.PubMedCrossRefGoogle Scholar
  16. 16.
    Kola B, Hubina E, Tucci SA, Kirkham TC, Garcia EA, Mitchell SE, et al. Cannabinoids and ghrelin have both central and peripheral metabolic and cardiac effects via AMP-activated protein kinase. J Biol Chem. 2005;280(26):25196–201.PubMedCrossRefGoogle Scholar
  17. 17.
    Neary NM, Druce MR, Small CJ, Bloom SR. Acylated ghrelin stimulates food intake in the fed and fasted states but desacylated ghrelin has no effect. Gut. 2006;55(1):135.PubMedGoogle Scholar
  18. 18.
    Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132(3):387–96.PubMedCrossRefGoogle Scholar
  19. 19.
    Gualillo O, Lago F, Dieguez C. Introducing GOAT: A target for obesity and anti-diabetic drugs? Trends Pharmacol Sci. 2008;29(8):398–401.PubMedCrossRefGoogle Scholar
  20. 20.
    Gutierrez JA, Solenberg PJ, Perkins DR, Willency JA, Knierman MD, Jin Z, et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA. 2008;105(17):6320–5.PubMedCrossRefGoogle Scholar
  21. 21.
    Lim CT, Kola B, Igreja SC, Grossman AB, Korbonits M. Expression of ghrelin O-acyltransferase (GOAT), the newly-identified ghrelin acylation enzyme, in various human tissues. Endocr Abstr. 2009;19:P123.Google Scholar
  22. 22.
    Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci. 2000;25(3):111–2.PubMedCrossRefGoogle Scholar
  23. 23.
    Kirchner H, Gutierrez JA, Solenberg PJ, Pfluger PT, Czyzyk TA, Willency JA, et al. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med. 2009;15(7):741–5.PubMedCrossRefGoogle Scholar
  24. 24.
    Zhao TJ, Liang G, Li RL, Xie X, Sleeman MW, Murphy AJ, et al. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA. 2010;107(16):7467–72.PubMedCrossRefGoogle Scholar
  25. 25.
    Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res. 1997;48(1):23–9.PubMedCrossRefGoogle Scholar
  26. 26.
    Schellekens H, Dinan TG, Cryan JF. Lean mean fat reducing “ghrelin” machine: Hypothalamic ghrelin and ghrelin receptors as therapeutic targets in obesity. Neuropharmacology. 2010;58(1):2–16.PubMedCrossRefGoogle Scholar
  27. 27.
    Leung PK, Chow KB, Lau PN, Chu KM, Chan CB, Cheng CH, et al. The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal. 2007;19(5):1011–22.PubMedCrossRefGoogle Scholar
  28. 28.
    Chan CB, Cheng CH. Identification and functional characterization of two alternatively spliced growth hormone secretagogue receptor transcripts from the pituitary of black seabream Acanthopagrus schlegeli. Mol Cell Endocrinol. 2004;214(1–2):81–95.PubMedCrossRefGoogle Scholar
  29. 29.
    Leite-Moreira AF, Soares JB. Physiological, pathological and potential therapeutic roles of ghrelin. Drug Discov Today. 2007;12(7–8):276–88.PubMedCrossRefGoogle Scholar
  30. 30.
    van der Lely AJ, Tschop M, Heiman ML, Ghigo E. Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev. 2004;25(3):426–57.PubMedCrossRefGoogle Scholar
  31. 31.
    Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB. Ghrelin-a hormone with multiple functions. Front Neuroendocrinol. 2004;25(1):27–68.PubMedCrossRefGoogle Scholar
  32. 32.
    Lim CT, Kola B, Korbonits M. AMPK as a mediator of hormonal signalling. J Mol Endocrinol. 2010;44(2):87–97.PubMedCrossRefGoogle Scholar
  33. 33.
    Kluge M, Riedl S, Uhr M, Schmidt D, Zhang X, Yassouridis A, et al. Ghrelin affects the hypothalamus-pituitary-thyroid axis in humans by increasing free thyroxine and decreasing TSH in plasma. Eur J Endocrinol. 2010;162(6):1059–65.PubMedCrossRefGoogle Scholar
  34. 34.
    Charoenthongtrakul S, Giuliana D, Longo KA, Govek EK, Nolan A, Gagne S, et al. Enhanced gastrointestinal motility with orally active ghrelin receptor agonists. J Pharmacol Exp Ther. 2009;329(3):1178–86.PubMedCrossRefGoogle Scholar
  35. 35.
    Carlini VP, Martini AC, Schioth HB, Ruiz RD, Fiol de Cuneo M, de Barioglio SR. Decreased memory for novel object recognition in chronically food-restricted mice is reversed by acute ghrelin administration. Neuroscience. 2008;153(4):929–34.PubMedCrossRefGoogle Scholar
  36. 36.
    Kojima M, Hosoda H, Kangawa K. Clinical endocrinology and metabolism. Ghrelin, a novel growth-hormone-releasing and appetite-stimulating peptide from stomach. Best Pract Res Clin Endocrinol Metab. 2004;18(4):517–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(6806):908–13.PubMedCrossRefGoogle Scholar
  38. 38.
    Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50(8):1714–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am J Physiol Endocrinol Metab. 2004;287(2):E297–304.PubMedCrossRefGoogle Scholar
  40. 40.
    Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes. 2001;50(11):2438–43.PubMedCrossRefGoogle Scholar
  41. 41.
    Small CJ, Bloom SR. Gut hormones and the control of appetite. Trends Endocrinol Metab. 2004;15(6):259–63.PubMedCrossRefGoogle Scholar
  42. 42.
    Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, et al. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001;86(12):5992.PubMedCrossRefGoogle Scholar
  43. 43.
    Cummings DE, Shannon MH. Roles for ghrelin in the regulation of appetite and body weight. Arch Surg. 2003;138(4):389–96.PubMedCrossRefGoogle Scholar
  44. 44.
    Venkova K, Greenwood-Van Meerveld B. Application of ghrelin to gastrointestinal diseases. Curr Opin Investig Drugs. 2008;9(10):1103–7.PubMedGoogle Scholar
  45. 45.
    Cowley MA, Smith RG, Diano S, Tschop M, Pronchuk N, Grove KL, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37(4):649–61.PubMedCrossRefGoogle Scholar
  46. 46.
    Mano-Otagiri A, Nemoto T, Sekino A, Yamauchi N, Shuto Y, Sugihara H, et al. Growth hormone-releasing hormone (GHRH) neurons in the arcuate nucleus (Arc) of the hypothalamus are decreased in transgenic rats whose expression of ghrelin receptor is attenuated: Evidence that ghrelin receptor is involved in the up-regulation of GHRH expression in the arc. Endocrinology. 2006;147(9):4093–103.PubMedCrossRefGoogle Scholar
  47. 47.
    Olszewski PK, Grace MK, Billington CJ, Levine AS. Hypothalamic paraventricular injections of ghrelin: Effect on feeding and c-Fos immunoreactivity. Peptides. 2003;24(6):919–23.PubMedCrossRefGoogle Scholar
  48. 48.
    Kohno D, Gao HZ, Muroya S, Kikuyama S, Yada T. 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. 2003;52(4):948–56.PubMedCrossRefGoogle Scholar
  49. 49.
    Andrews ZB, Liu ZW, Walllingford N, Erion DM, Borok E, Friedman JM, et al. UCP2 mediates ghrelin’s action on NPY/AgRP neurons by lowering free radicals. Nature. 2008;454(7206):846–51.PubMedCrossRefGoogle Scholar
  50. 50.
    Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology. 2004;145(6):2607–12.PubMedCrossRefGoogle Scholar
  51. 51.
    Toshinai K, Date Y, Murakami N, Shimada M, Mondal MS, Shimbara T, et al. Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology. 2003;144(4):1506–12.PubMedCrossRefGoogle Scholar
  52. 52.
    Kola B, Farkas I, Christ-Crain M, Wittmann G, Lolli F, Amin F, et al. The orexigenic effect of ghrelin is mediated through central activation of the endogenous cannabinoid system. PLoS ONE. 2008;3(3):e1797.PubMedCrossRefGoogle Scholar
  53. 53.
    Kageyama H, Takenoya F, Shiba K, Shioda S. Neuronal circuits involving ghrelin in the hypothalamus-mediated regulation of feeding. Neuropeptides. 2010;44(2):133–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Hori Y, Kageyama H, Guan JL, Kohno D, Yada T, Takenoya F, et al. Synaptic interaction between ghrelin- and ghrelin-containing neurons in the rat hypothalamus. Regul Pept. 2008;145(1–3):122–7.PubMedCrossRefGoogle Scholar
  55. 55.
    Cowley MA. Hypothalamic melanocortin neurons integrate signals of energy state. Eur J Pharmacol. 2003;480(1–3):3–11.PubMedCrossRefGoogle Scholar
  56. 56.
    Guan JL, Okuda H, Takenoya F, Kintaka Y, Yagi M, Wang L, et al. Synaptic relationships between proopiomelanocortin- and ghrelin-containing neurons in the rat arcuate nucleus. Regul Pept. 2008;145(1–3):128–32.PubMedCrossRefGoogle Scholar
  57. 57.
    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(3):1072–87.PubMedGoogle Scholar
  58. 58.
    Shrestha YB, Wickwire K, Giraudo SQ. Role of AgRP on Ghrelin-induced feeding in the hypothalamic paraventricular nucleus. Regul Pept. 2006;133(1–3):68–73.PubMedCrossRefGoogle Scholar
  59. 59.
    Tschop M, Statnick MA, Suter TM, Heiman ML. GH-releasing peptide-2 increases fat mass in mice lacking NPY: Indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology. 2002;143(2):558–68.PubMedCrossRefGoogle Scholar
  60. 60.
    Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X, et al. Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol. 2002;22(14):5027–35.PubMedCrossRefGoogle Scholar
  61. 61.
    Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005;310(5748):683–5.PubMedCrossRefGoogle Scholar
  62. 62.
    Gropp E, Shanabrough M, Borok E, Xu AW, Janoschek R, Buch T, et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005;8(10):1289–91.PubMedCrossRefGoogle Scholar
  63. 63.
    Ste Marie L, Luquet S, Cole TB, Palmiter RD. Modulation of neuropeptide Y expression in adult mice does not affect feeding. Proc Natl Acad Sci USA. 2005;102(51):18632–7.PubMedCrossRefGoogle Scholar
  64. 64.
    Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, et al. Post-embryonic ablation of AgRP neurons in mice leads to a lean, hypophagic phenotype. FASEB J. 2005;19(12):1680–2.PubMedGoogle Scholar
  65. 65.
    Tolle V, Low MJ. In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice. Diabetes. 2008;57(1):86–94.PubMedCrossRefGoogle Scholar
  66. 66.
    Shaw AM, Irani BG, Moore MC, Haskell-Luevano C, Millard WJ. Ghrelin-induced food intake and growth hormone secretion are altered in melanocortin 3 and 4 receptor knockout mice. Peptides. 2005;26(10):1720–7.PubMedCrossRefGoogle Scholar
  67. 67.
    Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428(6982):569–74.PubMedCrossRefGoogle Scholar
  68. 68.
    Kola B, Boscaro M, Rutter GA, Grossman AB, Korbonits M. Expanding role of AMPK in endocrinology. Trends Endocrinol Metab. 2006;17(5):205–15.PubMedCrossRefGoogle Scholar
  69. 69.
    Hawley SA, Pan DA, Mustard KJ, Ross L, Bain J, Edelman AM, et al. Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005;2(1):9–19.PubMedCrossRefGoogle Scholar
  70. 70.
    Woods A, Dickerson K, Heath R, Hong SP, Momcilovic M, Johnstone SR, et al. Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005;2(1):21–33.PubMedCrossRefGoogle Scholar
  71. 71.
    Suzuki A, Kusakai G, Kishimoto A, Shimojo Y, Ogura T, Lavin MF, et al. IGF-1 phosphorylates AMPK-alpha subunit in ATM-dependent and LKB1-independent manner. Biochem Biophys Res Commun. 2004;324(3):986–92.PubMedCrossRefGoogle Scholar
  72. 72.
    Momcilovic M, Hong SP, Carlson M. Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem. 2006;281(35):25336–43.PubMedCrossRefGoogle Scholar
  73. 73.
    Fu X, Wan S, Lyu YL, Liu LF, Qi H. Etoposide induces ATM-dependent mitochondrial biogenesis through AMPK activation. PLoS ONE. 2008;3(4):e2009.PubMedCrossRefGoogle Scholar
  74. 74.
    Sanders MJ, Grondin PO, Hegarty BD, Snowden MA, Carling D. Investigating the mechanism for AMP activation of the AMP-activated protein kinase cascade. Biochem J. 2007;403(1):139–48.PubMedCrossRefGoogle Scholar
  75. 75.
    Qi J, Gong J, Zhao T, Zhao J, Lam P, Ye J, et al. Downregulation of AMP-activated protein kinase by Cidea-mediated ubiquitination and degradation in brown adipose tissue. EMBO J. 2008;27(11):1537–48.PubMedCrossRefGoogle Scholar
  76. 76.
    Costanzo-Garvey DL, Pfluger PT, Dougherty MK, Stock JL, Boehm M, Chaika O, et al. KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity. Cell Metab. 2009;10(5):366–78.PubMedCrossRefGoogle Scholar
  77. 77.
    Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6(1):55–68.PubMedCrossRefGoogle Scholar
  78. 78.
    Kola B, Christ-Crain M, Lolli F, Arnaldi G, Giacchetti G, Boscaro M, et al. Changes in adenosine 5′-monophosphate-activated protein kinase as a mechanism of visceral obesity in Cushing’s syndrome. J Clin Endocrinol Metab. 2008;93(12):4969–73.PubMedCrossRefGoogle Scholar
  79. 79.
    Christ-Crain M, Kola B, Lolli F, Fekete C, Seboek D, Wittmann G, et al. AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: A novel mechanism in Cushing’s syndrome. FASEB J. 2008;22(6):1672–83.PubMedCrossRefGoogle Scholar
  80. 80.
    Kola B, Korbonits M. Shedding light on the intricate puzzle of ghrelin’s effects on appetite regulation. J Endocrinol. 2009;202(2):191–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Lopez M, Lage R, Saha AK, Perez-Tilve D, Vazquez MJ, Varela L, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 2008;7(5):389–99.PubMedCrossRefGoogle Scholar
  82. 82.
    Kohno D, Sone H, Minokoshi Y, Yada T. Ghrelin raises [Ca2+]i via AMPK in hypothalamic arcuate nucleus NPY neurons. Biochem Biophys Res Commun. 2008;366(2):388–92.PubMedCrossRefGoogle Scholar
  83. 83.
    Anderson KA, Ribar TJ, Lin F, Noeldner PK, Green MF, Muehlbauer MJ, et al. Hypothalamic CaMKK2 contributes to the regulation of energy balance. Cell Metab. 2008;7(5):377–88.PubMedCrossRefGoogle Scholar
  84. 84.
    Sleeman MW, Latres E. The CAMplexities of central ghrelin. Cell Metab. 2008;7(5):361–2.PubMedCrossRefGoogle Scholar
  85. 85.
    He W, Lam TK, Obici S, Rossetti L. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci. 2006;9(2):227–33.PubMedCrossRefGoogle Scholar
  86. 86.
    Obici S, Feng Z, Arduini A, Conti R, Rossetti L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat Med. 2003;9(6):756–61.PubMedCrossRefGoogle Scholar
  87. 87.
    Pocai A, Lam TK, Obici S, Gutierrez-Juarez R, Muse ED, Arduini A, et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J Clin Invest. 2006;116(4):1081–91.PubMedCrossRefGoogle Scholar
  88. 88.
    Sangiao-Alvarellos S, Varela L, Vazquez MJ, Boit KD, Saha AK, Cordido F, Dieguez C, Lopez M. Influence of ghrelin and GH deficiency on AMPK and hypothalamic lipid metabolism. J Neuroendocrinol 2010.Google Scholar
  89. 89.
    Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr Rev. 2006;27(1):73–100.PubMedCrossRefGoogle Scholar
  90. 90.
    Kirkham TC, Tucci SA. Endocannabinoids in appetite control and the treatment of obesity. CNS Neurol Disord Drug Targets. 2006;5(3):272–92.PubMedCrossRefGoogle Scholar
  91. 91.
    Di Marzo V, Goparaju SK, Wang L, Liu J, Batkai S, Jarai Z, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410(6830):822–5.PubMedCrossRefGoogle Scholar
  92. 92.
    Zbucki RL, Sawicki B, Hryniewicz A, Winnicka MM. Cannabinoids enhance gastric X/A-like cells activity. Folia Histochem Cytobiol. 2008;46(2):219–24.PubMedCrossRefGoogle Scholar
  93. 93.
    Rigault C, Le Borgne F, Georges B, Demarquoy J. Ghrelin reduces hepatic mitochondrial fatty acid beta oxidation. J Endocrinol Investig. 2007;30(4):RC4–8.Google Scholar
  94. 94.
    Sangiao-Alvarellos S, Vazquez MJ, Varela L, Nogueiras R, Saha AK, Cordido F, et al. Central ghrelin regulates peripheral lipid metabolism in a growth hormone-independent fashion. Endocrinology. 2009;150(10):4562–74.PubMedCrossRefGoogle Scholar
  95. 95.
    Rodriguez A, Gomez-Ambrosi J, Catalan V, Gil MJ, Becerril S, Sainz N, et al. Acylated and desacyl ghrelin stimulate lipid accumulation in human visceral adipocytes. Int J Obes Lond. 2009;33(5):541–52.PubMedCrossRefGoogle Scholar
  96. 96.
    Theander-Carrillo C, Wiedmer P, Cettour-Rose P, Nogueiras R, Perez-Tilve D, Pfluger P, et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Invest. 2006;116(7):1983–93.PubMedCrossRefGoogle Scholar
  97. 97.
    Baran K, Preston E, Wilks D, Cooney GJ, Kraegen EW, Sainsbury A. Chronic central melanocortin-4 receptor antagonism and central neuropeptide-Y infusion in rats produce increased adiposity by divergent pathways. Diabetes. 2002;51(1):152–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Lage R, Vazquez MJ, Varela L, Saha AK, Vidal-Puig A, Nogueiras R, et al. Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender. FASEB J. 2010;24(8):2670–9.PubMedCrossRefGoogle Scholar
  99. 99.
    Tsubone T, Masaki T, Katsuragi I, Tanaka K, Kakuma T, Yoshimatsu H. Ghrelin regulates adiposity in white adipose tissue and UCP1 mRNA expression in brown adipose tissue in mice. Regul Pept. 2005;130(1–2):97–103.PubMedCrossRefGoogle Scholar
  100. 100.
    Barazzoni R, Bosutti A, Stebel M, Cattin MR, Roder E, Visintin L, et al. Ghrelin regulates mitochondrial-lipid metabolism gene expression and tissue fat distribution in liver and skeletal muscle. Am J Physiol Endocrinol Metab. 2005;288(1):E228–35.PubMedCrossRefGoogle Scholar
  101. 101.
    Sun Y, Asnicar M, Saha PK, Chan L, Smith RG. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab. 2006;3(5):379–86.PubMedCrossRefGoogle Scholar
  102. 102.
    Andrews ZB, Erion DM, Beiler R, Choi CS, Shulman GI, Horvath TL. Uncoupling protein-2 decreases the lipogenic actions of ghrelin. Endocrinology. 2010;151(5):2078–86.PubMedCrossRefGoogle Scholar
  103. 103.
    Mano-Otagiri A, Iwasaki-Sekino A, Nemoto T, Ohata H, Shuto Y, Nakabayashi H, et al. Genetic suppression of ghrelin receptors activates brown adipocyte function and decreases fat storage in rats. Regul Pept. 2010;160(1–3):81–90.PubMedCrossRefGoogle Scholar
  104. 104.
    Krsek M, Rosicka M, Papezova H, Krizova J, Kotrlikova E, Haluz’k M, et al. Plasma ghrelin levels and malnutrition: A comparison of two etiologies. Eat Weight Disord. 2003;8(3):207–11.PubMedGoogle Scholar
  105. 105.
    Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med. 2002;8(7):643–4.PubMedCrossRefGoogle Scholar
  106. 106.
    Bizzarri C, Rigamonti AE, Luce A, Cappa M, Cella SG, Berini J, et al. Children with Prader-Willi syndrome exhibit more evident meal-induced responses in plasma ghrelin and peptide YY levels than obese and lean children. Eur J Endocrinol. 2010;162(3):499–505.PubMedCrossRefGoogle Scholar
  107. 107.
    Goldstone AP, Patterson M, Kalingag N, Ghatei MA, Brynes AE, Bloom SR, et al. Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma. J Clin Endocrinol Metab. 2005;90(5):2681–90.PubMedCrossRefGoogle Scholar
  108. 108.
    Nicholls RD, Knepper JL. Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu Rev Genomics Hum Genet. 2001;2:153–75.PubMedCrossRefGoogle Scholar
  109. 109.
    DelParigi A, Tschop M, Heiman ML, Salbe AD, Vozarova B, Sell SM, et al. High circulating ghrelin: A potential cause for hyperphagia and obesity in prader-willi syndrome. J Clin Endocrinol Metab. 2002;87(12):5461–4.PubMedCrossRefGoogle Scholar
  110. 110.
    Gimenez-Palop O, Gimenez-Perez G, Mauricio D, Gonzalez-Clemente JM, Potau N, Berlanga E, et al. A lesser postprandial suppression of plasma ghrelin in Prader-Willi syndrome is associated with low fasting and a blunted postprandial PYY response. Clin Endocrinol Oxf. 2007;66(2):198–204.PubMedCrossRefGoogle Scholar
  111. 111.
    Karczewska-Kupczewska M, Straczkowski M, Adamska A, Nikolajuk A, Otziomek E, Gorska M, et al. Increased suppression of serum ghrelin concentration by hyperinsulinemia in women with anorexia nervosa. Eur J Endocrinol. 2010;162(2):235–9.PubMedCrossRefGoogle Scholar
  112. 112.
    Liu G, Fortin JP, Beinborn M, Kopin AS. Four missense mutations in the ghrelin receptor result in distinct pharmacological abnormalities. J Pharmacol Exp Ther. 2007;322(3):1036–43.PubMedCrossRefGoogle Scholar
  113. 113.
    Ukkola O, Ravussin E, Jacobson P, Snyder EE, Chagnon M, Sjostrom L, et al. Mutations in the preproghrelin/ghrelin gene associated with obesity in humans. J Clin Endocrinol Metab. 2001;86(8):3996–9.PubMedCrossRefGoogle Scholar
  114. 114.
    Garcia EA, King P, Sidhu K, Ohgusu H, Walley A, Lecoeur C, et al. The role of ghrelin and ghrelin-receptor gene variants and promoter activity in type 2 diabetes. Eur J Endocrinol. 2009;161(2):307–15.PubMedCrossRefGoogle Scholar
  115. 115.
    Larsen LH, Gjesing AP, Sorensen TI, Hamid YH, Echwald SM, Toubro S, et al. Mutation analysis of the preproghrelin gene: No association with obesity and type 2 diabetes. Clin Biochem. 2005;38(5):420–4.PubMedCrossRefGoogle Scholar
  116. 116.
    Steinle NI, Pollin TI, O’Connell JR, Mitchell BD, Shuldiner AR. Variants in the ghrelin gene are associated with metabolic syndrome in the Old Order Amish. J Clin Endocrinol Metab. 2005;90(12):6672–7.PubMedCrossRefGoogle Scholar
  117. 117.
    Bing C, Ambye L, Fenger M, Jorgensen T, Borch-Johnsen K, Madsbad S, et al. Large-scale studies of the Leu72Met polymorphism of the ghrelin gene in relation to the metabolic syndrome and associated quantitative traits. Diabet Med. 2005;22(9):1157–60.PubMedCrossRefGoogle Scholar
  118. 118.
    Choi HJ, Cho YM, Moon MK, Choi HH, Shin HD, Jang HC, et al. Polymorphisms in the ghrelin gene are associated with serum high-density lipoprotein cholesterol level and not with type 2 diabetes mellitus in Koreans. J Clin Endocrinol Metab. 2006;91(11):4657–63.PubMedCrossRefGoogle Scholar
  119. 119.
    Kuzuya M, Ando F, Iguchi A, Shimokata H. Preproghrelin Leu72Met variant contributes to overweight in middle-aged men of a Japanese large cohort. Int J Obes Lond. 2006;30(11):1609–14.PubMedCrossRefGoogle Scholar
  120. 120.
    Kim SY, Jo DS, Hwang PH, Park JH, Park SK, Yi HK, et al. Preproghrelin Leu72Met polymorphism is not associated with type 2 diabetes mellitus. Metabolism. 2006;55(3):366–70.PubMedCrossRefGoogle Scholar
  121. 121.
    Korbonits M, Gueorguiev M, O’Grady E, Lecoeur C, Swan DC, Mein CA, et al. A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J Clin Endocrinol Metab. 2002;87(8):4005–8.PubMedCrossRefGoogle Scholar
  122. 122.
    Poykko S, Ukkola O, Kauma H, Savolainen MJ, Kesaniemi YA. Ghrelin Arg51Gln mutation is a risk factor for Type 2 diabetes and hypertension in a random sample of middle-aged subjects. Diabetologia. 2003;46(4):455–8.PubMedGoogle Scholar
  123. 123.
    Zavarella S, Petrone A, Zampetti S, Gueorguiev M, Spoletini M, Mein CA, et al. A new variation in the promoter region, the −604 C>T, and the Leu72Met polymorphism of the ghrelin gene are associated with protection to insulin resistance. Int J Obes Lond. 2008;32(4):663–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Berthold HK, Giannakidou E, Krone W, Mantzoros CS, Gouni-Berthold I. The Leu72Met polymorphism of the ghrelin gene is associated with a decreased risk for type 2 diabetes. Clin Chim Acta. 2009;399(1–2):112–6.PubMedCrossRefGoogle Scholar
  125. 125.
    Garcia EA, Heude B, Petry CJ, Gueorguiev M, Hassan-Smith ZK, Spanou A, et al. Ghrelin receptor gene polymorphisms and body size in children and adults. J Clin Endocrinol Metab. 2008;93(10):4158–61.PubMedCrossRefGoogle Scholar
  126. 126.
    Gueorguiev M, Lecoeur C, Benzinou M, Mein CA, Meyre D, Vatin V, et al. A genetic study of the ghrelin and growth hormone secretagogue receptor (GHSR) genes and stature. Ann Hum Genet. 2009;73(1):1–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Gueorguiev M, Lecoeur C, Meyre D, Benzinou M, Mein CA, Hinney A, et al. Association studies on ghrelin and ghrelin receptor gene polymorphisms with obesity. Obes Silver Spring. 2009;17(4):745–54.CrossRefGoogle Scholar
  128. 128.
    Fobi MA. Surgical treatment of obesity: A review. J Natl Med Assoc. 2004;96(1):61–75.PubMedGoogle Scholar
  129. 129.
    Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–30.PubMedCrossRefGoogle Scholar
  130. 130.
    Thaler JP, Cummings DE. Minireview: Hormonal and metabolic mechanisms of diabetes remission after gastrointestinal surgery. Endocrinology. 2009;150(6):2518–25.PubMedCrossRefGoogle Scholar
  131. 131.
    Williams DL, Grill HJ, Cummings DE, Kaplan JM. Vagotomy dissociates short- and long-term controls of circulating ghrelin. Endocrinology. 2003;144(12):5184–7.PubMedCrossRefGoogle Scholar
  132. 132.
    Zorrilla EP, Iwasaki S, Moss JA, Chang J, Otsuji J, Inoue K, et al. Vaccination against weight gain. Proc Natl Acad Sci USA. 2006;103(35):13226–31.PubMedCrossRefGoogle Scholar
  133. 133.
    Perez-Tilve D, Gonzalez-Matias L, Alvarez-Crespo M, Leiras R, Tovar S, Dieguez C, et al. Exendin-4 potently decreases ghrelin levels in fasting rats. Diabetes. 2007;56(1):143–51.PubMedCrossRefGoogle Scholar
  134. 134.
    Ariyasu H, Takaya K, Iwakura H, Hosoda H, Akamizu T, Arai Y, et al. Transgenic mice overexpressing des-acyl ghrelin show small phenotype. Endocrinology. 2005;146(1):355–64.PubMedCrossRefGoogle Scholar
  135. 135.
    Iwakura H, Hosoda K, Son C, Fujikura J, Tomita T, Noguchi M, et al. Analysis of rat insulin II promoter-ghrelin transgenic mice and rat glucagon promoter-ghrelin transgenic mice. J Biol Chem. 2005;280(15):15247–56.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Chung Thong Lim
    • 1
  • Blerina Kola
    • 1
  • Márta Korbonits
    • 1
  1. 1.Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and DentistryQueen Mary University of LondonLondonUK

Personalised recommendations