Advertisement

Leptin and Des-acyl Ghrelin: Their Role in Physiological Body Weight Regulation and in the Pathological State

  • Simona Perboni
  • Giovanni Mantovani
  • Akio Inui

Abstract

Obesity, eating disorders and cachexia endanger the lives of millions of people worldwide. Fortunately, during the past decade, there has been a rapid and substantial progress toward uncovering the molecular and neural mechanisms by which energy imbalance develops. Central to this research has been the identification and characterisation of certain peripheral metabolic signals, such as leptin and ghrelin, which serve as fundamental indices of energy sufficiency [1].

Keywords

Arcuate Nucleus Acyl Ghrelin Growth Hormone Secretagogue Receptor POMC Neuron Orexin Neuron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Zigman JM, Elmquist JK (2003) Minireview: from anorexia to obesity—the yin and yang of body weight control. Endocrinology 144:3749–3756PubMedCrossRefGoogle Scholar
  2. 2.
    Asakawa A, Inui A, Kaga T et al (2003) Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 52:947–952PubMedCrossRefGoogle Scholar
  3. 3.
    Kojima M, Hosoda H, Date Y et al (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402:656–660PubMedCrossRefGoogle Scholar
  4. 4.
    Mondai MS, Date Y, Yamaguchi H et al (2005) Identification of ghrelin and its receptor in neurons of the rat arcuate nucleus. Regul Pept 126:55–59CrossRefGoogle Scholar
  5. 5.
    Date Y, Kojima M, Hosoda H et al (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 141:4255–4266PubMedCrossRefGoogle Scholar
  6. 6.
    Sato T, Fukue Y, Teranishi H et al (2005) Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-D-glucose administration. Endocrinology 146:2510–2516PubMedCrossRefGoogle Scholar
  7. 7.
    Beaumont NJ, Skinner VO, Tan TM et al (2003) Ghrelin can bind to a species of high density lipoprotein associated with paraoxonase. J Biol Chem 278:8877–8880PubMedCrossRefGoogle Scholar
  8. 8.
    Nishi Y, Hiejima H, Hosoda H et al (2005) Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin. Endocrinology 146:2255–2264PubMedCrossRefGoogle Scholar
  9. 9.
    Ariyasu H, Takaya K, Hosoda H et al (2002) Delayed short-term secretory regulation of ghrelin in obese animals: evidenced by a specific RIA for the active form of ghrelin. Endocrinology 143:3341–3350PubMedCrossRefGoogle Scholar
  10. 10.
    Patterson M, Murphy KG, le Roux CW et al (2005) Characterization of ghrelin-like immunoreactivity in human plasma. J Clin Endocrinol Metab 90:2205–2211PubMedCrossRefGoogle Scholar
  11. 11.
    Chen CY, Chao Y, Chang FY et al (2005) Intracisternal des-acyl ghrelin inhibits food intake and non-nutrient gastric emptying in conscious rats. Int J Mol Med 16:695–699PubMedGoogle Scholar
  12. 12.
    Toshinai K, Yamaguchi H, Sun Y et al (2006) Desacyl ghrelin induced food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology (in press)Google Scholar
  13. 13.
    Hosoda H, Kojima M, Matsuo H et al (2000) Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 281:1220–1225Google Scholar
  14. 14.
    Inui A (2001) Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci 2:1–11CrossRefGoogle Scholar
  15. 15.
    Matsumoto M, Hosoda H, Kitajima Y et al (2001) Structure-activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Com un 287:142–146CrossRefGoogle Scholar
  16. 16.
    Broglio F, Gottero C, Prodam F et al (2004) Non-acylated ghrelin counteracts the metabolic but not neuroendocrine response to acylated ghrelin in humans. J Endocrinol Invest 89:3062–3065CrossRefGoogle Scholar
  17. 17.
    Akamizu T, Shimomiya T, Irako T et al (2005) Separate measurement of plasma levels of acylated and desacylated ghrelin in healthy subjects using a new direct ELISA assay. J Clin Endocrinol Metab 90:6–9PubMedCrossRefGoogle Scholar
  18. 18.
    Ariyasu H, Takaya K, Iwakura H et al (2005) Transgenic mice overexpressing des-acyl ghrelin show small phenotype. Endocrinology 146:355–364PubMedCrossRefGoogle Scholar
  19. 19.
    Balzani G, Filigheddu N, Cutrupi S et al (2004) Ghrelin and de-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 159:1029–1037Google Scholar
  20. 20.
    Cassoni P, Papotti M, Ghe C et al (2001) Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. Eur J Endocrinol 150:173–184CrossRefGoogle Scholar
  21. 21.
    Cassoni P, Ghe C, Marrocco T et al (2004) Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell line. Eur J Endocrinol 150:173–184PubMedCrossRefGoogle Scholar
  22. 22.
    Muccioli G, Pons N, Ghe C et al (2004) Ghrelin and des-acyl ghrelin both inhibit isoproterenol-induced lipolysis in rat adipocytes via a non-type 1 growth hormone secretagogue receptor. Eur J Pharmacol 498:27–35PubMedCrossRefGoogle Scholar
  23. 23.
    Thompson NM, Gill DAS, Davies R et al (2004) Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1 growth hormone secretagogue receptor. Endocrinology 145:234–242PubMedCrossRefGoogle Scholar
  24. 24.
    Toshinai K, Date Y, Muratami N et al (2003) Ghrelin induced food intake is mediated via the orexin pathway. Endocrinology 144:1506–1512PubMedCrossRefGoogle Scholar
  25. 25.
    Asakawa A, Inui A, Fujimiya M et al (2005) Stomach regulates energy balance via acylated ghrelin and desacyl ghrelin. Gut 54:18–24PubMedCrossRefGoogle Scholar
  26. 26.
    Chen CY, Inui A, Asakawa A et al (2005) Des-acyl ghrelin acts by CRF type 2 receptors to disrupt fasted stomach motility in conscious rats. Gastroenterology 129:8–25PubMedCrossRefGoogle Scholar
  27. 27.
    Banks WA, Tschop M, Robinson SM et al (2002) Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 302:822–827PubMedCrossRefGoogle Scholar
  28. 28.
    Gauna G, Delhanty PJ, Hofland LJ et al (2005) Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes. J Clin Endocrinol Metab 90:1055–1060PubMedCrossRefGoogle Scholar
  29. 29.
    Gauna C, Meyler FM, Janssen MJ et al (2004) Administration of acylated ghrelin reduces insulin sensitivity, whereas the combination of acylated plus unacylated ghrelin strongly improves insulin sensitivity. J Clin Endocrinol Metab 89:5035–5042PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang Y, Proenca R, Maffei M et al (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432PubMedCrossRefGoogle Scholar
  31. 31.
    Machado AP, Costa Rosa LF, Seelaender MC (2004) Adipose tissue in Walker 256 tumour-induced cachexia: possible association between decreased leptin concentration and mononuclear cell infiltration. Cell Tissue Res 318:503–514PubMedCrossRefGoogle Scholar
  32. 32.
    Somasundar P, McFadden DW, Hileman SM et al (2004) Leptin is a growth factor in cancer. J Surg Res 116:337–349PubMedCrossRefGoogle Scholar
  33. 33.
    Bates SH, Stearns WH, Dundon TA et al (2003) STAT3 signaling is required for leptin regulation of energy balance but not reproduction. Nature 421:856–859PubMedCrossRefGoogle Scholar
  34. 34.
    Tartaglia LA, Dembski M, Weng X et al (1995) Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271PubMedCrossRefGoogle Scholar
  35. 35.
    Friedman JM, Halaas JL (1998) Leptin and the regulation of body weight in mammals. Nature 395:763–770PubMedCrossRefGoogle Scholar
  36. 36.
    Inui A (1999) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res 59:4493–4501PubMedGoogle Scholar
  37. 37.
    Banks WA (2004) The many lives of leptin. Peptides 25:331–338PubMedCrossRefGoogle Scholar
  38. 38.
    Figlewicz DP (2003) Adiposity signals and food reward: expanding the CNS roles of insulin and leptin. Am J Physiol Regul Comp Physiol 284:R882–R892Google Scholar
  39. 39.
    Montague CT, Farooqi IS, Whitehead JP et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908PubMedCrossRefGoogle Scholar
  40. 40.
    Neary NM, Small CJ, Bloom SR (2003) Gut and mind. Gut 52:918–921PubMedCrossRefGoogle Scholar
  41. 41.
    Schwartz MW, Woods SC, Seeley RJ et al (2003) Is the energy homeostasis system inherently biased toward weight gain? Diabetes 52:232–238PubMedCrossRefGoogle Scholar
  42. 42.
    Popovic V, Duntas LH (2005) Brain somatic crosstalk: ghrelin, leptin and ultimate challengers of obesity. Nutr Neurosci 8:1–5PubMedCrossRefGoogle Scholar
  43. 43.
    Havel PJ (2000) Role of adipose tissue in bodyweight regulation: mechanisms regulating leptin production and energy balance. Proc Nutr Soc 59:359–371PubMedCrossRefGoogle Scholar
  44. 44.
    Havel PJ, Townsend R, Chaump L et al (1999) Highfat meals reduce 24-h circulating leptin concentrations in women. Diabetes 48:334–341PubMedCrossRefGoogle Scholar
  45. 45.
    Havel PJ (2001) Peripheral signals conveying metabolic information to the brain: short-term and longterm regulation of food intake and energy homeostasis. Exp Biol Med 226:963–977Google Scholar
  46. 46.
    Clegg DJ, Riedy CA, Blake Smith KA et al (2003) Differential sensitivity to central leptin and insulin in male and female rats. Diabetes 52:682–687PubMedCrossRefGoogle Scholar
  47. 47.
    Ukkola O (2004) Peripheral regulation of food intake: new insights. J Endocrinol Invest 27:96–98PubMedGoogle Scholar
  48. 48.
    Saper CB, Chou TC, Elmquist JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36:199–211PubMedCrossRefGoogle Scholar
  49. 49.
    Ueno N, Dube MG, Inui A et al (2004) Leptin modulates orexigenic effects of ghrelin and attenuates adiponectin and insulin levels and selectively the darkphase feeling as revealed by central leptin gene therapy. Endocrinology 145:4176–4184PubMedCrossRefGoogle Scholar
  50. 50.
    Griffen SC, Oostema K, Stanhope KL et al (2006) Administration of Lispro insulin with meals improves glycemic control, increases circulating leptin, and suppresses ghrelin, compared with regular/NPH insulin in female patients with type 1 diabetes. J Clin Endocrinol Metab 91:485–491PubMedCrossRefGoogle Scholar
  51. 51.
    Perez C, Fernandez-Galaz C, Fernandez-Agullo T et al (2004) Leptin impairs insulin signaling in rat adipocytes. Diabetes 53:347–353PubMedCrossRefGoogle Scholar
  52. 52.
    Banks WA, Kastin AJ, Huang W et al (1996) Leptin enters brain by a saturable system independent of insulin. Peptides 17:305–311PubMedCrossRefGoogle Scholar
  53. 53.
    Peters JH, McKay BM, Simasko SM et al (2005) Leptin-induced satiation mediated by abdominal vagal afferents. Am J Physiol Regul Integr Comp Physiol 288:R879–R884PubMedGoogle Scholar
  54. 54.
    Halaas JL, Friedman JM (1997)Leptin and its receptor. J Endocrinol 155:215–216PubMedCrossRefGoogle Scholar
  55. 55.
    Cowley MA, Smart JL, Rubinstein M et al (2001) Leptin activates anorexigenic POMC neurons through a neuronal network in the arcuate nucleus. Nature 411:480–484PubMedCrossRefGoogle Scholar
  56. 56.
    Wolden-Hanson T, Marck BT, Matsumoto AM (2004) Blunted hypothalamic neuropeptide gene expression in response to fasting, but preservation of feeding response to AgRP in aging male Brown Norway rats. Am J Physiol Regul Integr Comp Physiol 287:R138–R146PubMedGoogle Scholar
  57. 57.
    Sahu A (2004) Minireview: a hypothalamic role in energy balance with special emphasis on leptin. Endocrinology 145:2613–2620PubMedCrossRefGoogle Scholar
  58. 58.
    Pinto S, Roseberry AG, Liu H et al (2004) Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science 304:110–115PubMedCrossRefGoogle Scholar
  59. 59.
    Harrold JA (2004) Leptin leads hypothalamic feeding circuits in a new direction. BioEssays 26:1043–1045PubMedCrossRefGoogle Scholar
  60. 60.
    Bouret SG, Draper SJ, Simerly RB (2004) Trophic action of leptin on hypothalamic neurons that regulate feeding. Nature 304:108–110Google Scholar
  61. 61.
    Bouret SG, Simerly RB (2004) Minirevew: leptin and development of hypothalamic feeding circuits. Endocrinology 145:2621–2626PubMedCrossRefGoogle Scholar
  62. 62.
    Petrovich GD, Setlow B, Holland PC et al (2002) Amygdalo-hypothalamic circuit allows learned cues to override satiety and promote eating. J Neurosci 22:8748–8753PubMedGoogle Scholar
  63. 63.
    Han Z, Yan JQ, Luo GG et al (2003) Leptin receptor expression in the basolateral nucleus of amygdala of conditioned taste aversion rats. World J Gastroenterol 9:1034–1037PubMedGoogle Scholar
  64. 64.
    Jequier E (2002) Leptin signaling, adiposity and energy balance. Ann NY Acad Sci 967:378–388Google Scholar
  65. 65.
    McDuffie JR, Riggs PA, Calis KA et al (2004) Effects of exogenous leptin on satiety and satiation in patients with lipo dystrophy and leptin insufficiency. J Clin Endocrinol 89:4258–4263CrossRefGoogle Scholar
  66. 66.
    Morton GJ, Blevins JE, Williams DL et al (2005) Leptin action in the forebrain regulates the hindbrain response to satiety signals. J Clin Invest 115:703–710PubMedCrossRefGoogle Scholar
  67. 67.
    de Graaf C, Bloom WAM, Smeets PAM et al (2004) Biomarkers of satiation and satiety. Am J Clin Nutr 79:946–961PubMedGoogle Scholar
  68. 68.
    Zorrilla EP, Inoue K, Valdez GR et al (2005) Leptin and post-prandial satiety: acute central leptin more potently reduces meal frequency than meal size in the rat. Psychopharmacology 177:324–335PubMedCrossRefGoogle Scholar
  69. 69.
    Blevins JE, Schwartz MW, Baskin DG (2002) Peptide signals regulating food intake and energy homeostasis. Can J Physiol Pharmacol 80:396–406PubMedCrossRefGoogle Scholar
  70. 70.
    Inui A (2000) Transgenic approach to the study of body weight regulation. Pharmacol Rev 52:35–62PubMedGoogle Scholar
  71. 71.
    Scarpace PJ, Nicolson M, Matheny M (1998) UCP2, UCP3 and leptin gene expression: modulation by food restriction and leptin. J Endocrinol 15:349–357CrossRefGoogle Scholar
  72. 72.
    Nagy TM, Gower BA, Shewchuk RM et al (1997) Serum leptin and energy expenditure in children. J Clin Endocrinol Metab 82:4149–4153PubMedCrossRefGoogle Scholar
  73. 73.
    Hukshorn CJ, Saris WH (2004) Leptin and energy expenditure. Curr Opin Clin Nutr Metab Care 7:629–633PubMedCrossRefGoogle Scholar
  74. 74.
    Lahlou N, Issad T, Lebouc Y et al (2002) Mutations in the human leptin and leptin receptor genes as models of serum leptin receptor regulation. Diabetes 51:980–985CrossRefGoogle Scholar
  75. 75.
    Farooqi IS, Keogh JM, Kamath S et al (2001) Partial leptin deficiency and human adiposity. Nature 414:34–35PubMedCrossRefGoogle Scholar
  76. 76.
    Gibson WT, Farooqi IS, Moreau M et al (2004) Congenital leptin deficiency due to homozygosity for the D133G mutation: report of another case and evaluation of response to four years of leptin therapy. J Clin Endocrinol Metab 89:4821–4826PubMedCrossRefGoogle Scholar
  77. 77.
    Licinio J, Caglayan S, Ozata M et al(2004) Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behaviour in leptin-deficient adults. Proc Natl Acad Sci USA 101:4531–4536PubMedCrossRefGoogle Scholar
  78. 78.
    Ahima RS, Osei SY (2004) Leptin signaling. Physiol Behav 81:223–241PubMedCrossRefGoogle Scholar
  79. 79.
    Sarkar S, Legradi G, Lechan RM (2002) Intracerebroventricular administration of a-melanocyte stimulating hormone increases phosphorylation of CREB in TRHand CRH-producing neurons of the hypothalamic paraventricular nucleus. Brain Res 945:50–59PubMedCrossRefGoogle Scholar
  80. 80.
    Moran O, Phillip M (2003) Leptin: obesity, diabetes and other peripheral effects—a review. Pediatr Diabetes 4:101–109PubMedCrossRefGoogle Scholar
  81. 81.
    Banks WA (2003) Is obesity a disease of the bloodbrain barrier? Physiological, pathological and evolutionary considerations. Curr Pharmac Design 9:801–809CrossRefGoogle Scholar
  82. 82.
    Caro JF, Kolaczynski JW, Nyce MR et al (1996) Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348:159–161PubMedCrossRefGoogle Scholar
  83. 83.
    Martin RL, Perez E, He YJ et al (2000) Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation. Metabolism 49:1479–1484PubMedCrossRefGoogle Scholar
  84. 84.
    Mori H, Hanada R, Hanada T et al (2004) Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat Med 10:739–743PubMedCrossRefGoogle Scholar
  85. 85.
    Murphy KG, Bloom SR (2004) Gut hormones in the control of appetite. Exp Physiol 89:507–516PubMedCrossRefGoogle Scholar
  86. 86.
    Inui A (2002) Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J Clin 52:72–91PubMedCrossRefGoogle Scholar
  87. 87.
    Dixit VD, Schaffer EM, Pyle RS et al (2004) Ghrelin inhibits leptinand activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 114:57–66PubMedCrossRefGoogle Scholar
  88. 88.
    Lugarini F, Hrupka BJ, Schwartz GJ et al (2005) Acute and chronic administration of immunomodulators induces anorexia in Zucker rats. Physiol Behav 84:165–173PubMedCrossRefGoogle Scholar
  89. 89.
    Aleman MR, Santolaria F, Batista N et al (2002) Leptin role in advanced lung cancer. A mediator of the acute phase response or a marker of the status of nutrition? Cytokine 19:21–26PubMedCrossRefGoogle Scholar
  90. 90.
    Simons JP, Schols AM, Campfield LA et al (1997) Plasma concentration of total leptin and human lung-cancer-associated cachexia. Clin Sci (Lond) 93:273–277Google Scholar
  91. 91.
    Brown DR, Berkowitz DE, Breslow MJ (2001 ) Weight loss is not associated with hyperleptinemia in humans with pancreatic cancer. J Clin Endocrinol Metab 86:162–166PubMedCrossRefGoogle Scholar
  92. 92.
    Wallace AM, Sattar N, McMillan DC (1998) Effect of weight loss and the inflammatory response on leptin concentrations in gastrointestinal cancer patients. Clin Cancer Res 4:2977–2979PubMedGoogle Scholar
  93. 93.
    Mantovani G, Macciò A, Mura L et al (2000) Serum levels of leptin and proinflammatory cytokines in patients with advanced-stage cancer at different sites. J Mol Med 78:554–561PubMedCrossRefGoogle Scholar
  94. 94.
    Mantovani G, Macciò A, Madeddu C et al (2001) Serum values of proinflammatory cytokines are inversely correlated with serum leptin levels in patients with advanced stage cancer at different sites. J Mol Med 79:406–414PubMedCrossRefGoogle Scholar
  95. 95.
    Bing C, Taylor S, Tisdale MJ et al (2001) Cachexia in MAC 16 adenocarcinoma: suppression of hunger despite normal regulation of leptin, insulin andhypothalamic neuropeptide Y. J Neurochem 79:1004–1012PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2006

Authors and Affiliations

  • Simona Perboni
    • 1
  • Giovanni Mantovani
    • 1
  • Akio Inui
    • 2
  1. 1.Department of Medical OncologyUniversity of CagliariCagliariItaly
  2. 2.Department of Behavioral MedicineKagoshima University Graduate School of Medical and Dental SciencesKagoshimaJapan

Personalised recommendations