Journal of Endocrinological Investigation

, Volume 25, Issue 10, pp 836–854 | Cite as

Neuroendocrine regulation of eating behavior

  • Roberto Vettor
  • R. Fabris
  • C. Pagano
  • G. Federspil
Review Article


The dual center hypothesis in the central control of energy balance originates from the first observations performed more than 5 decades ago with brain lesioning and stimulation experiments. On the basis of these studies the “satiety center” was located in the ventromedial hypothalamic nucleus, since lesions of this region caused overfeeding and excessive weight gain, while its electrical stimulation suppressed eating. On the contrary, lesioning or stimulation of the lateral hypothalamus elicited the opposite set of responses, thus leading to the conclusion that this area represented the “feeding center”. The subsequent expansion of our knowledge of specific neuronal subpopulations involved in energy homeostasis has replaced the notion of specific “centers” controlling energy balance with that of discrete neuronal pathways fully integrated in a more complex neuronal network. The advancement of our knowledge on the anatomical structure and the function of the hypothalamic regions reveals the great complexity of this system. Given the aim of this review, we will focus on the major structures involved in the control of energy balance.

Key words

Hypothalamus neuropeptides food intake obesity appetite control leptin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Baskin D.G., Breininger J.F., Schwartz M.W. Leptin receptor mRNA identifies a subpopulation of neuropeptide Y neurons activated by fasting in rat hypothalamus. Diabetes 1999, 48: 828–833.PubMedGoogle Scholar
  2. 2.
    Cheung C.C., Clifton D.K., Steiner R.A. Proopiomelanocortin neurons are direct targets for leptin in the hypothalamus. Endocrinology 1997, 138: 4489–4492.PubMedGoogle Scholar
  3. 3.
    Cintra A., Bortolotti F. Presence of strong glucocorticoid receptor immunoreactivity within hypothalamic and hypophyseal cells containing pro-opiomelanocortic peptides. Brain. Res. 1992, 577: 127–133.PubMedGoogle Scholar
  4. 4.
    Hisano S., Kagotani Y., Tsuruo Y., Daikoku S., Chihara K., Whitnall M.H. Localization of glucocorticoid receptor in neuropeptide Y-containing neurons in the arcuate nucleus of the rat hypothalamus. Neurosci. Lett. 1988, 95: 13–18.PubMedGoogle Scholar
  5. 5.
    Jirikowski G.F., Merchenthaler I., Rieger G.E., Stumpf W.E. Estradiol target sites immunoreactive for beta-endorphin in the arcuate nucleus of rat and mouse hypothalamus. Neurosci. Lett. 1986, 65: 121–126.PubMedGoogle Scholar
  6. 6.
    Fox S.R., Harlan R.E., Shivers B.D., Pfaff D.W. Chemical characterization of neuroendocrine targets for progesterone in the female rat brain and pituitary. Neuroendocrinology 1990, 51: 276–283.PubMedGoogle Scholar
  7. 7.
    Kamegai J., Minami S., Sugihara H., Hasegawa O., Higuchi H., Wakabayashi I. Growth hormone receptor gene is expressed in neuropeptide Y neurons in hypothalamic arcuate nucleus of rats. Endocrinology 1996, 137: 2109–2112.PubMedGoogle Scholar
  8. 8.
    Broadwell R.D., Brightman M.W. Entry of peroxidase into neurons of the central and peripheral nervous systems from extracerebral and cerebral blood. J. Comp. Neurol. 1976, 166: 257–283.PubMedGoogle Scholar
  9. 9.
    Muroya S., Yada T., Shioda S., Takigawa M. Glucose-sensitive neurons in the rat arcuate nucleus contain neuropeptide Y. Neurosci. Lett. 1999, 264: 113–116.PubMedGoogle Scholar
  10. 10.
    Dunn-Meynell A.A., Routh V.H., McArdle J.J., Levin B.E. Low affinity sulfonylurea binding sites reside on neuronal cell bodies in the brain. Brain. Res. 1997, 745: 1–9.PubMedGoogle Scholar
  11. 11.
    Williams G., Bing C., Cai X.J., Harrold J.A., King P.J., Liu X.H. The hypothalamus and the control of energy homeostasis: different circuits, different purposes. Physiol. Behav. 2001, 74: 683–701.PubMedGoogle Scholar
  12. 12.
    Obici S., Feng Z., Morgan K., Stein D., Karkanias G., Rosseti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 2002, 51: 271–275.PubMedGoogle Scholar
  13. 13.
    Shimokawa T., Kumar M.V., Lane M.D. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl. Acad. Sci. USA 2002, 99: 66–71.PubMedCentralPubMedGoogle Scholar
  14. 14.
    Hahn T.M., Breininger J.F., Baskin D.G., Schwartz M.W. Coexpression of AgRP and NPY in fasting-activated hypothalamic neurons. Nature Neurosci. 1998, 1: 271–272.PubMedGoogle Scholar
  15. 15.
    Broberger C., Johansen J., Johasson C., Schalling M., Hokfelt T. The neuropeptide Y/agouti gene-related protein (AgRP) brain circuitry in normal, anorectic and monosodium glutamate-treated mice. Proc. Natl. Acad. Sci. USA 1998, 95: 15043–15048.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Khachaturian H., Lewis M.E., Haber S.N., Akil H., Watson S.J. Proopiomelanocortin peptide immunocytochemistry in rhesus monkey brain. Brain. Res. Bull. 1984, 13: 785–800.PubMedGoogle Scholar
  17. 17.
    Elias C.F., Lee C., Kelly J. et al. Leptin activates hypothalamic CART neurons projecting to the spinal cord. Neuron 1998, 21: 1375–1385.PubMedGoogle Scholar
  18. 18.
    Tatemoto K. Neuropeptide Y: complete amino acid sequence of the brain peptide. Proc. Natl. Acad. Sci. USA 1982, 79: 5485–5489.PubMedCentralPubMedGoogle Scholar
  19. 19.
    Allen Y.S., Adrian T.E., Allen J.M. et al. Neuropeptide Y distribution in the rat brain. Science 1983, 221: 877–879.PubMedGoogle Scholar
  20. 20.
    Bai F.L., Yamano M., Shiotani Y. et al. An arcuate-paraventricular and -dorsomedial hypothalamic neuropeptide Y-containing system which lacks noradrenaline in the rat. Brain Res. 1985, 331: 172–175.PubMedGoogle Scholar
  21. 21.
    Smith S.M., Lactation alters neuropeptide-Y and proopiomelanocortin gene expression in the arcuate nucleus of the rat. Endocrinology 1993, 133: 1258–1265.PubMedGoogle Scholar
  22. 22.
    Sawchenko P.E., Swanson L.W., Grzanna R., Howe P.R.C., Bloom S.R., Polak J.M. Colocalization of neuropeptide Y immunoreactivity in brainstem catecholaminergic neurons that project to the paraventricular nucleus of the hypothalamus. J. Comp. Neurol. 1985, 241: 138–153.PubMedGoogle Scholar
  23. 23.
    Broberger C., Landry M., Wong H., Walsh J.N., Hokfelt T. Subtypes Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin- and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 1997, 66: 393–408.PubMedGoogle Scholar
  24. 24.
    Schwartz M.W., Sipols A.J., Marks J.L. et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 1992, 130: 3608–3616.PubMedGoogle Scholar
  25. 25.
    Inui A. Neuropeptide Y feeding receptors: are multiple subtypes involved? TIPS 1999, 20: 43–46.PubMedGoogle Scholar
  26. 26.
    Herzog H., Hort Y.J., Ball H.J., Hayes G., Shine J., Selbie L.A. Cloned human neuropeptide Y receptor couples to two different second messenger systems. Proc. Natl. Acad. Sci. USA 1992, 89: 5794–5798.PubMedCentralPubMedGoogle Scholar
  27. 27.
    Larhammar D., Blomqvist A.G., Yee F., Jazin E., Yoo H., Wahlestedt C. Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J. Biol. Chem. 1992, 267: 10935–10938.PubMedGoogle Scholar
  28. 28.
    Grundemar L., Krstenansky J.L., Håkanson R. Activation of neuropeptide Y1 and neuropeptide Y2 receptors by substituted and truncated neuropeptide Y analogs: identification of signal epitopes. Eur. J. Pharmacol. 1993, 232: 271–278.PubMedGoogle Scholar
  29. 29.
    Gehlert D.R., Gackenheimer S., Millington W.R., Manning A.B., Chronwall B.M. Localization of neuropeptide Y immunoreactivity and 125I-PYY binding sites in the human pituitary. Peptides 1994, 15: 651–656.PubMedGoogle Scholar
  30. 30.
    Bard J.A., Walker M.W., Branchek T.A., Weinshank R.L. Cloning and functional-expression of a human Y4 subtype receptor for pancreatic polypeptide, neuropeptide Y, and peptide YY. J. Biol. Chem. 1995, 270: 26762–26765.PubMedGoogle Scholar
  31. 31.
    Gerald C., Walker M.W., Vaysse P.J., He C., Branchek T.A., Weinshank R.L. Expression cloning and pharmacological characterization of a human hippocampal neuropeptide Y/peptide YY Y2, receptor subtype. J. Biol. Chem. 1995, 270: 26758–26761.PubMedGoogle Scholar
  32. 32.
    Gerald C., Walker M.W., Criscione L. et al. A receptor subtype involved in neuropeptide-Y-induced food intake see comments. Nature 1996, 382: 168–171.PubMedGoogle Scholar
  33. 33.
    Leibowitz S.F., Alexander J.T. Analysis of neuropeptide Yinduced feeding: dissociation of Y1 and Y2 receptor effects on natural meal patterns. Peptides 1991, 12: 1251–1260.PubMedGoogle Scholar
  34. 34.
    Stanley B.G., Daniel D.R., Chin A.S., Lebowitz S.F. Paraventricular nucleus injections of peptide YY and neuropeptide Y preferentially enhance carbohydrate ingestion. Peptides 1985, 6: 1205–1211.PubMedGoogle Scholar
  35. 35.
    Cheng X., Broberger C., Tong Y., Yongtao X., Ju G., Zhang X., Hökfelt T. Regulation of expression of neuropeptide Y Y1 and Y2 receptors in the arcuate nucleus of fasted rats. Brain Res. 1998, 792: 89–96.PubMedGoogle Scholar
  36. 36.
    Oomura Y., Ooyama H., Sugimori M., Nakamura T., Yamada Y. Glucose inhibition of the glucose-sensitive neurone in the rat lateral hypothalamus. Nature 1974, 247: 284–286.PubMedGoogle Scholar
  37. 37.
    Spanswick D., Smith M.A., Groppi V.E., Logan S.D., Ashford M.L. Leptin inhibits hypothalamic neurons by activation of ATP-sensitive potassium channels. Nature 1997, 390: 521–525.PubMedGoogle Scholar
  38. 38.
    Schaffhauser A.O., Stricker-Krongrad A., Brunner L. et al. Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 1997, 46: 1792–1798.PubMedGoogle Scholar
  39. 39.
    Hofbauer K.G., Schaffhauser A.O., Batzl-Hartmann C. et al. Antisense oligonucleotides targeted against the NPY Y5 receptor and selective Y5 receptor antagonist inhibit food intake in rodents. Regul. Pept. 1997, 71: 211–212.Google Scholar
  40. 40.
    Schaffhauser A.O., Whitebread S., Haener R., Hofbauer K.G., Stricker-Krongrad A. Neuropeptide Y Y1 receptor antisense oligodeoxynucleotides enhance food intake in energy-deprived rats. Regul. Pept. 1998, 75: 417–423.PubMedGoogle Scholar
  41. 41.
    Widdowson P.S., Upton R., Henderson L., Buckingham R., Wilson S., Williams G. Reciprocal regional changes in brain NPY receptor density during dietary restriction and dietary-induced obesity in the rat. Brain Res. 1997, 774: 1–10.PubMedGoogle Scholar
  42. 42.
    Kanatani A., Fukami T., Fukuroda T. et al. Y5 receptors are not involved in physiologically relevant feeding in rodents. Regul. Pept. 1997, 71: 212–213.Google Scholar
  43. 43.
    Flynn M.C., Turrin N.P., Plata-Salaman C.R., Ffrench-Mullen J.M.H. Feeding responses to neuropeptide Y-related compounds in rats treated with Y5 receptor antisense or sense phosphothio-oligonucleotides. Physiol. Behav. 1999, 66: 881–884.PubMedGoogle Scholar
  44. 44.
    Naveilhan P., Hassani H., Canals J.M. et al. Normal feeding behavior, body weight and leptin response require the neuropeptide Y Y2 receptor. Nat. Med. 1999, 5: 1188–1193.PubMedGoogle Scholar
  45. 45.
    King P.J., Widdowson P.S., Doods H.N., Williams G. Regulation of neuropeptide Y release by neuropeptide Y receptor ligands and calcium channel antagonists in hypothalamic slices. J. Neurochem. 1999, 73: 641–646.PubMedGoogle Scholar
  46. 46.
    Sahu A., Karla S.P. Neuropeptidergic regulation of feeding behavior, neuropeptide Y. Trends Endocrinol. Metabol. 1993, 4: 217–224.Google Scholar
  47. 47.
    Frankish H.M., Dryden S., Hopkins D., Wang Q., Williams G. Neuropeptide Y, the hypothalamus, and diabetes: insights into the central control of metabolism. Peptides 1995, 16: 757–771.PubMedGoogle Scholar
  48. 48.
    Kalra S.P., Dube M.G., Sahu A., Phelps C.P., Kalra P.S. Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc. Natl. Acad. Sci. USA 1991, 88: 10931–10935.PubMedCentralPubMedGoogle Scholar
  49. 49.
    Sahu A., Sninsky C.A., Phelps C.P., Dube M.G., Kalra P.S., Kalra S.P. Neuropeptide Y release from the paraventricular nucleus increases in association with hyperphagia in streptozotocin-induced diabetic rats. Endocrinology 1992, 131: 2979–2985.PubMedGoogle Scholar
  50. 50.
    Kalra S.P., Dube M.G., Fournier A., Kalra P.S. Structurefunction analysis of stimulation of food intake by neuropeptide Y: effects of receptor agonists. Physiol. Behav. 1991, 50: 5–9.PubMedGoogle Scholar
  51. 51.
    Zarjevski N., Cusin I., Vettor R., Rohner-Jeanrenaud F., Jeanrenaud B. Chronic intracerebroventricular neuropeptide- Y administration to normal rats mimics hormonal and metabolic changes of obesity. Endocrinology 1993, 133: 1753–1758PubMedGoogle Scholar
  52. 52.
    Zarjevski N., Cusin I., Vettor R., Rohner-Jeanrenaud F., Jeanrenaud B. Intracerebroventricular administration of neuropeptide Y to normal rats has divergent effects on glucose utilization by adipose tissue and skeletal muscle. Diabetes 1994, 43: 764–769PubMedGoogle Scholar
  53. 53.
    Vettor R., Zarjevski N., Cusin I., Rohner-Jeanrenaud F., Jeanrenaud B. Induction and reversibility of an obesity syndrome by intracerebroventricular neuropeptide Y administration to normal rats. Diabetologia 1994, 37: 1202–1208.PubMedGoogle Scholar
  54. 54.
    Sainsbury A., Cusin I., Doyle P., Rohner-Jeanrenaud F., Jeanrenaud B. Intracerebroventricular administration of neuropeptide Y to normal rats increases obese gene expression in white adipose tissue. Diabetologia 1996, 39: 353–356.PubMedGoogle Scholar
  55. 55.
    Mercer J.G., Hoggard N., Williams L.M. et al. Coexpression of leptin receptor and preproneuropeptide Y mRNA in ARC of mouse hypothalamus. J. Neuroendocrinol. 1996, 8: 733–775.PubMedGoogle Scholar
  56. 56.
    Baskin D.G., Schwartz M.W., Seeley R.J. et al. Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and co-localization with neuropeptide Y mNRA in the arcuate nucleus. J. Histochem. Cytochem. 47: 353–362.Google Scholar
  57. 57.
    Wang Q., Bing C., Al-Barazanji K. et al. Interactions between leptin and hypothalamic neuropeptide Y neurons in the control of food intake and energy homeostasis in the rat. Diabetes 1997, 46: 335–341.PubMedGoogle Scholar
  58. 58.
    Wang J., Leibowitz K.L. Central insulin inhibits hypothalamic galanin an neuropeptide Y gene expression and peptide release in intact rats. Brain Res. 1997, 777: 231–236.PubMedGoogle Scholar
  59. 59.
    Bray G.A., York D.A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol. Rev. 1979, 59: 719–809.PubMedGoogle Scholar
  60. 60.
    Chen H., Charlat O., Tartaglia L.A. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 1996, 84: 491–495.PubMedGoogle Scholar
  61. 61.
    Iida M., Murakami T., Ishida K., Mizuno A., Kuwajima M., Shima K. Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochem. Biophys. Res. Commun. 1996, 222: 19–26.PubMedGoogle Scholar
  62. 62.
    Stanley B.G., Daniel D.R., Chin A.S., Lebowitz S.F. Paraventricular nucleus injections of peptide YY and neuropeptide Y preferentially enhance carbohydrate ingestion. Peptides 1985, 6: 1205–1211.PubMedGoogle Scholar
  63. 63.
    Schwartz M.W., Sipols A.J., Marks J.L. et al. Inhibition of hypothalamic neuropeptide Y gene expression by insulin. Endocrinology 1992, 130: 3608–3616.PubMedGoogle Scholar
  64. 64.
    Hollopeter G., Erickson J.C., Seeley R.J., Marsh D.J., Palmiter R.D. Response of neuropeptide Y-deficient mice to feeding effectors. Regulat. Pept. 1998, 785: 383–389.Google Scholar
  65. 65.
    Marsh D.J., Miura Y., Yagaloff K.A., Schwartz M.W., Barsh G.S., Palmiter R.D. Effects of neuropeptide Y deficiency on hypothalamic agouti-related expression and responsiveness to melanocortin analogues. Brain Res. 1999, 848: 66–77.PubMedGoogle Scholar
  66. 66.
    Tatemoto K., Carlquist M., Mutt V. Neuropeptide Y-a novel brain peptide with structural similarities to peptide YY and pancreatic polypeptide. Nature 1982, 296: 659–660.PubMedGoogle Scholar
  67. 67.
    Pedersen-Bjergaard U., Host U., Kelbaek H. et al. Influence of meal composition on postprandial peripheral plasma concentrations of vasoactive peptides in man. Scand. J. Clin. Lab. Invest. 1996, 56: 497–503.PubMedGoogle Scholar
  68. 68.
    Pieribone V.A., Brodin L., Friberg K. et al. Differential expression of mRNAs for neuropeptide Y-related peptides in rat nervous tissues: possible evolutionary conservation. J. Neurosci. 1992, 12: 3361–3371.PubMedGoogle Scholar
  69. 69.
    Jazin E.E., Zhang X., Soderstrom S. et al. Expression of peptide YY and mRNA for the NPY/PYY receptor of the Y1 subtype in dorsal root ganglia during rat embryogenesis. Brain Res. Dev. Brain Res. 1993, 76: 105–113.PubMedGoogle Scholar
  70. 70.
    Keire D.A., Mannon P., Kobayashi M., Walsh J.H., Solomon T.E., Reeve J.R.Jr. Primary structures of PYY, [Pro34] PYY and PYY-(3–36) confer different conformations and receptor selectivity. Am. J. Physiol. 2000, 279: G126–G131.Google Scholar
  71. 71.
    Broberger C., Landry M., Wong H., Walsh J.N., Hökfelt T. Subtypes of Y1 and Y2 of the neuropeptide Y receptor are respectively expressed in pro-opiomelanocortin and neuropeptide-Y-containing neurons of the rat hypothalamic arcuate nucleus. Neuroendocrinology 1997, 66: 393–408.PubMedGoogle Scholar
  72. 72.
    Kalra S.P., Dube M.G., Pu S., Xu B., Horvath T.L., Kalra P.S. Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 1999, 20: 68–100.PubMedGoogle Scholar
  73. 73.
    Batterham R.L., Cowley M.A., Small C.J. et al. Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 2002, 418: 650–654.PubMedGoogle Scholar
  74. 74.
    Cowley M.A., Smart J.L., Rubinstein M. et al. Leptin activates the anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 2001, 411: 480–484.PubMedGoogle Scholar
  75. 75.
    Hagan M.M., Rushing P.A., Pritchard L.M. et al. Long-term orexigenic effect of AgRP-(82–132) involve mechanisms other than melanocortin receptor blockade. Am. J. Physiol. 2000, 279: R47–R52.Google Scholar
  76. 76.
    Elmquist J.K., Elias C.F., Saper C.B. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 1999, 22: 221–232.PubMedGoogle Scholar
  77. 77.
    Ollman M.M., Wilson B.D., Yang Y.K. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 1997, 278: 135–138.Google Scholar
  78. 78.
    Schwartz M.W., Woods S.C., Porte Jr.D., Seeley R.J., Baskin D.G. Central nervous system control of food intake. Nature 2000, 404: 661–671.PubMedGoogle Scholar
  79. 79.
    Fong T.M., Mao C., MacNeil T. et al. ART (protein product of agouti-related transcript) as an antagonist of MC-3 and MC-4 receptors. Biochem. Biophys. Res. Commun. 1997, 237: 629–631.PubMedGoogle Scholar
  80. 80.
    Cone R.D., Lu D., Koppula S. et al. The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog. Horm. Res. 1996, 51: 287–317.PubMedGoogle Scholar
  81. 81.
    Benoit S.C., Schwartz M.W., Lachey J.L. et al. A novel selective melanocortin-4 receptor agonist reduces food intake in rats and mice without producing aversive consequences. J. Neurosci. 2000, 20: 3442–3448.PubMedGoogle Scholar
  82. 82.
    Thiele T.E., van Dijk G., Yagaloff K.A. et al. Central infusion of melanocortin agonist MTII in rats: assessment of c-Fos expression and taste aversion. Am. J. Physiol. 1998, 274: R248–R254.PubMedGoogle Scholar
  83. 83.
    Yaswen L., Diehl N., Brennan M.B., Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 1999, 5: 1066–1070.PubMedGoogle Scholar
  84. 84.
    Huszar D., Lynch C.A., Fairchild-Huntress V. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 1997, 88: 131–141.PubMedGoogle Scholar
  85. 85.
    Chen A.S., Marsh D.J., Trumbauer M.E. et al. Inactivation of the mouse melanocortin-3 receptor results in increased fat mass and reduced lean body mass. Nat. Genet. 2000, 26: 97–102.PubMedGoogle Scholar
  86. 86.
    Krude H., Biebermann H., Luck W., Horn R., Brabant G., Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 1998, 19: 155–157.PubMedGoogle Scholar
  87. 87.
    Vaisse C., Clement K., Durand E., Hercberg S., Guy-Grand B., Froguel P. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 2000, 106: 253–262PubMedCentralPubMedGoogle Scholar
  88. 88.
    Lee Y.S., Poh L.K., Loke K.Y. A novel melanocortin 3 receptor gene (MC3R) mutation associated with severe obesity. J. Clin. Endocrinol. Metab. 2002, 87: 1423–1426.PubMedGoogle Scholar
  89. 89.
    Koylu E.O., Couceyro P.R., Lambert P.D., Ling N.C., DeSouza E.B., Kuhar M.J. Immunohistochemical localization of novel CART peptides in rat hypothalamus, pituitary and adrenal gland. J. Neuroendocr. 1997, 9: 823–833.Google Scholar
  90. 90.
    Kristensen P., Judge M.E., Thim L. et al. Hypothalamic CART is a new anorectic peptide regulated by leptin. Nature 1998, 393: 72–76.PubMedGoogle Scholar
  91. 91.
    Abbott C.R., Rossi M., Wren A.M. et al. Evidence of an orexigenic role for cocaine- and amphetamine-regulated transcript after administration into discrete hypothalamic nuclei. Endocrinology 2001, 142: 3457–3463.PubMedGoogle Scholar
  92. 92.
    Sipols A.J., Baskin D.G., Schwartz M.W. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 1995, 44: 147–151.PubMedGoogle Scholar
  93. 93.
    Baskin D.G., Wilcox B.J., Figlewicz D.P., Dorsa D.M. Insulin and insulin-like growth factors in the CNS. Trends Neurosci. 1988, 11: 107–111.PubMedGoogle Scholar
  94. 94.
    Schwartz M.W., Seeley R.J., Woods S.C., Weigle D.S., Campfield L.A., Burn P., Baskin D.G. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 1997, 46: 2119–2123.PubMedGoogle Scholar
  95. 95.
    Thornton J.E., Cheung C.C., Clifton D.K., Steiner R.A. Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 1997, 138: 5063–5066.PubMedGoogle Scholar
  96. 96.
    Broberger C., Visser T.J., Kuhar M.J., Hokfelt T. Neuropeptide Y innervations and Neuropeptide-Y-Y1-receptorexpressing neurons in the paraventricular hypothalamic nucleus of the mouse. Neurondocrinology 1999, 70: 295–305.Google Scholar
  97. 97.
    Fekete C., Legradi G., Mihaly E. et al. Alpha-Melanocytestimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. J. Neurosci. 2000, 20: 1550–1558.PubMedGoogle Scholar
  98. 98.
    Fekete C., Mihaly E., Luo L.G. et al. Association of cocaineand amphetamine-regulated transcript-immunoreactive elements with thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and its role in the regulation of the hypothalamic-pituitary-thyroid axis during fasting. J. Neurosci. 2000, 20: 9224–9234.PubMedGoogle Scholar
  99. 99.
    Legradi G., Lechan R.M. The arcuate nucleus is the major source for neuropeptide Y-innervation of thyrotropinreleasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology 1998, 139: 3262–3270.PubMedGoogle Scholar
  100. 100.
    Liposits Z., Sievers L., Paull W.K. Neuropeptide-Y and ACTH-immunoreactive innervation of corticotropin releasing factor (CRF)-synthesizing neurons in the hypothalamus of the rat. An immunocytochemical analysis at the light and electron microscopic levels. Histochemistry 1988, 88: 227–234.PubMedGoogle Scholar
  101. 101.
    Venihaki M., Majzoub J.A. Animal models of CRH deficiency. Front. Neuroendocrinol. 1999, 20: 122–145.Google Scholar
  102. 102.
    Schwartz M.W., Woods S.C., Porte D.Jr., Seeley R.J., Baskin D.G. Central nervous system control of food intake. Nature 2000, 404: 661–671.PubMedGoogle Scholar
  103. 103.
    Richard D., Huang Q., Timofeeva E. The corticotropinreleasing hormone system in the regulation of energy balance in obesity. Int. J. Obes. 2000, 24 (Suppl. 2): S36–S39.Google Scholar
  104. 104.
    Smagin G.N., Howell L.A., Ryan D.H., De Souza E.B., Harris R.B. The role of CRF2 receptors in corticotropin-releasing factor- and urocortin-induced anorexia. Neuroreport 1998, 9: 1601–1606.PubMedGoogle Scholar
  105. 105.
    Beck B. KO’s and organisation of peptidergic feeding behavior mechanisms. Neurosci. Biobehav. Rev. 2001, 25: 143–158.PubMedGoogle Scholar
  106. 106.
    Arase K., York D.A., Shimazu H., Shargill M., Bray G.A. Effects of corticotrophin releasing factor on food intake and brown adipose tissue thermogenesis. Am. J. Physiol. 1998, 55: E225–E259.Google Scholar
  107. 107.
    Spina M., Merlo-Pich E., Chan R.K. et al. Appetite-suppressing effects of urocortin, a CRF-related neuropeptide. Science 1996, 273: 1561–1564.PubMedGoogle Scholar
  108. 108.
    Hsu S.Y., Hsueh A.J. Human stresscopin and stresscopinrelated peptide are selective ligands for the type 2 corticotropin- releasing hormone receptor. Nature Med. 2001, 7: 605–611.PubMedGoogle Scholar
  109. 109.
    Li C., Vaughan J., Sawchenko P.E., Vale W.W. Urocortin III-immunoreactive projections in rat brain: partial overlap with sites of type 2 corticotrophin-releasing factor receptor expression. J. Neurosci. 2002, 22: 991–1001.PubMedGoogle Scholar
  110. 110.
    Inui A. Transgenic approach to the study of body weight regulation. Pharmacol. Rev. 2000, 52: 35–61.PubMedGoogle Scholar
  111. 111.
    Härfstrand A., Fuxe K., Agnati L.F. et al. Studies on neuropeptide Y-catecholamine interactions in the hypothalamus and in the forebrain of the male rat. Relationship to neuroendocrine function. Neurochem. Int. 1986, 8: 355–1376.PubMedGoogle Scholar
  112. 112.
    Broberger C., De Lecea L., Sutcliffe J.G., Hokfelt T. Hypocretin/orexin- and melanin-concentrating hormoneexpressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J. Comp. Neurol. 1998, 402: 460–474.PubMedGoogle Scholar
  113. 113.
    Qu D., Ludwig D.S., Gammeltoft S. et al. A role for melanin-concentrating hormone in the central regulation of feeding behavior. Nature 1996, 380: 243–247.PubMedGoogle Scholar
  114. 114.
    Shimada M., Tritos N.A., Lowell B.B., Flier J.S., Maratos-Flier E. Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature 1998, 396 (6712): 670–674.PubMedGoogle Scholar
  115. 115.
    Ludwig D.S., Tritos N.A., Mastaitis J.W. et al. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin resistance. J. Clin. Invest. 2001, 107: 379–386.PubMedCentralPubMedGoogle Scholar
  116. 116.
    Saito Y., Nothacker H.P., Wang Z., Lin S.H., Leslie F., Civelli O. Molecular characterization of the melanin-concentrating- hormone receptor. Nature 1999, 400: 265–269PubMedGoogle Scholar
  117. 117.
    Chambers J., Ames R.S., Bergsma D. et al. Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1. Nature 1999, 400: 261–265.PubMedGoogle Scholar
  118. 118.
    Sakurai T., Amemiya A., Ishii M. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998, 92: 573–585.PubMedGoogle Scholar
  119. 119.
    Yamanaka A., Sakurai T., Katsumoto T., Yanagisawa M., Goto K. Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res. 1999, 849: 248–252.PubMedGoogle Scholar
  120. 120.
    Hara J., Beuckmann C.T., Nambu T. et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001, 30: 345–354.PubMedGoogle Scholar
  121. 121.
    Wang J., Osaka T., Inoue S. Energy expenditure by intracerebroventricular administration of orexin to anesthetized rats. Neurosci. Lett. 2001, 315: 49–52.PubMedGoogle Scholar
  122. 122.
    Chemelli R.M., Willie J.T., Sinton C.M. et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999, 98: 437–451.PubMedGoogle Scholar
  123. 123.
    Griffond B., Risold P.Y., Jacquemard C., Colard C., Fellmann D. Insulin-induced hypoglycemia increases preprohypocretin (orexin) mRNA in the rat lateral hypothalamic area. Neurosci. Lett. 1999, 262: 77–80.PubMedGoogle Scholar
  124. 124.
    Cai X.J., Widdowson P.S., Harold J. et al. Hypothalamic orexin expression: modulation by blood glucose and feeding. Diabetes 1999, 48: 2132–2137.PubMedGoogle Scholar
  125. 125.
    Risold P.Y., Thompson R.H., Swanson L.W. The structural organization of connections between hypothalamus and cerebral cortex. Brain Res. Rev. 1997, 24: 197–254.PubMedGoogle Scholar
  126. 126.
    Bittencourt J.C., Presse F., Arias C. et al. The melanin-concentrating hormone system of the rat brain: an immunoand hybridization histochemical characterization. J. Comp. Neurol. 1992, 319: 218–245.PubMedGoogle Scholar
  127. 127.
    Broberger C., Hokfelt T. Hypothalamic and vagal neuropeptide circuitries regulating food intake. Physiol. Behav. 2001, 74: 669–682.PubMedGoogle Scholar
  128. 128.
    Skofitsch G., Jacobowitz D.M. Immunoistochemical mapping of galanin-like neurons in the rat nervous system. Peptides 1985, 6: 509–546.PubMedGoogle Scholar
  129. 129.
    Lopez F.J., Liposits Z., Merchenthaler I. Evidence for a negative ultrashort loop feedback regulating galanin release from the arcuate nucleus-median eminence functional unit. Endocrinology 1992, 130: 1499–1507.PubMedGoogle Scholar
  130. 130.
    Horvath T.L., Naftolin F., Leranth C., Sahu A., Kalra S.P. Morphological and pharmacological evidence for neuropeptide Y-galanin interaction in the rat hypothalamus. Endocrinology 1996, 137: 3069–3077.PubMedGoogle Scholar
  131. 131.
    Smith B.K., York D.A., Bray G.A. Chronic cerebroventricular does not induce sustained hyperphagia or obesity. Peptides 1994, 15: 1267–1272.PubMedGoogle Scholar
  132. 132.
    Wynick D., Small S.J., Bacon A. et al. Galanin regulates prolactin release and lactotroph proliferation. Proc. Natl. Acad. Sci. USA 1994, 95: 12671–12676.Google Scholar
  133. 133.
    Stratford T.R., Kelley A.E. GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. J. Neurosci. 1997, 19: 121–131.Google Scholar
  134. 134.
    Berridge K.C., Pecina S. Benzodiazepines, appetite, and taste palatability. Neurosci. Biobehav. Rev. 1995, 37: 735–740.Google Scholar
  135. 135.
    Dickson P.R., Vaccarino F.J. Characterization of feeding behavior induced by central injection of GRF. Am. J. Physiol. 1990, 259: R651–R657.PubMedGoogle Scholar
  136. 136.
    Salton S.R., Ferri G.L., Hahm S. et al. VGF: a novel role for this neuronal and neuroendocrine polypeptide in the regulation of energy balance. Front. Neuroendocrinol. 2000, 21: 199–219.PubMedGoogle Scholar
  137. 137.
    Hahm S., Mizuno T.M., Wu T.J. et al. Targeted deletion of the Vgf gene indicates that the encoded secretory peptide precursor plays a novel role in the regulation of energy balance. Neuron 1999, 23: 537–548.PubMedGoogle Scholar
  138. 138.
    Collier G.R., McMillan J.S., Windmill K. et al. Beacon: a novel gene involved in the regulation of energy balance. Diabetes 2000, 49: 1766–1771.PubMedGoogle Scholar
  139. 139.
    Merali Z., McIntosh J., Anisman H. Role of bombesin-related peptides in the control of food intake. Neuropeptides 1999, 33: 376–386.PubMedGoogle Scholar
  140. 140.
    Fathi Z., Corjay M.H., Shapira H. et al. BRS-3: a novel bombesin receptor subtype selectively expressed in testis and lung carcinoma cells. J. Biol. Chem. 1993, 268: 5979–5984.PubMedGoogle Scholar
  141. 141.
    Turton M.D., O’Shea D., Gunn I. et al. A role for glucagonlike peptide-1 in the central regulation of feeding. Nature 1996, 379: 69–72.PubMedGoogle Scholar
  142. 142.
    Kieffer T.J., Habener J.F. The glucagon-like peptides. Endocr. Rev. 1999, 20: 876–913.PubMedGoogle Scholar
  143. 143.
    Tang-Christensen M., Larsen P.J., Thulesen J., Romer J., Vrang N. The proglucagon-derived peptide, glucagon- like peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat. Med. 2000, 6: 802–807.PubMedGoogle Scholar
  144. 144.
    Barrachina M.D., Martinez V., Wang L., Wei J.Y., Tache Y. Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc. Natl. Acad. Sci. USA 1997, 94: 10455–10460.PubMedCentralPubMedGoogle Scholar
  145. 145.
    Kopin A.S., Mathes W.F., McBride E.W. et al. The cholecystokinin- A receptor mediates inhibition of food intake yet is not essential for the maintenance of body weight. J. Clin. Invest. 1999, 103: 383–391.PubMedCentralPubMedGoogle Scholar
  146. 146.
    Lawrence C.B., Celsi F., Brennand J., Luckman S.M. Alternative role for prolactin-releasing peptide in the regulation of food intake. Nature Neurosci. 2000, 3: 645–646.PubMedGoogle Scholar
  147. 147.
    Roland B.L., Sutton S.W., Wilson S.J. et al. Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery. Endocrinology 1999, 140: 5736–5745.PubMedGoogle Scholar
  148. 148.
    Seal L.J., Small C.J., Dhillo W.S. et al. PRL-releasing peptide inhibits food intake in male rats via the dorsomedial hypothalamic nucleus and not the paraventricular hypothalamic nucleus. Endocrinology 2001, 142: 4236–4243.PubMedGoogle Scholar
  149. 149.
    Johansson J.O., Jarbe T.U., Henriksson B.G. Acute and subchronic influences of tetrahydrocannabinols on water and food intake, body weight and temperature in rats. Life Sci. 1975, 5: 17–27.Google Scholar
  150. 150.
    Gonzalez S., Manzanares J., Berrendero F. et al. Identification of endocannabinoids and cannabinoid CB(1) receptor mRNA in the pituitary gland. Neuroendocrinology 1999, 70: 137–145.PubMedGoogle Scholar
  151. 151.
    Pagotto U., Marsicano G., Fezza F. et al. Normal human pituitary gland and pituitary adenomas express cannabinoid receptor type 1 and synthesize endogenous cannabinoids: first evidence for a direct role of cannabinoids on hormone modulation at the human pituitary level. J. Clin. Endocr. Metab. 2001, 86: 2687–2696.PubMedGoogle Scholar
  152. 152.
    Devane W.A., Hanus L., Breuer A. et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992, 258: 1946–1949.PubMedGoogle Scholar
  153. 153.
    Williams C.M., Kirkham T.C. Anandamide induces overeating: mediation by central cannabinoid (CB1) receptors. Psycopharmacol. 1999, 143: 315–317.Google Scholar
  154. 154.
    Arnone M., Maruani J., Chaperone F., Thiebot M.H., Soubrie P., LeFur G. Selective inhibition of sucrose and ethanol intake by SR141716, an antagonist of central cannabinoid (CB1) receptor. Psycopharmacol. 1997, 132: 104–106.Google Scholar
  155. 155.
    Simiand J., Keane M., Keane P.E., Soubrie P. SR141716, a CB1 cannabinoid receptor antagonist, selectively reduces sweet food intake in marmoset. Behav. Pharmacol. 1998, 9: 179–181.PubMedGoogle Scholar
  156. 156.
    Marzo V., Goparaju S.K., Wang L. et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 2001, 410: 822–825.PubMedGoogle Scholar
  157. 157.
    Greenberg I., Kuehnle J., Mendelson J.H., Bernstein J.G. Effects of marihuana use on body weight and caloric intake in humans. Psychopharmacol. 1976, 49: 79–84.Google Scholar
  158. 158.
    Foltin R.W., Brady J.V., Fischman M.W. Behavioral analysis of marijuana effects on food intake in humans. Pharmacol. Biochem. Behav. 1986, 25: 577–582.PubMedGoogle Scholar
  159. 159.
    Foltin R.W., Fischman M.W., Byrne M.F. Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory. Appetite 1988, 11: 1–14.PubMedGoogle Scholar
  160. 160.
    Mattes R.D., Engelman K., Shaw L.M., Elsohly M.A. Cannabinoids and appetite stimulation. Pharmacol. Biochem. Behav. 1994, 49: 187–195.PubMedGoogle Scholar
  161. 161.
    Jatoi A., Windschitl H.E., Loprinzi C.L. et al. Dronabinol vs megestrol acetate vs combination therapy for cancer-associated anorexia: A north central cancer treatment group study. J. Clin. Oncol. 2002, 20: 567–573.PubMedGoogle Scholar
  162. 162.
    Beal J.E., Olson R., Lefkowitz L. et al. Long-term efficacy and safety of dronabinol for acquired immunodeficiency syndrome-associated anorexia. J. Pain Sympt. Man. 1997, 14: 7–14.Google Scholar
  163. 163.
    Gibbs J., Young R.C., Smith G.P. Cholecystokinin deceases food intake in rats. J. Comp. Physiol. Psychol. 1973, 84: 488–495.PubMedGoogle Scholar
  164. 164.
    Gibbs J., Falasco J.D., McHugh P.R. Cholecystokinin decreases food intake in rhesus monkeys. Am. J. Physiol. 1976, 230: 15–18.PubMedGoogle Scholar
  165. 165.
    Kissilieff H.R., Pi Sunyer F.X., Thornton J. et al. C-terminal octapeptide of cholecystokinin decreased food intake in man. Am. J. Clin. Nutr. 1981, 34: 154–160.Google Scholar
  166. 166.
    Ballinger A., McLoughlin L., Medbak S., Clark M. Cholecystokinin is a satiety hormone I humans at physilogical post-prandial plasma concentrations. Clin. Sci. (Lond.) 1995, 89: 375–381.Google Scholar
  167. 167.
    West D.B., Fey D., Woods S.C. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am. J. Physiol. 1984, 246: R776–R787.PubMedGoogle Scholar
  168. 168.
    Moran T.H., Ameglio P.J., Schwartz G.J., McHugh P.R. Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK. Am. J. Physiol. 1992, 262: R46–R50.PubMedGoogle Scholar
  169. 169.
    Moran T.H., McHugh P.R. Gastric and non-gastric mechanisms for satiety action of cholecystokinin. Am. J. Physiol. 1988, 254: R628–R632.PubMedGoogle Scholar
  170. 170.
    Smith G.P., Jerome C., Cushin B.J., Eterno R., Simnansky K.J. Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 213: 1036–1037, 1981.PubMedGoogle Scholar
  171. 171.
    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: 656–660.PubMedGoogle Scholar
  172. 172.
    Nakazato M., Murakami N., Date Y. et al. A role for ghrelin in the central regulation of feeding. Nature 2001, 409: 194–198.PubMedGoogle Scholar
  173. 173.
    Howard A.D., Feighner S.D., Cully D.F. et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996, 273: 974–977.PubMedGoogle Scholar
  174. 174.
    Gnanapavan S., Kola B., Bustin S.A. et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J. Clin. Endocr. Metab. 2002, 87: 2988–2991.PubMedGoogle Scholar
  175. 175.
    Ariyasu H., Takaya K., Tagami T. et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocr. Metab. 2001, 86: 4753–4758.PubMedGoogle Scholar
  176. 176.
    Tschop M., Smiley D.L., Heiman M.L. Ghrelin induces adiposity in rodents. Nature 2000, 407: 908–913.PubMedGoogle Scholar
  177. 177.
    Tschop M., Wawarta R., Riepl R.L. et al. Post-prandial decrease of circulating human ghrelin levels. J. Endocr. Invest. 2001, 24: 19–21.Google Scholar
  178. 178.
    Wren A.M., Seal L.J., Cohen M.A. et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocr. Metab. 2001, 86: 5992–5995.PubMedGoogle Scholar
  179. 179.
    Tschop M., Weyer C., Tataranni P.A., Devanarayan V., Ravussin E., Heiman M.L. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001, 50: 707–709.PubMedGoogle Scholar
  180. 180.
    English P.J., Ghatei M.A., Malik I.A., Bloom S.R., Wilding J.P.H. Food fails to suppress ghrelin levels in obesity. J. Clin. Endocr. Metab. 2002, 87: 2984–2987.PubMedGoogle Scholar
  181. 181.
    Cummings D.E., Weigle D.S., Frayo R.S. et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 2002, 346: 1623–1630.PubMedGoogle Scholar
  182. 182.
    Saad M.F., Bernaba B., Hwu C.M. et al. Insulin regulates plasma ghrelin concentration. J. Clin. Endocr. Metab. 2002, 87: 3997–4000.PubMedGoogle Scholar
  183. 183.
    Nakagawa E., Nagaya N., Okumura H. et al. Hyperglycaemia suppresses the secretion of ghrelin, a novel growth-hormone-releasing peptide: responses to the intravenous and oral administration of glucose. Clin. Sci. (Lond.) 2002, 103: 325–328.Google Scholar
  184. 184.
    Shintani M., Ogawa Y., Ebihara K. et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 2001, 50: 227–232.PubMedGoogle Scholar
  185. 185.
    Ukkola O., Ravussin E., Jacobson P. et al. Role of ghrelin polymorphisms in obesity based on three different studies. Obes. Res. 2002, 10: 782–791.PubMedGoogle Scholar
  186. 186.
    Korbonits M., Gueorguiev M., O’Grady E. et al. A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J. Clin. Endocr. Metab. 2002, 87: 4005–4008.PubMedGoogle Scholar
  187. 187.
    Zhang Y., Proenca R., Maffei M., Barone M., Leopold L., Friedman J.M. Positional cloning of the mouse obese gene and its human homologue. Nature 1994, 372: 425–432.PubMedGoogle Scholar
  188. 188.
    Zlokovic B.V., Jovanovic S., Miao W., Samara S., Verma S., Farrell C.L. Differential regulation of leptin transport by the choroid plexus and blood-brain barrier and high affinity transport systems for entry into hypothalamus and across the blood-cerebrospinal fluid barrier. Endocrinology 2000, 141: 1434–1441.PubMedGoogle Scholar
  189. 189.
    Friedman J.M., Halaas J.L. Leptin and the regulation of body weight in mammals. Nature 1998, 395: 763–770.PubMedGoogle Scholar
  190. 190.
    Ahima R.S., Saper C.B., Flier J.S., Elmquist J.K. Leptin regulation of neuroendocrine systems. Front. Neuroendocr. 2000, 21: 263–307.Google Scholar
  191. 191.
    Woods A.J., Stock M.J. Leptin activation in hypothalamus. Nature 1996, 381: 745.PubMedGoogle Scholar
  192. 192.
    Mantzoros C.S. Leptin and the hypothalamus: neuroendocrine regulation of food intake. Mol. Psychiatry 1999, 4: 8–12.PubMedGoogle Scholar
  193. 193.
    Mizuno T.M., Kleopoulos S.P., Bergen H.T., Roberts J.L., Priest C.A., Mobbs C.V. Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 1998, 47: 294–297.PubMedGoogle Scholar
  194. 194.
    Ur E., Grossman A., Despres J.P. Obesity results as a consequence of glucocorticoid induced leptin resistance. Horm. Metab. Res. 1996, 28: 744–747.PubMedGoogle Scholar
  195. 195.
    Tritos N.A., Mantzoros C.S. Leptin: its role in obesity and beyond. Diabetologia 1997, 40: 1371–1379.PubMedGoogle Scholar
  196. 196.
    Ahima R.S., Prabakaran D., Mantzoros C. et al. Role of leptin in the neuroendocrine response to fasting. Nature 1996, 382: 250–252.PubMedGoogle Scholar
  197. 197.
    Considine R.V., Considine E.L., Williams C.J. et al. Evidence against either a premature stop codon or the absence of obese gene mRNA in human obesity. J. Clin. Invest. 1995, 95: 2986–2988.PubMedCentralPubMedGoogle Scholar
  198. 198.
    Considine R.V., Considine E.L., Williams C.J. et al. Mutation screening and identification of a sequence variation in the human ob gene coding region. Biochem. Biophys. Res. Commun. 1996, 220: 735–759.PubMedGoogle Scholar
  199. 199.
    Clement K., Garner C., Hager J. et al. Indication for linkage of the human OB gene region with extreme obesity. Diabetes 1996, 45: 687–690.PubMedGoogle Scholar
  200. 200.
    Strobel A., Issad T., Camoin L., Ozata M., Strosberg A.D. A leptin missense mutation associated with hypogonadism and morbid obesity. Nat. Genet. 1998, 18: 213–215.PubMedGoogle Scholar
  201. 201.
    Schwartz M.W., Peskind E., Raskind M., Boyko E.J., Porte D. Jr. Cerebrospinal fluid leptin levels: relationship to plasma levels and to adiposity in humans. Nat. Med. 1996, 2: 589–593.PubMedGoogle Scholar
  202. 202.
    Ahima R.S., Osei S.Y. Molecular regulation of eating behavior: new insights and prospects for therapeutic strategies. Trends Mol. Med. 2001, 7: 205–213.PubMedGoogle Scholar
  203. 203.
    Bjorbaek C., Elmquist J.K., Frantz J.D., Shoelson S.E., Flier J.S. Identification of SOCS-3 as a potential mediator of central leptin resistance. Mol. Cell. 1998, 1: 619–625.PubMedGoogle Scholar
  204. 204.
    Woods S.C., Lotter E.C., McKay L.D., Porte D.Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 1979, 282: 503–505.PubMedGoogle Scholar
  205. 205.
    Sipols A.J., Baskin D.G., Schwartz M.W. Effect of intracerebroventricular insulin infusion on diabetic hyperphagia and hypothalamic neuropeptide gene expression. Diabetes 1995, 44: 147–151.PubMedGoogle Scholar
  206. 206.
    Cusin I., Dryden S., Wang Q., Rohner-Jeanrenaud F., Jeanrenaud B., Williams C. Effect of sustained physiological hyperinsulinaemia on hypothalamic neuropeptide Y and NPY mRNA levels in the rat. J. Neuroendocr. 1995, 7: 193–197.Google Scholar
  207. 207.
    Williams G., Steel J.H., Cardoso H. et al. Increased hypothalamic neuropeptide Y concentrations in diabetic rat. Diabetes 1988, 37: 763–772.PubMedGoogle Scholar
  208. 208.
    Bruning J.C., Gautam D., Burks D.J. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 2000, 289: 2122–2125.PubMedGoogle Scholar
  209. 209.
    Bray G.A., York D.A. Hypothalamic and genetic obesity in experimental animals: an autonomic and endocrine hypothesis. Physiol. Rev. 1979, 59: 719–809.PubMedGoogle Scholar
  210. 210.
    Dallman M.F., Strack A.M., Akana S.F. et al. Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front. Neuroendocrinol. 1993, 14: 303–347.PubMedGoogle Scholar
  211. 211.
    Bradley R.L., Cheatham B. Regulation of ob gene expression and leptin secretion by insulin and dexamethasone in rat adipocytes. Diabetes 1999, 48: 272–278.PubMedGoogle Scholar
  212. 212.
    Newcomer J.W., Selke G., Melson A.K., Gross J., Vogler G.P., Dagogo-Jack S. Dose-dependent cortisol-induced increases in plasma leptin concentration in healthy humans. Arch. Gen. Psychiatry 1998, 55: 995–1000.PubMedGoogle Scholar
  213. 213.
    Jeanrenaud B., Rohner-Jeanrenaud F. CNS-periphery relationships and body weight homeostasis: influence of the glucocorticoid status. Int. J. Obes. 2000, 24 (Suppl. 2): S74–S76.Google Scholar
  214. 214.
    Malendowicz L.K., Macchi C., Nussdorfer G.G., Nowak K.W. Acute effects of recombinant murine leptin on rat pituitaryadrenocortical function. Endocr. Res. 1998, 24: 235–246.PubMedGoogle Scholar
  215. 215.
    Ainslie D.A., Morris M.J., Wittert G., Turnbull H., Proietto J., Thorburn A.W. Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y. Int. J. Obes. 2001, 25: 1680–1688.Google Scholar
  216. 216.
    Mystkowski P., Schwartz M.W. Gonadal steroids and energy homeostasis in the leptin era. Nutrition 2000, 16: 937–946.PubMedGoogle Scholar
  217. 217.
    Plata-Salaman C.R. Cytokine-induced anorexia. Behavioral, cellular, and molecular mechanisms. Ann. N. Y. Acad. Sci. 1998, 856: 160–170.PubMedGoogle Scholar
  218. 218.
    Fawcett R.L., Waechter A.S., Williams L.B. et al. Tumor necrosis factor-alpha inhibits leptin production in subcutaneous and omental adipocytes from morbidly obese humans. J. Clin. Endocr. Metab. 2000, 85: 530–535.PubMedGoogle Scholar
  219. 219.
    Langhans W., Hrupka B. Interleukins and tumor necrosis factor as inhibitors of food intake. Neuropeptides 1999, 33: 415–524.PubMedGoogle Scholar
  220. 220.
    Wallenius V., Wallenius K., Ahren B. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 2002, 8: 75–79.PubMedGoogle Scholar
  221. 221.
    Gloaguen I., Costa P., Demartis A. et al. Ciliary neurotrophic factor corrects obesity and diabetes associated with leptin deficiency and resistance. Proc. Natl. Acad. Sci. USA, 1997, 94: 6456–6461.PubMedCentralPubMedGoogle Scholar
  222. 222.
    Bjorbaek C., Elmquist J.K., El-Haschimi K. et al. Activation of SOCS-3 messenger ribonucleic acid in the hypothalamus by ciliary neurotrophic factor. Endocrinology 1999, 140: 2035–2043.PubMedGoogle Scholar
  223. 223.
    Leibowitz S.F., Roossin P., Rosenn M. Chronic norepinephrine injection into the hypothalamic paraventricular nucleus produces hyperphagia and increased body weight in the rat. Pharmacol. Biochem. Behav. 1984, 21: 801–808.PubMedGoogle Scholar
  224. 224.
    Oltmans G.A. Norepinephrine and dopamine levels in hypothalamic nuclei of the genetically obese mouse (ob/ob). Brain Res. 1983, 273: 369–373.PubMedGoogle Scholar
  225. 225.
    Brunetti L., Michelotto B., Orlando G., Vacca M. Leptin inhibits norepinephrine and dopamine release from rat hypothalamic neuronal endings. Eur. J. Pharmacol. 1999, 372: 237–240.PubMedGoogle Scholar
  226. 226.
    Salamone J.D., Mahan K., Rogers S. Ventrolateral striatal dopamine depletions impair feeding and food handling in rats. Pharmacol. Biochem. Behav. 1993, 44: 605–610.PubMedGoogle Scholar
  227. 227.
    Szczypka M.S., Rainey M.A., Kim D.S. et al. Feeding behavior in dopamine-deficient mice. Proc. Natl. Acad. Sci. USA 1999, 96: 12138–12143.PubMedCentralPubMedGoogle Scholar
  228. 228.
    Pothos E.N., Creese I., Hoebel B.G. Restricted eating with weight loss selectively decreases extracellular dopamine in the nucleus accumbens and alters dopamine response to amphetamine, morphine, and food intake. J. Neurosci. 1995, 15: 6640–6650.PubMedGoogle Scholar
  229. 229.
    Nonogaki K., Strack A.M., Dallman M.F., Tecott L.H. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptorgene. Nat. Med. 1998, 4: 1152–1156.PubMedGoogle Scholar

Copyright information

© Italian Society of Endocrinology (SIE) 2002

Authors and Affiliations

  • Roberto Vettor
    • 1
  • R. Fabris
    • 1
  • C. Pagano
    • 1
  • G. Federspil
    • 1
  1. 1.Internal Medicine, Department of Medical and Surgical SciencesUniversity of PadovaPadovaItaly

Personalised recommendations