Ghrelin, appetite, and gastric motility: The emerging role of the stomach as an endocrine organ

FASEB Journal

Volumn 18, Issue 3, 2004, Pages 439-456

  Inui, Akio ^a   Asakawa, Akihiro ^a   Bowers, Cyril Y ^b   Mantovani, Giovanni ^c   Laviano, Alessandro ^d   Meguid, Michael M ^e   Fujimiya, Mineko ^f  

^a KOBE UNIVERSITY GRADUATE SCHOOL OF MEDICINE   (Japan)

^b TULANE UNIVERSITY HEALTH SCIENCES CENTER   (United States)

^c UNIVERSITY OF CAGLIARI   (Italy)

^d SAPIENZA UNIVERSITY OF ROME   (Italy)

^e State University of New York Upstate Medical University: College of Medicine   (United States)

^f SHIGA UNIVERSITY OF MEDICAL SCIENCE   (Japan)

Author keywords

Enteric nutrition; GHS; NYP AgRP neurons; Orexigenic signal

Indexed keywords

AGOUTI RELATED PROTEIN; CAPROMORELIN; DEXTRO 3 LYSYLHISTIDYL DEXTRO TRYPTOPHYLALANYLTRYPTOPHYL DEXTRO PHENYLALANYLLYSINAMIDE; ERYTHROMYCIN; GHRELIN; GROWTH HORMONE SECRETAGOGUE; GROWTH HORMONE SECRETAGOGUE RECEPTOR; GROWTH HORMONE SECRETAGOGUE RECEPTOR AGONIST; HISTIDYL DEXTRO TRYPTOPHYLALANYLTRYPTOPHYL DEXTRO PHENYLALANYLLYSINAMIDE; HORMONE RECEPTOR BLOCKING AGENT; IBUTAMOREN; LEPTIN; MOTILIN; NEUROPEPTIDE; NEUROPEPTIDE Y; NNC 260703; PRALMORELIN; PROKINETIC AGENT; REGULATOR PROTEIN; UNCLASSIFIED DRUG;

ANOREXIA NERVOSA; APPETITE; CACHEXIA; DRUG RESPONSE; DRUG STRUCTURE; EATING DISORDER; ENDOCRINE GLAND; ENERGY BALANCE; ENTERIC FEEDING; GASTRITIS; GASTROINTESTINAL DISEASE; GLUCOSE METABOLISM; GROWTH HORMONE DEFICIENCY; GROWTH HORMONE RELEASE; HORMONAL REGULATION; HORMONE ACTION; HUMAN; HYPERPHAGIA; ILEUS; NEUROENDOCRINE SYSTEM; NEUROSECRETORY CELL; NONHUMAN; OBESITY; PRADER WILLI SYNDROME; PRIORITY JOURNAL; REVIEW; SENSORY NERVE; SHORT BOWEL SYNDROME; SIGNAL TRANSDUCTION; STOMACH; STOMACH MOTILITY; STOMACH PARESIS; STOMACH ULCER; VAGUS NERVE; WEIGHT GAIN;

AGED; ANIMALS; APPETITE; CHILD; EATING DISORDERS; ENERGY METABOLISM; GASTROINTESTINAL DISEASES; GASTROINTESTINAL MOTILITY; GROWTH; GROWTH HORMONE; HUMAN GROWTH HORMONE; HUMANS; HYPOTHALAMUS; NEUROPEPTIDES; NEUROSECRETORY SYSTEMS; OBESITY; PEPTIDE HORMONES; RATS; RECEPTORS, G-PROTEIN-COUPLED; STOMACH; VAGUS NERVE;

AGOUTI;

EID: 1542343913     PISSN: 08926638     EISSN: None     Source Type: Journal    
DOI: 10.1096/fj.03-0641rev     Document Type: Review

References (275)

1. Friedman, J. M., and Halaas, J. L. (1998) Leptin and the regulation of body weight in mammals. Nature (London) 395, 763-770
2. Woods, S. C., Seeley, R. J., Porte, D., Jr., and Schwartz, M. W. (1998) Signals that regulate food intake and energy homeostasis. Science 280, 1378-1383
3. Elmquist, J. K., Maratos-Flier, E., Saper, C. B., and Flier, J. S. (1998) Unraveling the central nervous system pathways underlying responses to leptin. Nat. Neurosci. 1, 445-450
4. Flier, J. S., and Maratos-Flier, E. (1998) Obesity and the hypothalamus: novel peptides for new pathways. Cell 92, 437-440
5. Bray, G.A., and York, D.A. (1998) The MONA LISA hypothesis in the time of leptin. Recent Prog. Horm. Res. 53, 95-117
6. Inui, A. (1999) Feeding and body-weight regulation by hypothalamic neuropeptides-mediation of the actions of leptin. Trends Neurosci. 22, 62-67
7. Kalra, S. P., Dube, M. G., Pu, S., Xu, B., Horvath, T. L., and Kalra, P. S. (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20, 68-100
8. Inui, A. (2000) Transgenic study of energy homeostasis equation: implications and confounding influences. FASEB J. 14, 2158-2170
9. Inui, A. (2000) Transgenic approach to the study of body weight regulation. Pharmacol. Rev. 52, 35-61
10. Bray, G. A., and Tartaglia, L. A. (2000) Medicinal strategies in the treatment of obesity. Nature (London) 404, 672-677
11. Schwartz, M. W., Woods, S. C., Porte, D., Jr., Seeley, R.J., and Baskin, D. G. (2000) Central nervous system control of food intake. Nature (London) 404, 661-671
12. Spiegelman, B. M., and Flier, J. S. (2001) Obesity and the regulation of energy balance. Cell 104, 531-543
13. Saper, C. B., Chou, T. C., and Elmquist, J. K. (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199-211
14. Kojima, M., Hosoda, H., Date, Y., Nakazato, M., Matsuo, H., and Kangawa, K. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature (London) 402, 656-660
15. Tschöp, M., Smiley, D. L., and Heiman, M. L. (2000) Ghrelin induces adiposity in rodents. Nature (London) 407, 908-913
16. Asakawa, A., Inui, A., Kaga, T., Yuzuriha, H., Nagata, T., Ueno, N., Makino, S., Fujimiya, M., Niijima, A., Fujino, M. A., et al. (2001) Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 120, 337-345
17. Inui, A. (2001) Ghrelin: an orexigenic and somatotrophic signal from stomach. Nat. Rev. Neurosci. 2, 551-560
18. Frohman, L. A., Downs, T. R., and Chomczynski, P. (1992) Regulation of growth hormone secretion. Front. Neuroendocrinol. 13, 344-405
19. Smith, R. G., Van der Ploeg, L. H., Howard, A. D., Feighner, S. D., Cheng, K., Hickey, G. J., Wyvratt, M.J., Jr., Fisher, M. H., Nargund, R. P., and Patchett, A. A. (1997) Peptidomimetic regulation of growth hormone secretion. Endocr. Rev. 18, 621-645
20. Bowers, C. Y., Momany, F., Reynolds, G. A., Chang, D., Hong, A., and Chang, K. (1980) Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 106, 663-667
21. Bowers, C. Y., Momany, F. A., Reynolds, G. A., and Hong, A. (1984) On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 114, 1537-1545
22. Bowers, C. Y. (2001) Unnatural growth hormone-releasing peptide begets natural ghrelin. J. Clin. Endocrinol. Metab. 86, 1464-1469
23. Guillemin, R., Brazeau, P., Bohlen, P., Esch, F., Ling, N., and Wehrenberg, W. B. (1982) Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 218, 585-587
24. Casanueva, F. F., and Dieguez, C. (1999) Growth hormone secretagogues: physiological role and clinical utility. Trends Endocrinol. Metab. 10, 30-38
25. Chapman, I. M., Bach, M. A., Van Cauter, E., Farmer, M., Krupa, D., Taylor, A. M., Schilling, L. M., Cole, K. Y., Skiles, E. H., Pezzoli, S. S., et al. (1996) Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. J. Clin. Endocrinol. Metab. 81, 4249-4257
26. Ghigo, E., Arvat, E., Giordano, R., Broglio, F., Gianotti, L., Maccario, M., Bisi, G., Graziani, A., Papotti, M., Muccioli, G., et al. (2001) Biologic activities of growth hormone secretagogues in humans. Endocrine 14, 87-93
27. Guan, X. M., Yu, H., Palyha, O. C., McKee, K. K., Feighner, S. D., Sirinathsinghji, D. J., Smith, R. G., Van der Ploeg, L. H., and Howard, A. D. (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Mol. Brain Res. 48, 23-29
28. Gnanapavan, S., Kola, B., Bustin, S. A., Morris, D. G., McGee, P., Fairclough, P., Bhattacharya, S., Carpenter, R., Grossman, A. B., and Korbonits, M. (2002) The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J. Clin. Endocrinol. Metab. 87, 2988
29. Hattori, N., Saito, T., Yagyu, T., Jiang, B. H., Kitagawa, K., and Inagaki, C. (2001) GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. J. Clin. Endocrinol. Metab. 86, 4284-4291
30. Papotti, M., Ghe, C., Cassoni, P., Catapano, F., Deghenghi, R., Ghigo, E., and Muccioli, G. (2000) Growth hormone secretagogue binding sites in peripheral human tissues. J. Clin. Endocrinol. Metab. 85, 3803-3807
31. Shuto, Y., Shibasaki, T., Wada, K., Parhar, I., Kamegai, J., Sugihara, H., Oikawa, S., and Wakabayashi, I. (2001) Generation of polyclonal antiserum against the growth hormone secretagogue receptor (GHS-R): evidence that the GHS-R exists in the hypothalamus, pituitary and stomach of rats. Life Sci. 68, 991-996
32. Casanueva, F. F., and Dieguez, C. (2002) Ghrelin: the link connecting growth with metabolism and energy homeostasis. Rev. Endocr. Metab. Disord. 3, 325-338
33. Muccioli, G., Tschop, M., Papotti, M., Deghenghi, R., Heiman, M., and Ghigo, E. (2002) Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur. J. Pharmacol. 440, 235-254
34. Wang, G., Lee, H. M., Englander, E., and Greeley, G. H., Jr. (2002) Ghrelin-not just another stomach hormone. Regul. Pept. 105, 75-81
35. Howard, A. D., Feighner, S. D., Cully, D. F., Arena, J. P., Liberator, P. A., Rosenblum, C. I., Hamelin, M., Hreniuk, D. L., Palyha, O. C., Anderson, J., et al. (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273, 974-977
36. Tomasetto, C., Karam, S. M., Ribieras, S., Masson, R., Lefebvre, O., Staub, A., Alexander, G., Chenard, M. P., and Rio, M. C. (2000) Identification and characterization of a novel gastric peptide hormone: the motilin-related peptide. Gastroenterology 119, 395-405
37. Itoh, Z. (1997) Motilin and clinical application. Peptides 18, 593-608
38. Samson, W. K., Lumpkin, M. D., Nilaver, G., and McCann, S. M. (1984) Motilin: a novel growth hormone releasing agent. Brain Res. Bull. 12, 57-62
39. Rehfeld, J. F. (1998) The new biology of gastrointestinal hormones. Physiol. Rev. 78, 1087-1108
40. Nilsson, A. H. (2001) The gut as the largest endocrine organ in the body. Ann. Oncol. 12 (Suppl. 2), S63-S68
41. Hosoda, H., Kojima, M., Matsuo, H., and Kangawa, K. (2000) Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J. Biol. Chem. 275, 21995-22000
42. Baldanzi, G., Filigheddu, N., Cutrupi, S., Catapano, F., Bonissoni, S., Fubini, A., Malan, D., Baj, G., Granata, R., Broglio, F., et al. (2002) Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI3-kinase/AKT. J. Cell Biol. 159, 1029-1037
43. Hosoda, H., Kojima, M., Mizushima, T., Shimizu, S., and Kangawa, K. (2003) Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J. Biol. Chem. 278, 64-70
44. Bednarek, M. A., Feighner, S. D., Pong, S. S., McKee, K. K., Hreniuk, D. L., Silva, M. V., Warren, V. A., Howard, A. D., Van Der Ploeg, L. H., and Heck, J. V. (2000) Structure-function studies on the new growth hormone-releasing peptide, ghrelin: minimal sequence of ghrelin necessary for activation of growth hormone secretagogue receptor 1a. J. Med. Chem. 43, 4370-4306
45. Poitras, P. (1994) Motilin. In Gut Peptides: Biochemistry and Physiology (Walsh J. H., and Dockray, G. J., eds) pp. 261-304 Raven, New York
46. Tomasetto, C., Wendling, C., Rio, M. C., and Poitras, P. (2001) Identification of cDNA encoding motilin related peptide/ghrelin precursor from dog fundus. Peptides 22, 2055-2059
47. Date, Y., Kojima, M., Hosoda, H., Sawaguchi, A., Mondal, M. S., Suganuma, T., Matsukura, S., Kangawa, K., and Nakazato, M. (2000) Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 141, 4255-4261
48. Hosoda, H., Kojima, M., Matsuo, H., and Kangawa, K. (2000) Ghrelin and des-acyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem. Biophys. Res. Commun. 279, 909-913
49. Lee, H. M., Wang, G., Englander, E. W., Kojima, M., and Greeley, G. H., Jr. (2002) Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 143, 185-190
50. Rindi, G., Necchi, V., Savio, A., Torsello, A., Zoli, M., Locatelli, V., Raimondo, F., Cocchi, D., and Solcia, E. (2002) Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem. Cell Biol. 117, 511-519
51. Ariyasu, H., Takaya, K., Tagami, T., Ogawa, Y., Hosoda, K., Akamizu, T., Suda, M., Koh, T., Natsui, K., et al. (2001) Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 86, 4753-4758
52. Sakata, I., Nakamura, K., Yamazaki, M., Matsubara, M., Hayashi, Y., Kangawa, K., and Sakai, T. (2002) Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides 23, 531-536
53. Korbonits, M., Bustin, S. A., Kojima, M., Jordan, S., Adams, E. F., Lowe, D. G., Kangawa, K., and Grossman, A. B. (2001) The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J. Clin. Endocrinol. Metab. 86, 881-887
54. Date, Y., Nakazato, M., Hashiguchi, S., Dezaki, K., Mondal, M. S., Hosoda, H., Kojima, M., Kangawa, K., Arima, T., Matsuo, H., et al. (2002) Ghrelin is present in pancreatic alpha-cells of humans and rats and stimulates insulin secretion. Diabetes 51, 124-129
55. Volante, M., Allia, E., Gugliotta, P., Funaro, A., Broglio, F., Deghenghi, R., Muccioli, G., Ghigo, E., and Papotti, M. (2002) Expression of ghrelin and of the GH secretagogue receptor by pancreatic islet cells and related endocrine tumors. J. Clin. Endocrinol. Metab. 87, 1300-1308
56. Wierup, N., Svensson, H., Mulder, H., and Sundler, F. (2002) The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regul. Pept. 107, 63-69
57. Mori, K., Yoshimoto, A., Takaya, K., Hosoda, K., Ariyasu, H., Yahata, K., Mukoyama, M., Sugawara, A., Hosoda, H., Kojima, M., et al. (2000) Kidney produces a novel acylated peptide, ghrelin. FEBS Lett. 486, 213-216
58. Tena-Sempere, M., Barreiro, M. L., Gonzalez, L. C., Gaytan, F., Zhang, F. P., Caminos, J. E., Pinilla, L., Casanueva, F. F., Dieguez, C., and Aguilar, E. (2002) Novel expression and functional role of ghrelin in rat testis. Endocrinology 143, 717-725
59. Gualillo, O., Caminos, J., Blanco, M., Garcia-Caballero, T., Kojima, M., Kangawa, K., Dieguez, C., and Casanueva, F. (2001) Ghrelin, a novel placental-derived hormone. Endocrinology 142, 788-794
60. Pinkney, J., and Williams, G. (2002) Ghrelin gets hungry. Lancet 359, 1360-1361
61. Beck, B., Musse, N., and Stricker-Krongrad, A. (2002) Ghrelin, macronutrient intake and dietary preferences in long-evans rats. Biochem. Biophys. Res. Commun. 292, 1031-1035
62. Van der Toorn, F. M., Janssen, J. A., de Herder, W. W., Broglio, F., Ghigo, E., and van der Lely, A. J. (2002) Central ghrelin production does not substantially contribute to systemic ghrelin concentrations: a study in two subjects with active acromegaly. Eur. J. Endocrinol. 147, 195-199
63. Toshinai, K., Mondal, M. S., Nakazato, M., Date, Y., Murakami, N., Kojima, M., Kangawa, K., and Matsukura, S. (2001) Upregulation of ghrelin expression in the stomach upon fasting, insulin-induced hypoglycemia, and leptin administration. Biochem. Biophys. Res. Commun. 281, 1220-1225
64. Asakawa, A., Inui, A., Yuzuriha, H., Ueno, N., Katsuura, G., Fujimiya, M., Fujino, M. A., Niijima, A., Meguid, M. M., and Kasuga, M. (2003) Characterization of the effects of pancreatic polypeptide in the regulation of energy balance. Gastroenterology 124, 1325-1336
65. Asakawa, A., Inui, A., Kaga, T., Katsuura, G., Fujimiya, M., Fujino, M. A., and Kasuga, M. (2003) Antagonism of ghrelin receptor reduces food intake and body weight gain in mice. Gut 52, 947-952
66. Schaller, G., Schmidt, A., Pleiner, J., Woloszczuk, W., Wolzt, M., and Luger, A. (2003) Plasma ghrelin concentrations are not regulated by glucose or insulin: a double-blind, placebo-controlled crossover clamp study. Diabetes 52, 16-20
67. Garthwaite, T. L. (1985) Peripheral motilin administration stimulates feeding in fasted rats. Peptides 6, 41-44
68. Rosenfeld, D. J., and Garthwaite, T. L. (1987) Central administration of motilin stimulates feeding in rats. Physiol. Behav. 39, 753-756
69. Asakawa, A., Inui, A., Momose, K., Ueno, N., Fujino, M. A., and Kasuga, M. (1998) Motilin increases food intake in mice. Peptides 19, 987-990
70. Moran, T. H., Ameglio, P.J., Schwartz, G.J., and McHugh, P. R. (1992) Blockade of type A, not type B, CCK receptors attenuates satiety actions of exogenous and endogenous CCK. Am. J. Physiol. 262, R46-R50
71. Hirosue, Y., Inui, A., Teranishi, A., Miura, M., Nakajima, M., Okita, M., Nakajima, Y., Himori, N., Baba, S., and Kasuga, M. (1993) Cholecystokinin octapeptide analogues suppress food intake via central CCK-A receptors in mice. Am. J Physiol. 265, R481-R486
72. Barrachina, M. D., Martinez, V., Wang, L., Wei, J. Y., and Tache, Y. (1997) Synergistic interaction between leptin and cholecystokinin to reduce short-term food intake in lean mice. Proc. Natl. Acad. Sci. USA 94, 10455-10460
73. Lovshin, J. A., and Drucker, D. J. (2003) Glucagon-like peptides, the central nervous system, and the regulation of energy homeostasis. Curr. Med. Chem.-Central Nervous System Agents 3, 73-80
74. Batterham, R. L., Cowley, M. A., Small, C. J., Herzog, H., Cohen, M. A., Dakin, C. L., Wren, A. M., Brynes, A. E., Low, M.J., Ghatei, M. A., et al. (2002) Gut hormone PYY (3-36) physiologically inhibits food intake. Nature (London) 418, 650-654
75. Wren, A. M., Small, C. J., Ward, H. L., Murphy, K. G., Dakin, C. L., Taheri, S., Kennedy, A. R., Roberts, G. H., Morgan, D. G., Ghatei, M. A., et al. (2000) The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141, 4325-4328
76. Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., and Matsukura, S. A role for ghrelin in 2001. A role for ghrelin in the central regulation of feeding. Nature (London) 409, 194-198
77. Shintani, M., Ogawa, Y., Ebihara, K., Aizawa-Abe, M., Miyanaga, F., Takaya, K., Hayashi, T., Inoue, G., Hosoda, K., Kojima, M., et al. (2001) 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 50, 227-232
78. Inui, A. (1999) Neuropeptide Y feeding receptors: are multiple subtypes involved? Trends Pharmacol. Sci. 20, 43-46
79. Morton, G. J., and Schwartz, M. W. (2001) The NPY/AgRP neuron and energy homeostasis. Int. J. Obes. Relat. Metab. Disord. 25, S56-S62
80. Cone, R. D., Cowley, M. A., Butler, A. A., Fan, W., Marks, D. L., and Low, M. J. (2001) The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int. J. Obes. Relat. Metab. Disord. 25, S63-S67
81. Jeanrenaud, B., and Rohner-Jeanrenaud, F. (2001) Effects of neuropeptides and leptin on nutrient partitioning: dysregulations in obesity. Annu. Rev. Med. 52, 339-351
82. Cowley, M. A., Pronchuk, N., Fan, W., Dinulescu, D. M., Colmers, W. F., and Cone, R. D. (1999) Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat. Neuron 24, 155-163
83. Kaga, T., Inui, A., Okita, M., Asakawa, A., Ueno, N., Kasuga, M., Fujimiya, M., Nishimura, N., Dobashi, R., Morimoto, Y., et al. (2001) Modest overexpression of neuropeptide Y in the brain leads to obesity after high-sucrose feeding. Diabetes 50, 1206-1210
84. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., Williams, S. C., Richardson, J. A., Kozlowski, G. P., Wilson, S., et al. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573-585
85. Shimada, M., Tritos, N. A., Lowell, B. B., Flier, J. S., and Maratos-Flier, E. (1998) Mice lacking melanin-concentrating hormone are hypophagic and lean. Nature (London) 396, 670-674
86. Willesen, M. G., Kristensen, P., and Romer, J. (1999) Colocalization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306-316
87. Dickson, S. L., and Luckman, S. M. (1997) Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6. Endocrinology 138, 771-777
88. Hewson, A. K., and Dickson, S. L. (2000) Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J. Neuroendocrinol. 12, 1047-1049
89. Wang, L., Saint-Pierre, D. H., and Tache, Y. (2002) Peripheral ghrelin selectively increases Fos expression in neuropeptide Y-synthesizing neurons in mouse hypothalamic arcuate nucleus. Neurosci. Lett. 325, 47-51
90. Kamegai, J., Tamura, H., Shimizu, T., Ishii, S., Sugihara, H., and Wakabayashi, I. (2000) Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 4797-4800
91. Okada, K., Ishii, S., Minami, S., Sugihara, H., Shibasaki, T., and Wakabayashi, I. (1996) Intracerebroventricular administration of the growth hormone-releasing peptide KP-102 increases food intake in free-feeding rats. Endocrinology 137, 5155-5158
92. Torsello, A., Luoni, M., Schweiger, F., Grilli, R., Guidi, M., Bresciani, E., Deghenghi, R., Muller, E. E., and Locatelli, V. (1998) Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release. Eur. J. Pharmacol. 360, 123-129
93. Locke, W., Kirgis, H. D., Bowers, C. Y., and Abdoh, A. A. (1995) Intracerebroventricular growth-hormone-releasing peptide-6 stimulates eating without affecting plasma growth hormone responses in rats. Life Sci. 56, 1347-1352
94. Ghigo, E., Arvat, E., Broglio, F., Giordano, R., Gianotti, L., Muccioli, G., Papotti, M., Graziani, A., Bisi, G., Deghenghi, R., et al. (1999) Endocrine and non-endocrine activities of growth hormone secretagogues in humans. Horm. Res. 51, 9-15
95. Tschop, M., Statnick, M. A., Suter, T. M., and Heiman, M. L. (2002) GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology 143, 558-568
96. Lawrence, C. B., Snape, A. C., Baudoin, F. M., and Luckman, S. M. (2002) Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology 143, 155-162
97. Toshinai, K., Date, Y., Murakami, N., Shimada, M., Mondal, M. S., Shimbara, T., Guan, J. L., Wang, Q. P., Funahashi, H., Sakurai, T., et al. (2003) Ghrelin-induced food intake is mediated via the orexin pathway. Endocrinology 144, 1506-1512
98. Shuto, Y., Shibasaki, T., Otagiri, A., Kuriyama, H., Ohata, H., Tamura, H., Kamegai, J., Sugihara, H., Oikawa, S., and Wakabayashi, I. (2002) Hypothalamic growth hormone secretagogue receptor regulates growth hormone secretion, feeding, and adiposity. J. Clin. Invest. 109, 1429-1436
99. Tamura, H., Kamegai, J., Shimizu, T., Ishii, S., Sugihara, H., and Oikawa, S. (2002) Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology 143, 3268-3275
100. Bloch, B., Ling, N., Benoit, R., Wehrenberg, W. B., and Guillemin, R. (1984) Specific depletion of immunoreactive growth hormone-releasing factor by monosodium glutamate in rat median eminence. Nature (London) 307, 272-273
101. Morris, M.J., Tortelli, C. F., Filippis, A., and Proietto, J. (1998) Reduced BAT function as a mechanism for obesity in the hypophagic, neuropeptide Y deficient monosodium glutamate-treated rat. Regul. Pept. 75-76, 441-447
102. Hewson, A. K., Tung, L. Y., Connell, D. W., Tookman, L., and Dickson, S. L. (2002) The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. Diabetes 51, 3412-3419
103. Banks, W. A., Kastin, A. J., Huang, W., Jaspan, J. B., and Maness, L. M. (1996) Leptin enters the brain by a saturable system independent of insulin. Peptides 17, 305-311
104. Baura, G. D., Foster, D. M., Porte, D. Jr., Kahn, S. E., Bergman, R. N., Cobelli, C., and Schwartz, M. W. (1993) Saturable transport of insulin from plasma into the central nervous system of dogs in vivo. A mechanism for regulated insulin delivery to the brain. J. Clin. Invest. 92, 1824-1830
105. Banks, W. A., Tschop, M., Robinson, S. M., and Heiman, M. L. (2002) Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J. Pharmacol. Exp. Ther. 302, 822-827
106. Traebert, M., Riediger, T., Whitebread, S., Scharrer, E., and Schmid, H. A. (2002) Ghrelin acts on leptin-responsive neurones in the rat arcuate nucleus. J. Neuroendocrinol. 14, 580-586
107. 2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 52, 948-956
108. Cowley, M. A., Smith, R. G., Diano, S., Tschop, M., Pronchuk, N., Grove, K. L., Strasburger, C. J., Bidlingmaier, M., Esterman, M., Heiman, M. L., et al. (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649-661
109. Dube, M. G., Beretta, E., Dhillon, H., Ueno, N., Kalra, P. S., and Kalra, S. P. (2002) Central leptin gene therapy blocks high-hat diet-induced weight gain, hyperleptinemia, and hyperinsulinemia: increase in serum ghrelin levels. Diabetes 51, 1729-1736
110. Lowell, B. B., and Spiegelman, B. M. (2000) Towards a molecular understanding of adaptive thermogenesis. Nature (London) 404, 652-660
111. Horvath, T. L., Diano, S., Sotonyi, P., Heiman, M., and Tschop, M. (2001) Ghrelin and the regulation of energy balance-a hypothalamic perspective. Endocrinology 142, 4163-4169
112. Tschöp, M., Flora, D. B., Mayer, J. P., and Heiman, M. L. (2002) Hypophysectomy prevents ghrelin-induced adiposity and increases gastric ghrelin secretion in rats. Obes. Res. 10, 991-999
113. Masuda, Y., Tanaka, T., Inomata, N., Ohnuma, N., Tanaka, S., Itoh, Z., Hosoda, H., Kojima, M., and Kangawa, K. (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem. Biophys. Res. Commun. 276, 905-908
114. Trudel, L., Tomasetto, C., Rio, M. C., Bouin, M., Plourde, V., Eberling, P., and Poitras, P. (2002) Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. Am. J. Physiol. 282, G948-G952
115. Plourde, V., Wong, H. C., Walsh, J. H., Raybould, H. E., and Tache, Y. (1993) CGRP antagonists and capsaicin on celiac ganglia partly prevent postoperative gastric ileus. Peptides 14, 1225-1229
116. Poitras, P., Trudel, L., Miller, P., and Gu, C. M. (1997) Regulation of motilin release: studies with ex vivo perfused canine jejunum. Am. J. Physiol. 272, G4-G9
117. Wingate, D. L. (1981) Backwards and forwards with the migrating complex. Dig. Dis. Sci. 26, 641-666
118. Itoh, Z., and Sekiguchi, T. (1983) Interdigestive motor activity in health and disease. Scand. J. Gastroenterol. Suppl. 82, 121-134
119. Kellow, J. E., Borody, T. J., Phillips, S. F., Tucker, R. L., and Haddad, A. C. (1986) Human interdigestive motility: variations in patterns from esophagus to colon. Gastroenterology 91, 386-395
120. 2 receptors in conscious fed rats. Am. J. Physiol. 278, G32-G38
121. Fujino, K., Inui, A., Asakawa, A., Fujimura, M., and Fujimiya, M. (2003) Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J. Physiol. 550, 227-240
122. Verkijk, M., Gielkens, H. A., Lamers, C. B., and Masclee, A. A. (1998) Effect of gastrin on antroduodenal motility: role of intraluminal acidity. Am. J. Physiol. 275, G1209-G1216
123. Zhang, W., Chen, M., Chen, X., Segura, B. J., and Mulholl, M. W. (2001) Inhibition of pancreatic protein secretion by ghrelin in the rat. J. Physiol. (London) 537, 231-236
124. Fujimiya, M., and Inui, A. (2000) Peptidergic regulation of gastrointestinal motility in rodents. Peptides 21, 1565-1582
125. Ishiguchi, T., Amano, T., Matsubayashi, H., Tada, H., Fujita, M., and Takahashi, T. (2001) Centrally administered neuropeptide Y delays gastric emptying via Y2 receptors in rats. Am. J. Physiol. 281, R1522-R1530
126. Kihara, N., Yamamoto, I., Itoh, E., Inui, A., and Fujimiya, M. (2001) Effects of central and peripheral urocortin on gastroduodenal fed and fasted motor activities in conscious rats. Am. J. Physiol. 280, G406-G419
127. Bueno, L. (1993) Involvement of brain CCK in the adaptation of gut motility to digestive status and stress: a review. J. Physiol. (Paris) 87, 301-306
128. Hashmonai, M., and Szurszewski, J. H. (1998) Effect of cerebroventricular perfusion of bombesin on gastrointestinal myoelectric activity. Am. J. Physiol. 274, G677-G686
129. Kellow, J. E., Miller, L. J., Phillips, S. F., Haddad, A. C., Zinsmeister, A. R., and Charboneau, J. W. (1987) Sensitivities of humanjejunum, ileum, proximal colon, and gallbladder to cholecystokinin octapeptide. Am. J. Physiol. 252, G345-G356
130. Matsuda, M., Aono, M., Moriga, M., and Okuma, M. (1993) Centrally administered neuropeptide Y (NPY) inhibits gastric emptying and intestinal transit in the rat. Dig. Dis. Sci. 38, 845-850
131. Chen, C. H., Stephens, R. L., Jr., and Rogers, R. C. (1997) PYY and NPY: control of gastric motility via action on Y1 and Y2 receptors in the DVC. Neurogastroenterol. Motil. 9, 109-116
132. Peeters, T. L., Muls, E., Janssens, J., Urbain, J. L., Bex, M., Cutsem, E. V., Depoortere, I., Roo, M. D., Vantrappen, G., and Bouillon, R. (1992) Effect of motilin on gastric emptying in patients with diabetic gastroparesis. Gastroenterology 102, 97-101
133. Sibilia, V., Pagani, F., Guidobono, F., Locatelli, V., Torsello, A., Deghenghi, R., and Netti, C. (2002) Evidence for a central inhibitory role of growth hormone secretagogues and ghrelin on gastric acid secretion in conscious rats. Neuroendocrinology 75, 92-97
134. Masuda, Y., Tanaka, T., Inomata, N., Ohnuma, N., Tanaka, S., Itoh, Z., Hosoda, H., Kojima, M., and Kangawa, K. (2000) Ghrelin stimulates gastric acid secretion and motility in rats. Biochem. Biophys. Res. Commun. 276, 905-908
135. Date, Y., Nakazato, M., Murakami, N., Kojima, M., Kangawa, K., and Matsukura, S. (2001) Ghrelin acts in the central nervous system to stimulate gastric acid secretion. Biochem. Biophys. Res. Commun. 280, 904-907
136. Torsello, A., Locatelli, V., Melis, M. R., Succu, S., Spano, M. S., Deghenghi, R., Muller, E. E., Argiolas, A., Torsello, A., Locatelli, V., et al. (2000) Differential orexigenic effects of hexarelin and its analogs in the rat hypothalamus: indication for multiple growth hormone secretagogue receptor subtypes. Neuroendocrinology 72, 327-332
137. Lu, S., Guan, J. L., Wang, Q. P., Uehara, K., Yamada, S., Goto, N., Date, Y., Nakazato, M., Kojima, M., Kangawa, K., et al. (2002) Immunocytochemical observation of ghrelin-containing neurons in the rat arcuate nucleus. Neurosci. Lett. 321, 157-160
138. Schwartz, G. J. (2000) The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 16, 866-873
139. Asakawa, A., Inui, A., Ueno, N., Makino, S., Fujino, M. A., and Kasuga, M. (1999) Urocortin reduces food intake and gastric emptying in lean and ob/ob obese mice. Gastroenterology 116, 1287-1292
140. Duggan, J. P., and Booth, D. A. (1986) Obesity, overeating, and rapid gastric emptying in rats with ventromedial hypothalamic lesions. Science 231, 609-611
141. Tache, Y., Garrick, T., and Raybould, H. (1990) Central nervous system action of peptides to influence gastrointestinal motor function. Gastroenterology 98, 517-528
142. Suto, G., Kiraly, A., and Tache, Y. (1994) Interleukin 1 beta inhibits gastric emptying in rats: mediation through prostaglandin and corticotropin-releasing factor. Gastroenterology 106, 1568-1575
143. Tache, Y., Yang, H., and Kaneko, H. (1995) Caudal raphedorsal vagal complex peptidergic projections: role in gastric vagal control. Peptides 16, 431-435
144. 2 receptors. Am. J. Physiol. 274, G965-G970
145. Nozu, T., Martinez, V., Rivier, J. L., and Tache, Y. (1999) Peripheral urocortin delays gastric emptying: role of CRF receptor 2. Am. J. Physiol. 276, G867-G874
146. Forster, E. R., Green, T., Elliot, M., Bremner, A., and Dockray, G. J. (1990) Gastric emptying in rats: role of afferent neurons and cholecystokinin. Am. J. Physiol. 258, G552-G556
147. Inui, A. (1999) Cancer anorexia-cachexia syndrome: are neuropeptides the key? Cancer Res. 59, 4493-4501
148. Smith, G. P., and Gibbs, J. (1994) Satiating effect of cholecystokinin. Ann. N.Y. Acad. Sci. 713, 236-241
149. Schwartz, G. J., and Moran, T. H. (1994) CCK elicits and modulates vagal afferent activity arising from gastric and duodenal sites. Ann. N.Y. Acad. Sci. 713, 121-128
150. Moran, T. H. (2000) Cholecystokinin and satiety: current perspectives. Nutrition 16, 858-865
151. Moran, T. H., and McHugh, P. R. (1982) Cholecystokinin suppresses food intake by inhibiting gastric emptying. Am. J. Physiol. 242, R491-R497
152. Zander, M., Madsbad, S., Madsen, J. L., and Holst, J. J. (2002) Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 359, 824-830
153. Yamamoto, H., Lee, C. E., Marcus, J. N., Williams, T. D., Overton, J. M., Lopez, M. E., Hollenberg, A. N., Baggio, L., Saper, C. B., Drucker, D. J., et al. (2002) Glucagon-like peptide-1 receptor stimulation increases blood pressure and heart rate and activates autonomic regulatory neurons. J. Clin. Invest. 110, 43-52
154. Bado, A., Levasseur, S., Attoub, S., Kermorgant, S., Laigneau, J. P., Bortoluzzi, M. N., Moizo, L., Lehy, T., Guerre-Millo, M., Le Marchand-Brustel, Y., et al. (1998) The stomach is a source of leptin. Nature (London) 394, 790-793
155. Goiot, H., Attoub, S., Kermorgant, S., Laigneau, J. P., Lardeux, B., Lehy, T., Lewin, M. J., and Bado, A. (2001) Antral mucosa expresses functional leptin receptors coupled to STAT-3 signaling, which is involved in the control of gastric secretions in the rat. Gastroenterology 121, 1417-1427
156. Sobhani, I., Bado, A., Vissuzaine, C., Buyse, M., Kermorgant, S., Laigneau, J. P., Attoub, S., Lehy, T., Henin, D., Mignon, M., et al. (2000) Leptin secretion and leptin receptor in the human stomach. Gut 47, 178-183
157. Sobhani, I., Buyse, M., Goiot, H., Weber, N., Laigneau, J. P., Henin, D., Soul, J. C., and Bado, A. (2002) Vagal stimulation rapidly increases leptin secretion in human stomach. Gastroenterology 122, 259-263
158. Buyse, M., Ovesjo, M. L., Goiot, H., Guilmeau, S., Peranzi, G., Moizo, L., Walker, F., Lewin, M. J., Meister, B., and Bado, A. (2001) Expression and regulation of leptin receptor proteins in afferent and efferent neurons of the vagus nerve. Eur. J. Neurosci. 14, 64-72
159. Wang, L., Barachina, M. D., Martinez, V., Wei, J. Y., and Tache, Y. (2000) Synergistic interaction between CCK and leptin to regulate food intake. Regul. Pept. 92, 79-85
160. Buyse, M., Berlioz, F., Guilmeau, S., Tsocas, A., Voisin, T., Peranzi, G., Merlin, D., Laburthe, M., Lewin, M. J., Roze, C., et al. (2001) PepT1-mediated epithelial transport of dipeptides and cephalexin is enhanced by luminal leptin in the small intestine. J. Clin. Invest. 108, 1483-1494
161. Lindqvist, A., and Erlanson-Albertsson, C. (2003) Fat Digestion-its role in appetite regulation and energy balance-The importance of enterostation and tetrahydrolipstatin. Curr. Med. Chem.-Central Nervous System Agents 3, 157-175
162. Sorhede, M., Erlanson-Albertsson, C., Mei, J., Nevalainen, T., Aho, A., and Sundler, F. (1996) Enterostatin in gut endocrine cells-immunocytochemical evidence. Peptides 17, 609-614
163. Lin, L., McClanahan, S., York, D. A., and Bray, G. A. (1993) The peptide enterostatin may produce early satiety. Physiol. Behav. 53, 789-794
164. Lin, L., and York, D. A. (1997) Comparisons of the effects of enterostatin on food intake and gastric emptying in rats. Brain Res. 745, 205-209
165. Date, Y., Murakami, N., Toshinai, K., Matsukura, S., Niijima, A., Matsuo, H., Kangawa, K., and Nakazato, M. (2002) The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123, 1120-1128
166. Andrews, P. L., and Sanger, G. J. (2002) Abdominal vagal afferent neurones: an important target for the treatment of gastrointestinal dysfunction. Curr. Opin. Pharmacol. 2, 650-656
167. Burdyga, G., Spiller, D., Morris, R., Lal, S., Thompson, D. G., Saeed, S., Dimaline, R., Varro, A., and Dockray, G. J. (2002) Expression of the leptin receptor in rat and human nodose ganglion neurones. Neuroscience 109, 339-347
168. Gaige, S., Abysique, A., and Bouvier, M. (2002) Effects of leptin on cat intestinal vagal mechanoreceptors. J. Physiol. 543, 679-689
169. Bray, G. A. (2000) Afferent signals regulating food intake. Proc. Nutr. Soc. 59, 373-384
170. Furness, J. B., Koopmans, H. S., Robbins, H. L., Clerc, N., Tobin, J. M., and Morris, M. J. (2001) Effects of vagal and splanchnic section on food intake, weight, serum leptin and hypothalamic neuropeptide Y in rat. Auton. Neurosci. 92, 28-36
171. Burdyga, G., Lal, S., Spiller, D., Jiang, W., Thompson, D., Attwood, S., Saeed, S., Grundy, D., Varro, A., Dimaline, R., et al. (2003) Localization of orexin-1 receptors to vagal afferent neurons in the rat and humans. Gastroenterology 124, 129-139
172. Kirchgessner, A. L., and Liu, M. (1999) Orexin synthesis and response in the gut. Neuron 24, 941-951
173. Raybould, H. E., Gayton, R. J., and Dockray, G. J. (1988) Mechanisms of action of peripherally administered cholecystokinin octapeptide on brain stem neurons in the rat. J. Neurosci. 8, 3018-3024
174. Wang, L., Barachina, M. D., Martinez, V., Wei, J. Y., and Tache, Y. (2000) Synergistic interaction between CCK and leptin to regulate food intake. Regul. Pept. 92, 79-85
175. Schwartz, G. J., and Moran, T. H. (1996) Sub-diaphragmatic vagal afferent integration of meal-related gastrointestinal signals. Neurosci. Biobehav. Rev. 20, 47-56
176. Takaya, K., Ariyasu, H., Kanamoto, N., Iwakura, H., Yoshimoto, A., Harada, M., Mori, K., Komatsu, Y., Usui, T., Shimatsu, A., et al. (2000) Ghrelin strongly stimulates growth hormone release in humans. J. Clin. Endocrinol. Metab. 85, 4908-4911
177. Dieguez, C., and Casanueva, F. F. (2000) Ghrelin: a step forward in the understanding of somatotroph cell function and growth regulation. Eur. J. Endocrinol. 142, 413-417
178. Prager, D., and Melmed, S. (1993) Somatotroph insulin-like growth factor I signaling. Ann. N.Y. Acad. Sci. 692, 102-112
179. Laron, Z., Frenkel, J., Deghenghi, R., Anin, S., Klinger, B., and Silbergeld, A. (1995) Intranasal administration of the GHRP hexarelin accelerates growth in short children. Clin. Endocrinol. 43, 631-635
180. Cuneo, R. C., Salomon, F., McGauley, G. A., and Sonksen, P. H. (1992) The growth hormone deficiency syndrome in adults. Clin. Endocrinol. 37, 387-397
181. Jorgensen, J. O., Pedersen, S. A., Thuesen, L., Jorgensen, J., Ingemann-Hansen, T., Skakkebaek, N. E., and Christiansen, J. S. (1989) Beneficial effects of growth hormone treatment in GH-deficient adults. Lancet 1, 1221-1225
182. Casanueva, F. F., and Dieguez, C. (2002) Ghrelin: the link connecting growth with metabolism and energy homeostasis. Rev. Endocr. Metab. Disord. 3, 325-338
183. Janssen, J. A., van der Toorn, F. M., Hofland, L. J., van Koetsveld, P., Broglio, F., Ghigo, E., Lamberts, S. W., and Jan van der Lely, A. (2001) Systemic ghrelin levels in subjects with growth hormone deficiency are not modified by one year of growth hormone replacement therapy. Eur. J. Endocrinol. 145, 711-716
184. García, A., Alvarez, C. V., Smith, R. G., and Diéguez, C. (2001) Regulationof PIT-1 expression by ghrelin and GHRPP-6 through the GH secretagogue receptor. Mol. Endocrinol. 15, 1484-1495
185. Dieguez, C., and Casanueva, F. F. (1995) Influence of metabolic substrates and obesity on growth hormone secretion. Trends Endocrinol. Metab. 6, 55-59
186. Shiiya, T., Nakazato, M., Mizuta, M., Date, Y., Mondal, M. S., Tanaka, M., Nozoe, S., Hosoda, H., Kangawa, K., and Matsukura, S. (2002) Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J. Clin. Endocrinol. Metab. 87, 240-244
187. Tschop, M., Weyer, C., Tataranni, P. A., Devanarayan, V., Ravussin, E., and Heiman, M. L. (2001) Circulating ghrelin levels are decreased in human obesity. Diabetes 50, 707-709
188. Ikezaki, A., Hosoda, H., Ito, K., Iwama, S., Miura, N., Matsuoka, H., Kondo, C., Kojima, M., Kangawa, K., and Sugihara, S. (2002) Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Diabetes 51, 3408-3411
189. Hansen, T. K., Dall, R., Hosoda, H., Kojima, M., Kangawa, K., Christiansen, J. S., and Jorgensen, J. O. (2002) Weight loss increases circulating levels of ghrelin in human obesity. Clin. Endocrinol. 56, 203-206
190. Levin, B. E., and Keesey, R. E. (1998) Defense of differing body weight set points in diet-induced obese and resistant rats. Am. J. Physiol. 274, R412-R419
191. Levin, B. E. (1999) Arcuate NPY neurons and energy homeostasis in diet-induced obese and resistant rats. Am. J. Physiol. 276, R382-R387
192. English, P. J., Ghatei, M. A., Malik, I. A., Bloom, S. R., and Wilding, J. P. (2002) Food fails to suppress ghrelin levels in obese humans. J. Clin. Endocrinol. Metab. 87, 2984-2987
193. Cummings, D. E., Weigle, D. S., Frayo, R. S., Breen, P. A., Ma, M. K., Dellinger, E. P., and Purnell, J. Q. (2002) Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N. Engl. J. Med. 346, 1623-1630
194. Hasler, W. L. (2003) The stomach and weight reduction: The role of ghrelin. Gastroenterology 124, 575-577
195. Xu, Y., Ohinata, K., Meguid, M., et al. (2002) Model of Roux-en-Y gastric bypass in obese Zucker rats: effects on food intake and weight loss. Presented at the 26th meeting of the Association of VA Surgeons, Houston, TX, pp. 28-30
196. Nicholls, R. D., and Knepper, J. L. (2001) Genome organization, function, and imprinting in Prader-Willi and Angelman syndromes. Annu. Rev. Genomics Hum. Genet. 2, 153-175
197. Cummings, D. E., Clement, K., Purnell, J. Q., Vaisse, C., Foster, K. E., Frayo, R. S., Schwartz, M. W., Basdevant, A., and Weigle, D. S. (2002) Elevated plasma ghrelin levels in Prader Willi syndrome. Nat. Med. 8, 643-644
198. DelParigi, A., Tschop, M., Heiman, M. L., Salbe, A. D., Vozarova, B., Sell, S. M., Bunt, J. C., and Tataranni, P. A. (2002) High circulating ghrelin: a potential cause for hyperphagia and obesity in Prader-Willi syndrome. J. Clin. Endocrinol. Metab. 87, 5461-5464
199. Wren, A. M., Seal, L. J., Cohen, M. A., Brynes, A. E., Frost, G. S., Murphy, K. G., Dhillo, W. S., Ghatei, M. A., and Bloom, S. R. (2001) Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992-5995
200. Rittmaster, R. S., Loriaux, D. L., and Merriam, G. R. (1987) Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion. Neuroendocrinology 45, 118-122
201. Anderson, A. E., Soper, R. T., and Scott, D. H. (1980) Gastric bypass for morbid obesity in children and adolescents. J. Pediatr. Surg. 15, 876-881
202. Soper, R. T., Mason, E. E., Printen, K. J., and Zellweger, H. (1975) Gastric bypass for morbid obesity in children and adolescents. J. Pediatr. Surg. 10, 51-58
203. Campfield, L. A., Smith, F. J., and Burn, P. (1998) Strategies and potential molecular-targets for obesity treatment. Science 280, 1383-1387
204. Wright, R. A., Krinsky, S., Fleeman, C., Trujillo, J., and Teague, E. (1983) Gastric emptying and obesity. Gastroenterology 84, 747-751
205. Nauck, M. A., Niedereichholz, U., Ettler, R., Holst, J. J., Orskov, C., Ritzel, R., and Schmiegel, W. H. (1997) Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol. 273, E981-E988
206. Tschop, M., Wawarta, R., Riepl, R. L., Friedrich, S., Bidlingmaier, M., Landgraf, R., and Folwaczny, C. (2001) Post-prandial decrease of circulating human ghrelin levels. J. Endocrinol. Invest. 24, RC19-RC21
207. Okano, H., Inui, A., Ueno, N., Morimoto, S., Ohmoto, A., Miyamoto, M., Aoyama, N., Nakajima, Y., Baba, S., and Kasuga, M. (1996) EM523L, a nonpeptide motilin agonist, stimulates gastric emptying and pancreatic polypeptide secretion. Peptides 17, 895-900
208. Bonacini, M., Quiason, S., Reynolds, M., Gaddis, M., Pemberton, B., and Smith, O. (1993) Effect of intravenous erythromycin on postoperative ileus. Am. J. Gastroenterol. 88, 208-211
209. Ruppin, H., Kirndorfer, D., Domschke, S., Domschke, W., Schwemmle, K., Wunsch, E., and Demling, L. (1976) Effect of 13-Nle-motilin in postoperative ileus patients: a double-blind trial. Scand. J. Gastroenterol. Suppl. 39, 89-92
210. Neely, J., and Catchpole, B. (1971) Ileus: the restoration of alimentary-tract motility by pharmacological means. Br. J. Surg. 58, 21-28
211. Ishiguchi, T., Nakajima, M., Sone, H., Tada, H., Kumagai, A. K., and Takahashi, T. (2001) Gastric distension-induced pyloric relaxation: central nervous system regulation and effects of acute hyperglycaemia in the rat. J. Physiol. 533, 801-813
212. Janssens, J., Peeters, T. L., Vantrappen, G., Tack, J., Urbain, J. L., De Roo, M., Muls, E., and Bouillon, R. (1990) Improvement of gastric emptying in diabetic gastroparesis by erythromycin. N. Engl. J. Med. 322, 1028-1031
213. Tack, J., Janssens, J., Vantrappen, G., Peeters, T., Annese, V., Depoortere, I., Muls, E., and Bouillon, R. (1992) Effect of erythromycin on gastric motility in controls and in diabetic gastroparesis. Gastroenterology 103, 72-79
214. Krsek, M., Rosicka, M., Haluzik, M., Svobodova, J., Kotrlikova, E., Justova, V., Lacinoya, Z., and Jarkovska, Z. (2002) Plasma ghrelin levels in patients with short bowel syndrome. Endocr. Res. 28, 27-33
215. Nwokolo, C. U., Freshwater, D. A., O'Hare, P., and Randeva, H. S. (2003) Plasma ghrelin following cure of Helicobacter pylori. Gut 52, 637-640
216. Richter, T., Richter, T., List, S., Muller, D. M., Deutscher, J., Uhlig, H. H., Krumbiegel, P., Herbarth, O., Gutsmuths, F. J., and Kiess, W. (2001) Five- to 7-year-old children with Helicobacter pylori infection are smaller than Helicobacter-negative children: a cross-sectional population-based study of 3,315 children. J. Pediatr. Gastroenterol. Nutr. 33, 472-475
217. Buyukgebiz, A., Dundar, B., Bober, E., and Buyukgebiz, B. (2001) Helicobacter pylori infection in children with constitutional delay of growth and puberty. J. Pediatr. Endocrinol. Metab. 14, 549-551
218. Demir, H., Saltik, I. N., Kocak, N., Yuce, A., Ozen, H., and Gurakan, F. (2001) Subnormal growth in children with Helicobacter pylori infection. Arch. Dis. Child. 84, 89-90
219. Jolobe, O. M. (2000) Helicobacter pylori infection with iron deficiency anaemia and subnormal growth at puberty. Arch. Dis. Child. 82, 136-140
220. Sauve-Martin, H., Kalach, N., Raymond, J., Senouci, L., Benhamou, P. H., Martin, J. C., Briet, F., Maurel, M., Flourie, B., and Dupont, C. (1999) The rate of Helicobacter pylori infection in children with growth retardation. J. Pediatr. Gastroenterol. Nutr. 28, 354-355
221. Aggarwal, A. (1998) Helicobacter pylori infection: a cause of growth delay in children. Indian Pediatr. 35, 191-192
222. Ogura, K., Maeda, S., Nakao, M., Watanabe, T., Tada, M., Kyutoku, T., Yoshida, H., Shiratori, Y., and Omata, M. (2000) Virulence factors of Helicobacter pylori responsible for gastric diseases in Mongolian gerbil. J. Exp. Med. 192, 1601-1610
223. Sibilia, V., Rindi, G., Pagani, F., Rapetti, D., Locatelli, V., Torsello, A., Campanini, N., Deghenghi, R., and Netti, C. (2003) Ghrelin protects against ethanol-induced gastric ulcers in rats: studies on the mechanisms of action. Endocrinology 144, 353-359
224. Nagaya, N., Uematsu, M., Kojima, M., Date, Y., Nakazato, M., Okumura, H., Hosoda, H., Shimizu, W., Yamagishi, M., Oya, H., et al. (2001) Elevated circulating level of ghrelin in cachexia associated with chronic heart failure: relationships between ghrelin and anabolic/catabolic factors. Circulation 104, 2034-2038
225. Murphy, M. G., Plunkett, L. M., Gertz, B. J., He, W., Wittreich, J., Polvino, W. M., and Clemmons, D. R. (1998) MK-677, an orally active growth hormone secretagogue, reverses diet-induced catabolism. J. Clin. Endocrinol. Metab. 83, 320-325
226. Van den Berghe, G., de Zegher, F., Baxter, R. C., Veldhuis, J. D., Wouters, P., Schetz, M., Verwaest, C., Van der Vorst, E., Lauwers, P., Bouillon, R., et al. (1998) Neuroendocrinology of prolonged critical illness: effects of exogenous thyrotropin-releasing hormone and its combination with growth hormone secretagogues. J. Clin. Endocrinol. Metab. 83, 309-319
227. Welle, S. (1998) Growth hormone and insulin-like growth factor-I as anabolic agents. Curr. Opin. Clin. Nutr. Metab. Care 1, 257-262
228. Van den Berghe, G. (2000) Novel insights into the neuroendocrinology of critical illness. Eur. J. Endocrinol. 143, 1-13
229. Rigamonti, A. E., Pincelli, A. I., Corra, B., Viarengo, R., Bonomo, S. M., Galimberti, D., Scacchi, M., Scarpini, E., Cavagnini, F., and Muller, E. E. (2002) Plasma ghrelin concentrations in elderly subjects: comparison with anorexic and obese patients. J. Endocrinol. 175, R1-R5
230. Copinschi, G., Leproult, R., Van Onderbergen, A., Caufriez, A., Cole, K. Y., Schilling, L. M., Mendel, C. M., De Lepeleire, I., Bolognese, J. A., and Van Cauter, E. (1997) Prolonged oral treatment with MK-677, a novel growth hormone secretagogue, improves sleep quality in man. Neuroendocrinology 66, 278-286
231. Schwartz, M. W., Dallman, M. F., and Woods, S. C. (1995) Hypothalamic response to starvation: implications for the study of wasting disorders. Am. J. Physiol. 269, R949-R957
232. Inui, A. (2002) Cancer anorexia-cachexia syndrome: current issues in research and management. CA Cancer J. Clin. 52, 72-91
233. Gayle, D., Ilyin, S. E., and Plata-Salaman, C. R. (1997) Central nervous system IL-1 beta system and neuropeptide Y mRNAs during IL-1 beta-induced anorexia in rats. Brain Res. Bull. 44, 311-317
234. Plata-Salman, C. R. (1996) Anorexia during acute and chronic disease. Nutrition 12, 67-78
235. McCarthy, H. D., McKibbin, P. E., Perkins, A. V., Linton, E. A., and Williams, G. (1993) Alterations in hypothalamic NPY and CRF in anorexic tumor-bearing rats. Am. J. Physiol. 264, E638-E643
236. Chance, W. T., Balasubramaniam, A., and Fischer, J. E. (1995) Neuropeptide Y and the development of cancer anorexia. Ann. Surg. 221, 579-589
237. Inui, A. (1999) Neuropeptide Y: a key molecule in anorexia and cachexia in wasting disorders? Mol. Med. Today 5, 79-85
238. Plata-Salaman, C. R. (2000) Central nervous system mechanisms contributing to the cachexia-anorexia syndrome. Nutrition 16, 1009-1012
239. Meguid, M. M., Fetissov, S. O., Varma, M., Sato, T., Zhang, L., Laviano, A., and Rossi-Fanelli, F. (2000) Hypothalamic dopamine and serotonin in the regulation of food intake. Nutrition 16, 843-857
240. Chance, W. T., Balasubramaniam, A., and Sheriff, S. (2003) Neuropeptide Y and cancer anorexia. Curr. Med. Chem.-Central Nervous System Agents 3, 127-139
241. Wisse, B. E., Frayo, R. S., Schwartz, M. W., and Cummings, D. E. (2001) Reversal of cancer anorexia by blockade of central melanocortin receptors in rats. Endocrinology 142, 3292-3301
242. Shimizu, Y., Nagaya, N., Isobe, T., Imazu, M., Okumura, H., Hosoda, H., Kojima, M., Kangawa, K., and Kohno, N. (2003) Increased plasma ghrelin level in lung cancer cachexia. Clin. Cancer Res. 9, 774-778
243. Mantovani, G., Maccio, A., Massa, E., and Madeddu, C. (2001) Managing cancer-related anorexia/cachexia. Drugs 61, 499-514
244. Peeters, T. L. (1993) Erythromycin and other macrolides as prokinetic agents. Gastroenterology 105, 1886-1899
245. Inui, A. (2001) Eating behavior in anorexia nervosa-an excess of both orexigenic and anorexigenic signalling? Mol. Psychiatry 6, 620-624
246. Cuntz, U., Fruhauf, E., Wawarta, R., Tschop, M., Folwaczny, C., Riepl, R., Lehnert, P., Fichter, M., and Otto, B. (2002) A role for the novel weight-regulating hormone ghrelin in anorexia nervosa. Am. Clin. Lab. 21, 22-23
247. Nedvidkova, J., Krykorkova, I., Bartak, V., Papezova, H., Gold, P. W., Alesci, S., and Pacak, K. (2003) Loss of meal-induced decrease in plasma ghrelin levels in patients with anorexia nervosa. J. Clin. Endocrinol. Metab. 88, 1678-1682
248. Kaye, W. H., Berrettini, W., Gwirtsman, H., and George, D. T. (1990) Altered cerebrospinal fluid neuropeptide Y and peptide YY immunoreactivity in anorexia and bulimia nervosa. Arch. Gen. Psychiatry 47, 548-556
249. Otto, B., Cuntz, U., Fruehauf, E., Wawarta, R., Folwaczny, C., Riepl, R. L., Heiman, M. L., Lehnert, P., Fichter, M., and Tschop, M. (2001) Weight gain decreases elevated plasma ghrelin concentrations of patients with anorexia nervosa. Eur. J. Endocrinol. 145, 669-673
250. Tanaka, M., Naruo, T., Muranaga, T., Yasuhara, D., Shiiya, T., Nakazato, M., Matsukura, S., and Nozoe, S. (2002) Increased fasting plasma ghrelin levels in patients with bulimia nervosa. Eur. J. Endocrinol. 146, R1-R3
251. Inui, A. (2003) Diabetic hyperphagia, leptin and neuropeptide Y. Curr. Med. Chem. Central Nervous System Agents, i-iii
252. Ishii, S., Kamegai, J., Tamura, H., Shimizu, T., Sugihara, H., and Oikawa, S. (2002) Role of ghrelin in streptozotocin-induced diabetic hyperphagia. Endocrinology 143, 4934-4937
253. Sindelar, D. K., Mystkowski, P., Marsh, D. J., Palmiter, R. D., and Schwartz, M. W. (2002) Attenuation of diabetic hyperphagia in neuropeptide Y-deficient mice. Diabetes 51, 778-783
254. Broglio, F., Arvat, E., Benso, A., Gottero, C., Muccioli, G., Papotti, M., van der Lely, A. J., Deghenghi, R., and Ghigo, E. (2001) Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J. Clin. Endocrinol. Metab. 86, 5083-5086
255. Chapman, I. M., Bach, M. A., Van Cauter, E., Farmer, M., Krupa, D., Taylor, A. M., Schilling, L. M., Cole, K. Y., Skiles, E. H., Pezzoli, S. S., et al. (1996) Stimulation of the growth hormone (GH)-insulin-like growth factor I axis by daily oral administration of a GH secretogogue (MK-677) in healthy elderly subjects. J. Clin. Endocrinol. Metab. 81, 4249-4257
256. Volante, M., Fulcheri, E., Allia, E., Cerrato, M., Pucci, A., and Papotti, M. (2002) Ghrelin expression in fetal, infant, and adult human lung. J. Histochem. Cytochem. 50, 1013-1021
257. Hayashida, T., Nakahara, K., Mondal, M. S., Date, Y., Nakazato, M., Kojima, M., Kangawa, K., and Murakami, N. (2002) Ghrelin in neonatal rats: distribution in stomach and its possible role. J. Endocrinol. 173, 239-245
258. Iniguez, G., Ong, K., Pena, V., Avila, A., Dunger, D., and Mericq, V. (2002) Fasting and post-glucose ghrelin levels in SGA infants: relationships with size and weight gain at one year of age. J. Clin. Endocrinol. Metab. 87, 5830-5833
259. Nagaya, N., Kojima, M., Uematsu, M., Yamagishi, M., Hosoda, H., Oya, H., Hayashi, Y., and Kangawa, K. (2001) Hemodynamic and hormonal effects of human ghrelin in healthy volunteers. Am. J. Physiol. 280, R1483-R1487
260. Cassoni, P., Papotti, M., Ghe, C., Catapano, F., Sapino, A., Graziani, A., Deghenghi, R., Reissmann, T., Ghigo, E., and Muccioli, G. (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. J. Clin. Endocrinol. Metab. 86, 1738-1745
261. Cassoni, P., Papotti, M., Catapano, F., Ghe, C., Deghenghi, R., Ghigo, E., and Muccioli, G. (2000) Specific binding sites for synthetic growth hormone secretagogues in non-tumoral and neoplastic human thyroid tissue. J. Endocrinol. 165, 139-146
262. Ghe, C., Cassoni, P., Catapano, F., Marrocco, T., Deghenghi, R., Ghigo, E., Muccioli, G., and Papotti, M. (2002) The antiproliferative effect of synthetic peptidyl GH secretagogues in human CALU-1 lung carcinoma cells. Endocrinology 143, 484-491
263. Murata, M., Okimura, Y., lida, K., Matsumoto, M., Sowa, H., Kaji, H., Kojima, M., Kangawa, K., and Chihara, K. (2002) Ghrelin modulates the downstream molecules of insulin signaling in hepatoma cells. J. Biol. Chem. 277, 5667-5674
264. Jeffery, P. L., Herington, A. C., and Chopin, L. K. (2002) Expression and action of the growth hormone releasing peptide ghrelin and its receptor in prostate cancer cell lines. J. Endocrinol. 172, R7-R11
265. Petersenn, S. (2002) Growth hormone secretagogues and ghrelin: an update on physiology and clinical relevance. Horm. Res. 58, 56-61
266. Papotti, M., Cassoni, P., Volante, M., Deghenghi, R., Muccioli, G., and Ghigo, E. (2001) Ghrelin-producing endocrine tumors of the stomach and intestine. J. Clin. Endocrinol. Metab. 86, 5052-5059
267. Choi, K., Roh, S. G., Hong, Y. H., Shrestha, Y. B., Hishikawa, D., Chen, C., Kojima, M., Kangawa, K., and Sasaki, S. (2003) The role of ghrelin and growth hormone secretagogues receptor on rat adipogenesis. Endocrinology 144, 754-759
268. Carlini, V. P., Monzon, M. E., Varas, M. M., Cragnolini, A. B., Schioth, H. B., Scimonelli, T. N., and de Barioglio, S. R. (2002) Ghrelin increases anxiety-like behavior and memory retention in rats. Biochem. Biophys. Res. Commun. 299, 739-743
269. Asakawa, A., Inui, A., Kaga, T., Yuzuriha, H., Nagata, T., Fujimiya, M., Katsuura, G., Makino, S., Fujino, M. A., and Kasuga, M. (2001) A role of ghrelin in neuroendocrine and behavioral responses to stress in mice. Neuroendocrinology 74, 143-147
270. Weikel, J. C., Wichniak, A., Ising, M., Brunner, H., Friess, E., Held, K., Mathias, S., Schmid, D. A., Uhr, M., and Steiger, A. (2003) Ghrelin promotes slow-wave sleep in humans. Am. J. Physiol. 284, E407-E415
271. Ukkola, O., Ravussin, E., Jacobson, P., Perusse, L., Rankinen, T., Tschop, M., Heiman, M. L., Leon, A. S., Rao, D. C., Skinner, J. S., et al. (2002) Role of ghrelin polymorphisms in obesity based on three different studies. Obes. Res. 10, 782-791
272. Ukkola, O., and Poykko, S. (2002) Ghrelin, growth and obesity. Ann. Med. 34, 102-108
273. Ukkola, O., Ravussin, E., Jacobson, P., Snyder, E. E., Chagnon, M., Sjostrom, L., and Bouchard, C. (2001) Mutations in the preproghrelin/ghrelin gene associated with obesity in humans. J. Clin. Endocrinol. Metab. 86, 3996-3999
274. Korbonits, M., Gueorguiev, M., O'Grady, E., Lecoeur, C., Swan, D. C., Mein, C. A., Weill, J., Grossman, A. B., and Froguel, P. (2002) A variation in the ghrelin gene increases weight and decreases insulin secretion in tall, obese children. J. Clin. Endocrinol. Metab. 87, 4005-4008
275. Ravussin, E., Tschop, M., Morales, S., Bouchard, C., and Heiman, M. L. (2001) Plasma ghrelin concentration and energy balance: overfeeding and negative energy balance studies in twins. J. Clin. Endocrinol. Metab. 86, 4547-4551