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    Figure 1—

    Illustration of acylation of the ghrelin molecule. A hydroxyl group on the serine residue at position 3 of the ghrelin molecule is octanoylated. This esterification is unique to mammals and is essential for ghrelin binding to and activating GHS-R 1a and, consequently, for the GH-releasing action of ghrelin. The other endocrine actions of ghrelin are also likely dependent on acylation of the peptide. (Adapted from van der Lely et al.52 Reprinted with permission [copyright 2004, The Endocrine Society].)

  • 1

    Plotsky PMVale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science 1985; 230: 461463.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Tannenbaum GSLing N. The interrelationship of growth hormone releasing factor and somatostatin in generation of the ultradian rhythm of growth hormone secretion. Endocrinology 1984; 115: 19521957.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Kooistra HSden Hertog EOkkens AC, et al.Pulsatile secretion pattern of growth hormone during the luteal phase and mid-anoestrus in beagle bitches. J Reprod Fertil 2000; 119: 217222.

    • Search Google Scholar
    • Export Citation
  • 4

    Frohman LADowns TRChomzsynski P. Regulation of growth hormone secretion. Front Neuroendocrinol 1992; 13: 344405.

  • 5

    Ho KYVeldhuis JDJohnson ML. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988; 81: 968975.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Van Cauter EPlat LCopinschi G. Interrelations between sleep and the somatotropic axis. Sleep 1998; 21: 553566.

  • 7

    Vigneri RSquatrito SPezzino V, et al.Growth hormone levels in diabetes: correlation with the clinical control of the disease. Diabetes 1976; 25: 167172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Kojima MHosoda HDate Y, et al.Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656660.

  • 9

    Wallis M. The molecular evolution of pituitary growth hormone, prolactin and placental lactogen: a protein family showing variable rates of evolution. J Mol Evol 1981; 17: 1018.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Xu BCWang XDarus CJ, et al.Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J Biol Chem 1996; 271: 1976819773.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Barnard RWaters MJ. The serum growth hormone binding protein: pregnant with possibilities. J Endocrinol 1997; 153: 114.

  • 12

    Eigenmann JEPatterson DFFroesch ER. Body size parallels insulin-like growth factor I levels but not growth hormone secretory capacity. Acta Endocrinol (Copenh) 1984; 106: 448453.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Casanueva FF. Physiology of growth hormone secretion and action. Endocrinol Metab Clin North Am 1992; 21: 483517.

  • 14

    Carrel ALAllen DB. Effects of growth hormone on body composition and bone metabolism. Endocrine 2000; 12: 163172.

  • 15

    Daughaday WHHall KRaben MS, et al.Somatomedin: proposed designation for sulphation factor. Nature 1972; 235: 107.

  • 16

    Tamura KKobayashi MIshii Y, et al.Primary structure of rat insulin-like growth factor-I and its biological activities. J Biol Chem 1989; 264: 56165621.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Ceda GPDavis RGRosenfeld RG, et al.The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology 1987; 120: 16581662.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Pelligrini EBluet-Pajot MTMounier F, et al.Central administration of a growth hormone (GH) receptor mRNA antisense increases GH pulsatility and decreases hypothalamic somatostatin expression in rats. J Neurosci 1996; 16: 81408148.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Bowers CYChang JMomany FA, et al.Effect of the enkephalins and enkephalin analogs on release of pituitary hormones in vitro. Mol Endocrinol 1977;287292.

    • Search Google Scholar
    • Export Citation
  • 20

    Bowers CYMomany FAReynolds GA, et al.On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984; 114: 15371545.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Smith RGVan der Ploeg LHHoward AD, et al.Peptidomimetic regulation of growth hormone secretion. Endocr Rev 1997; 18: 621645.

  • 22

    Ghigo EArvat EGianotti L, et al.Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab 1994; 78: 693698.

    • Search Google Scholar
    • Export Citation
  • 23

    Chapman IMBach MAVan Cauter E, et al.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 1996; 81: 42494257.

    • Search Google Scholar
    • Export Citation
  • 24

    Casanueva FFDieguez C. Growth hormone secretagogues: physiological role and clinical utility. Trends Endocrinol Metab 1999; 10: 3038.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Laron Z. Growth hormone secretagogues. Clinical experience and therapeutic potential. Drugs 1995; 50: 595601.

  • 26

    Jacks TSmith RJudith F, et al.MK-0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin-like growth factor I, and other hormonal responses in beagles. Endocrinology 1996; 137: 52845289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Hayashida TMurakami KMogi K, et al.Ghrelin in domestic animals: distribution in stomach and its possible role. Domest Anim Endocrinol 2001; 21: 1724.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Bhatti SFMDe Vliegher SPVan Ham L, et al.Effects of growth hormone–releasing peptides in healthy dogs and in dogs with pituitary-dependent hyperadrenocorticism. Mol Cell Endocrinol 2002; 197: 97103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Bhatti SFMDuchateau LVan Ham LML, et al.Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs. Vet J 2006;in press.

    • Search Google Scholar
    • Export Citation
  • 30

    Massoud AFHindmarsh PCBrook DGD. Hexarelin-induced growth hormone, cortisol and prolactin release: a dose-response study. J Clin Endocrinol Metab 1996; 81: 43384341.

    • Search Google Scholar
    • Export Citation
  • 31

    Arvat EMaccario MDi Vito L, et al.Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 2001; 86: 11691174.

    • Search Google Scholar
    • Export Citation
  • 32

    Raun KHansen BSJohansen NL, et al.Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol 1998; 139: 552561.

  • 33

    Broglio FKoetsveld PVPBenso A, et al.Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans. J Clin Endocrinol Metab 2002; 87: 48294832.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Guillemin RBrazeau PBohlen P, et al.Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 1982; 218: 585587.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Rivier JSpiess JThorner MO, et al.Characterisation of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature 1982; 300: 276278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Howard ADFeighner SDCully DF, et al.A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974977.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Guan XMYu HPalyha OC, et al.Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 1997; 48: 2329.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Bowers CYReynolds GADurham D, et al.Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab 1990; 70: 975982.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    Pong S-SChaung L-YPDean DC, et al.Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol Endocrinol 1996; 10: 5761.

    • Search Google Scholar
    • Export Citation
  • 40

    McKee KKTan CPPalyha OC, et al.Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 1997; 46: 426434.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    McKee KKPalyha OCFeighner SD, et al.Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415423.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Palyha OCFeighner SDTan CP, et al.Ligand activation domain of human orphan growth hormone (GH) secretagogue receptor (GHS-R) conserved from Pufferfish to humans. Mol Endocrinol 2000; 14: 160169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Shuto YShibasaki TWada K, et al.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 2001; 68: 991996.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Cheng KChan WWButler B, et al.Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue. Endocrinology 1993; 132: 27292731.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Dickson SLLeng GDyball RE, et al.Central actions of peptide and non-peptide growth hormone secretagogues in the rat. Neuroendocrinology 1995; 61: 3643.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    Papotti MGhé CCassoni P, et al.Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab 2000; 85: 38033807.

    • Search Google Scholar
    • Export Citation
  • 47

    Kojima MHosoda HKangawa K. Purification and distribution of ghrelin: the natural ligand for the growth hormone secretagogue receptor. Horm Res 2001; 56: 9397.

    • Search Google Scholar
    • Export Citation
  • 48

    Gnanapavan SKola BBustin SA, et al.The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Casanueva FFDieguez C. Ghrelin: the link connecting growth with metabolism and energy homeostasis. Rev Endocr Metab Disord 2002; 3: 325338.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    Tomasetto CWendling CRio M-C, et al.Identification of cDNA encoding motilin related peptide/ghrelin precursor from dog fundus. Peptides 2001; 22: 20552059.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    Date YKojima MHosoda H, et al.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 2000; 141: 42554261.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    van der Lely AJTschop MHeiman ML, et al.Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25: 426457.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    Hosoda HKojima MMatsuo H, et al.Purification and characterization of rat des-Gln 14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000; 275: 2199522000.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54

    Bednarek MAFeighner SDPong SS, et al.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 2000; 43: 43704376.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55

    Broglio FGottero CArvat E, et al.Endocrine and nonendocrine actions of ghrelin. Horm Res 2003; 59: 109117.

  • 56

    Horvath TDiano SSotonyi P, et al.Mini review: ghrelin and the regulation of energy balance—a hypothalamic perspective. Endocrinology 2001; 142: 41634169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 57

    Cassoni PGhe CMarrocco T, et al.Expression of ghrelin and biological activity of specific receptors for ghrelin and des-acyl ghrelin in human prostate neoplasms and related cell lines. Eur J Endocrinol 2004; 150: 173184.

    • Search Google Scholar
    • Export Citation
  • 58

    Korbonits MKojima MKangawa K, et al.Presence of ghrelin in normal and adenomatous human pituitary. Endocrine 2001; 14: 101104.

  • 59

    Mori KYoshimoto ATakaya K, et al.Kidney produces a novel acylated peptide, ghrelin. FEBS Lett 2000; 486: 213216.

  • 60

    Gualillo OCaminos JBlanco M, et al.Ghrelin, a novel placental-derived hormone. Endocrinology 2001; 142: 788794.

  • 61

    Barreiro MLGaytan FCaminos JE, et al.Cellular location and hormonal regulation of ghrelin expression in rat testis. Biol Reprod 2002; 67: 17681776.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 62

    Kanamoto NAkamizu THosoda H, et al.Substantial production of ghrelin by a human medullary thyroid carcinoma cell line. J Clin Endocrinol Metab 2001; 86: 49844990.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 63

    Volante MAllia EGugliotta P, et al.Expression of ghrelin and of growth hormone secretagogue receptor by pancreatic islet cells and related endocrine tumors. J Clin Endocrinol Metab 2002; 87: 13001308.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 64

    Volante MFulcheri EAllia E, et al.Ghrelin expression in fetal, infant, and adult human lung. J Histochem Cytochem 2002; 50: 10131021.

  • 65

    Gaytan FBarreiro MLChopin LK, et al.Immunolocalization of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in the cyclic human ovary. J Clin Endocrinol Metab 2003; 88: 879887.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 66

    Hattori NSaito TYagyu T, et al.GH, GH receptor, GH secretagogue receptor, and ghrelin expression in human T cells, B cells, and neutrophils. J Clin Endocrinol Metab 2001; 86: 42844291.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 67

    Ariyasu HTakaya KTagami T, et al.Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J Clin Endocrinol Metab 2001; 86: 47534758.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 68

    Hosoda HKojima MMizushima T, et al.Structural divergence of human ghrelin. Identification of multiple ghrelin-derived molecules produced by post-translational processing. J Biol Chem 2003; 278: 6470.

    • Search Google Scholar
    • Export Citation
  • 69

    Moller NNygren JHansen TK, et al.Splanchnic release of ghrelin in humans. J Clin Endocrinol Metab 2003; 88: 850852.

  • 70

    Arvat EDi Vito lBroglio F, et al.Preliminary evidence that ghrelin, the natural growth hormone secretagogue receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 2000; 23: 493495.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 71

    Seoane LMTovar SBaldelli R, et al.Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats. Eur J Endocrinol 2000;143:R7R9.

    • Search Google Scholar
    • Export Citation
  • 72

    Takaya KAriyasu HKanamoto N, et al.Ghrelin strongly stimulates growth hormone release in humans. J Clin Endocrinol Metab 2000; 85: 49084911.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 73

    Ghigo EArvat EGiordano R, et al.Biologic activities of growth hormone secretagogues in humans. Endocrine 2001; 14: 8793.

  • 74

    Tannenbaum GSBowers CY. Interactions of growth hormone secretagogues and growth hormone-releasing hormone/somatostatin. Endocrine 2001; 14: 2127.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 75

    Hickey GJDrisko JFaidley T, et al.Mediation by the central nervous system is critical to the in vivo activity of the GH secretagogue L-692,585. J Endocrinol 1996; 148: 371380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 76

    Popovic VMiljic DMicic C, et al.Ghrelin main action on the regulation of growth hormone release is exerted at hypothalamic level. J Clin Endocrinol Metab 2003; 88: 34503453.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 77

    Bowers CYSartor AOReynolds GA, et al.On the actions of the growth hormone-releasing hexapeptide, GHRP. Endocrinology 1991; 128: 20272035.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 78

    Arvat Edi Vito LMaccagno B, et al.Effects of GHRP-2 and hexarelin, two synthetic GH-releasing peptides, on GH, prolactin, ACTH and cortisol levels in man. Comparison with the effects of GHRH, TRH and hCRH. Peptides 1997; 18: 885891.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 79

    Peino RBaldelli RRodriguez-Garcia J, et al.Ghrelin-induced growth hormone secretion in humans. Eur J Endocrinol 2000;143:R11R14.

    • Search Google Scholar
    • Export Citation
  • 80

    Renner UBrockmeier SStrasburger CJ, et al.Growth hormone (GH)-releasing peptide stimulation of GH release from human somatotroph adenoma cells: interaction with GH-releasing hormone, thyrotropin-releasing hormone, and octreotide. J Clin Endocrinol Metab 1994; 78: 10901096.

    • Search Google Scholar
    • Export Citation
  • 81

    Muccioli GTschop MPapotti M, et al.Neuroendocrine and peripheral activities of ghrelin: implications in metabolism and obesity. Eur J Pharmacol 2002; 440: 235254.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 82

    Frawley LSBoockfor FR. Mammosomatotropes: presence and functions in normal and neoplastic pituitary tissue. Endocr Rev 1991; 12: 337355.

  • 83

    Loche SCambiaso PMerola B, et al.The effect of hexarelin on growth hormone (GH) secretion in patients with GH deficiency. J Clin Endocrinol Metab 1995; 80: 26922696.

    • Search Google Scholar
    • Export Citation
  • 84

    Thomas GBFairhall KMRobinson ICAF. Activation of the hypothalamo-pituitary-adrenal axis by the growth-hormone (GH) secretagogue, GH-releasing peptide-6, in rats. Endocrinology 1997; 138: 15851591.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 85

    Korbonits MKaltsas GPerry LA, et al.The GHS hexarelin stimulates the hypothalamo-pituitary-adrenal axis via AVP. J Clin Endocrinol Metab 1999; 84: 24892495.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 86

    Arvat EDi Vito LBroglio F, et al.Preliminary evidence that ghrelin, the natural GH secretagogue (GHS)-receptor ligand, strongly stimulates GH secretion in humans. J Endocrinol Invest 2000; 23: 493495.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 87

    Tschop MSmiley DLHeiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407: 908913.

  • 88

    Wren AMSmall CJWard HL, et al.The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 2000; 141: 43254328.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 89

    Shintani MOgawa YEbihara 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: 227232.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 90

    Toogood AAThorner MO. Ghrelin, not just another growth hormone secretagogue. Clin Endocrinol (Oxf) 2001; 55: 589591.

  • 91

    Friedman JMHalaas JL. Leptin and the regulation of body weight in mammals. Nature 1998; 395: 763770.

  • 92

    Miner JL. The adipocyte as an endocrine cell. J Anim Sci 2004; 82: 935941.

  • 93

    Zhang YProenca RMaffei M, et al.Positional cloning of the mouse obese gene and its human analogue. Nature 1994; 372: 425432.

  • 94

    Neary NMSmall CJBloom SR. Gut and mind. Gut 2003; 52: 918921.

  • 95

    Bowers CY. Unnatural growth hormone-releasing peptide begets natural ghrelin. J Clin Endocrinol Metab 2001; 86: 14641469.

  • 96

    Spiegelman BMFlier JS. Obesity and the regulation of energy balance. Cell 2001; 104: 531543.

  • 97

    Farooqi ISJebb SALangmack G, et al.Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341: 879884.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 98

    Dickson SLLuckman SM. 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 1997; 138: 771777.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 99

    Kamegai JTamura HShimizu T, et al.Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and agouti-related protein mRNA levels and body weight in rats. Diabetes 2001; 50: 24382443.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 100

    Hewson AKDickson SL. Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J Neuroendocrinol 2000; 12: 10471049.

    • Search Google Scholar
    • Export Citation
  • 101

    Cowley MASmith RGDiano S, et al.The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 2003; 37: 649661.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 102

    Kohno DGao HZMuroya S, et al.Ghrelin directly interacts with neuropeptide-Y-containing neurons in the rat arcuate nucleus: Ca2+ signaling via protein kinase A and N-type channel-dependent mechanisms and cross-talk with leptin and orexin. Diabetes 2003; 52: 948956.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 103

    Olszewski PKLi DGrace MK, et al.Neural basis of orexigenic effects of ghrelin acting within lateral hypothalamus. Peptides 2003; 24: 597602.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 104

    Riediger TTraebert MSchmid HA, et al.Site-specific effects of ghrelin on the neuronal activity in the hypothalamic arcuate nucleus. Neurosci Lett 2003; 341: 151155.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 105

    Seoane LMLopez MTovar S, et al.Agouti-related peptide, neuropeptide Y, and somatostatin-producing neurons are targets for ghrelin actions in the rat hypothalamus. Endocrinology 2003; 144: 544551.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 106

    Tschop MWeyer CTataranni PA, et al.Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707709.

  • 107

    Cummings EPurnell JQFrayo SR, et al.A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001; 50: 17141719.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 108

    Sugino TYamaura JYamagishi M, et al.A transient surge of ghrelin secretion before feeding is modified by different feeding regimens in sheep. Biochem Biophys Res Commun 2002; 298: 785788.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 109

    Bowers CY. Editorial: a new dimension on the induced release of growth hormone in obese subjects. J Clin Endocrinol Metab 1993; 76: 817818.

    • Search Google Scholar
    • Export Citation
  • 110

    Dieguez CCasanueva F. Influence of metabolic substrates and obesity on growth hormone secretion. Trends Endocrinol Metab 1995; 6: 5559.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 111

    Tolle VBassant MHZizzari P, et al.Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats. Endocrinology 2002; 143: 13531361.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 112

    Banks WATschop MRobinson SM, et al.Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther 2002; 302: 822827.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 113

    Masuda YTanaka TInomata M, et al.Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun 2000; 276: 905908.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 114

    Asakawa AInui AKaga T, et al.Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 2001; 120: 337345.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 115

    Folwaczny CChang JKTschop M. Ghrelin and motilin: two sides of one coin? Eur J Endocrinol 2001;144:R1R3.

  • 116

    Garthwaite TL. Peripheral motilin administration stimulates feeding in fasted rats. Peptides 1985; 6: 4144.

  • 117

    Samson WKLumpkin MDNilaver G, et al.Motilin: a novel growth hormone releasing agent. Brain Res Bull 1984; 12: 5762.

  • 118

    Feighner SDTan CPMcKee KK, et al.Receptor for motilin identified in the human gastrointestinal system. Science 1999; 284: 21842188.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 119

    Brown JCMutt VDryburgh JR. The further purification of motilin, a gastric motor activity stimulating polypeptide from the mucosa of the small intestine of dogs. Can J Physiol Pharmacol 1971; 49: 399405.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 120

    Itoh Z. Motilin and clinical application. Peptides 1997; 18: 593608.

  • 121

    Date YNakazato MHashiguchi S, et al.Ghrelin is present in pancreatic α-cells of humans and rats and stimulates insulin secretion. Diabetes 2002; 51: 124129.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 122

    Rindi GNecchi VSavio A, et al.Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem Cell Biol 2002; 117: 511519.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 123

    Wierup NSvensson HMulder H, et al.The ghrelin cell: a novel developmentally regulated islet cell in the human pancreas. Regul Pept 2002; 107: 6369.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 124

    Lee HMWang GEnglander EW, et al.Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology 2002; 143: 185190.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 125

    Caixas ABashore CNash W, et al.Insulin, unlike food intake, does not suppress ghrelin in human subjects. J Clin Endocrinol Metab 2002; 87: 1902.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 126

    Broglio FArvat EBenso A, et al.Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab 2001; 86: 50835086.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 127

    Adeghate EPonery AS. Ghrelin stimulates insulin secretion from the pancreas of normal and diabetic rats. J Neuroendocrinol 2002; 14: 555560.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 128

    Svensson JLonn LJansson JO, et al.Two-month treatment of obese subjects with the oral GH secretagogue MK-677 increases GH secretion, fat-free mass, and energy expenditure. J Clin Endocrinol Metab 1998; 83: 362369.

    • Search Google Scholar
    • Export Citation
  • 129

    Muller AFJanssen JAHofland LJ, et al.Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide-6-mediated tissue-specific insulin resistance. J Clin Endocrinol Metab 2001; 86: 590593.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 130

    Masuda AShibasaki TNakahara M, et al.The effect of glucose on growth hormone (GH)-releasing hormone-mediated GH secretion in man. J Clin Endocrinol Metab 1985; 60: 523526.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 131

    Nakagawa ENagaya NOkumura 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: 325328.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 132

    Nagaya NMiyatake KUematsu M, et al.Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 2001; 86: 58545859.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 133

    Iglesias MJPineiro RBlanco M, et al.Growth hormone releasing peptide (ghrelin) is synthesized and secreted by cardiomyocytes. Cardiovasc Res 2004; 62: 481488.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 134

    Yang RBunting SGillet N, et al.Growth hormone improves cardiac performance in experimental heart failure. Circulation 1995; 92: 262267.

  • 135

    Fazio SSabatini DCapaldo B, et al.A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med 1996; 334: 809814.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 136

    Nagaya NKangawa K. Ghrelin, a novel growth hormone-releasing peptide, in the treatment of chronic heart failure. Regul Pept 2003; 114: 7177.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 137

    Nagaya NMoriya JYasumura Y, et al.Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004; 110: 36743679.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 138

    Filigheddu NFubini ABaldanzi G, et al.Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death. Endocrine 2001; 14: 113119.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 139

    Cassoni PPapotti MGhe C, et al.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 2001; 86: 17381745.

    • Search Google Scholar
    • Export Citation
  • 140

    Kanamoto NAkamizu THosoda H, et al.Substantial production of ghrelin by a human medullary thyroid carcinoma cell line. J Clin Endocrinol Metab 2001; 86: 49844990.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 141

    Cassoni PMuccioli GMarrocco T, et al.Cortistatin-14 inhibits cell proliferation of human thyroid carcinoma cell lines of both follicular and parafollicular origin. J Endocrinol Invest 2002; 25: 362368.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 142

    Muccioli GPapotti MLocatelli V, et al.Binding of 125Ilabeled ghrelin to membranes from human hypothalamus and pituitary gland. J Endocrinol Invest 2001;24:RC7RC9.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 143

    van den Berghe G. Novel insights into the neuroendocrinology of critical illness. Eur J Endocrinol 2000; 143: 113.

  • 144

    Petersenn S. Growth hormone secretagogues and ghrelin: an update on physiology and clinical relevance. Horm Res 2002; 58: 5661.

  • 145

    Torsello ALuoni MSchweiger F, et al.Novel hexarelin analogs stimulate feeding in the rat through a mechanism not involving growth hormone release. Eur J Pharmacol 1998; 360: 123129.

    • Crossref
    • Search Google Scholar
    • Export Citation

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Ghrelin, an endogenous growth hormone secretagogue with diverse endocrine and nonendocrine effects

Sofie F. BhattiDepartment of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.

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Luc M. Van HamDepartment of Small Animal Medicine and Clinical Biology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.

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Jan A. MolDepartment of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, NL-3508 TD, Utrecht, The Netherlands.

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Hans S. KooistraDepartment of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 8, NL-3508 TD, Utrecht, The Netherlands.

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Circulating ghrelin, the natural ligand of GHS-R 1a, is synthesized primarily in the stomach in mammals. The distribution of these receptors is consistent with the role of ghrelin in promoting secretion of GH; receptors are highly expressed in the hypothalamus and pituitary gland and are also distributed in other central and peripheral tissue sites. In addition to strong GH-releasing activity, ghrelin has other actions, including stimulation of lactotroph and corticotroph function, stimulation of appetite, regulation of energy homeostasis, stimulation of gastric motility and gastric acid secretion, regulation of insulin secretion and glucose metabolism, cardiovascular effects, and antiproliferative activity. These properties make ghrelin a candidate for future diagnostic and clinical applications.

In mammals, secretion of GH from the adenohypophysis is regulated by 2 hypothalamic hormones with antagonistic actions: a stimulatory GHRH that is produced in the arcuate nucleus and an inhibitory hormone, somatostatin, synthesized in the paraventricular nucleus.1 Both hormones are transported from the hypothalamus to target cells in the pituitary gland via the hypothalamo-hypophyseal portal system in the median eminence. Alternation in secretion of GHRH and somatostatin is responsible for the pulsatile pattern of GH release.2,3 Measurement of GHRH and somatostatin in hypophyseal-portal blood in humans and other animals reveals that the episodic pattern of GHRH and somatostatin secretion does not fully account for all pulses of GH secretion.4 The amplitude and frequency of GH secretory pulses are regulated by a complex array of external and internal stimuli, including body composition, age, sleep, gender, disease status, menstrual cycle phase, genetic background, and nutritional status.5–7

The discovery of ghrelin, the natural ligand of GHS-R 1a, was an important advance in the understanding of regulation of GH secretion.8 Ghrelin has been isolated from tissues of the stomach, where its expression is higher than in any other tissue.8 The site of ghrelin production and its molecular structure, which contains an octanoyl group, were initially surprising to investigators.

Apart from its role in stimulating pituitary release of GH, ghrelin has many other actions. The discovery of ghrelin and its various physiologic actions opened new avenues of research, not only in the field of neu-roendocrinology, but also in the areas of gastroenterol-ogy, immunology, oncology, cardiology, reproduction, cell proliferation and growth, energy homeostasis, and energy balance. In this overview, we summarize recent findings on the physiologic effects of ghrelin in several mammalian species and describe future diagnostic and clinical applications.

Growth Hormone

Growth hormone, a 191-amino acid, single-chain polypeptide, is synthesized, stored, and secreted by somatotroph cells in the adenohypophysis.9 The effects of GH on growth and metabolic functions are mediated through the GH receptor. Growth hormone forms complexes with 2 peripheral GH receptor components, leading to dimerization of the receptor, an event that is necessary for subsequent GH signaling. Growth hormone receptor dimerization elicits an intracellular phosphorylation cascade involving the JAK-STAT (Janus kinase signal transducers and activators of transcription) pathway.10

The liver contains abundant GH receptors, and several other peripheral tissues, including muscle and fat, express modest amounts of GH receptors.11 In contrast to most other pituitary hormones, the action of GH is not confined to a single target tissue and the hormone has both slow anabolic and rapid catabolic activities.12 The catabolic effects are exerted via direct interaction with target cells, resulting in enhanced lipolysis in fat cells, and restriction of glucose transport across the cell membrane, caused by anti-insulin activity12–14 The anabolic effects (ie, growth and cell proliferation) of GH are exerted indirectly, mainly mediated by growth factors known as IGFs or somatomedins.15 The liver is the primary source of circulating IGFs. Growth hormone also promotes the production of IGFs in peripheral tissues (eg, muscle, bone, cartilage, kidney, and skin), where they appear to have autocrine and paracrine effects.15

Insulin-like growth factors have approximately 50% amino acid sequence similarity with insulin.16 In contrast to circulating insulin, IGFs are bound to plasma proteins, which prolongs their half-life and contributes to their long-term growth-promoting effects. Circulating IGFs are important determinants of body size because they stimulate protein synthesis, chondrogenesis, and body growth. Insulin-like growth factor-1 has an inhibitory effect on GH secretion, most likely by stimulating the release of somatostatin and by a directly inhibitory influence at the level of the pituitary gland.17 Additionally, GH has a negative feedback effect on its own production at the level of the hypothalamus.18

Synthetic Growth Hormone Secretagogues

The usual sequence of discovery in endocrinology is isolation of a hormone, cloning of its receptor, and development of analogs of the hormone for clinical use. With ghrelin, this sequence was reversed: first, analogs were synthesized, then the receptor was cloned, and lastly, the natural ligand of the orphan receptor was isolated.

Briefly, in 1975, before the discovery of GHRH, the GH-releasing properties of enkephalins were reported.19 Chemical modification of the structure of met-enkephalin led to development of a highly potent GH-releasing hexapeptide, GHRP-6 [(His-D-Trp-Ala-Trp-D-Phe-Lys-NH2)3], in 1980.20 One of the most remarkable properties of GHRP-6 was the strong GH-releasing activity induced following oral administration.21 The hexapeptide was the basic structure from which synthetic GHSs, of either peptidergic structure such as hexarelin or nonpeptidergic structure such as MK-0677,22,23 were subsequently produced. Currently used synthetic GHSs are highly bioavailable and may be administered via IV, IM, intranasal, SC, oral, and transdermal routes.24 Because GH is a large protein that must be administered via injection or inhalation, administration of synthetic GHSs is often preferred over administration of GH. In addition, GHSs induce a more physiologic pulsatile pattern of GH release.24,25 For example, a single orally administered dose of MK-0677 increases mean 24-hour plasma GH concentrations.21,23,26

The synthetic GHSs have potent GH-releasing activity in several species, including humans, mice, rats, swine, goats, cows, and dogs.27–29 In humans, nearly all synthetic GHSs induce the release of more GH than does GHRH.24 However, the hormone-releasing action of synthetic GHSs is not always specific.24 In humans, synthetic GHSs such as GHRP-6 also have a stimulatory effect on the secretion of PRL, ACTH, and cortisol.24,30,31 Newer selective GHSs, such as ipamorelin, do not have ACTH- or PRL-releasing actions.32,33

Interest in GHSs faded after the isolation and characterization of GHRH in 1982,34,35 but was later revived when it was discovered that GHSs operated through receptors that are different from those for GHRH.24,36,37 Growth hormone secretagogues and GHRH have strongly synergistic actions, which indicates that synthetic GHSs are not physiologic surrogates of GHRH.38 In 1996, GHS-R, a G-protein-coupled 7-transmembrane receptor, was identified.39 This receptor has been cloned from cells of the pituitary gland in humans36,40 and rats.41

Two types of GHS-Rs, which are presumably the result of alternate processing of pre-mRNA, have been identified and designated as receptors 1a and 1b.21,36 Human GHS-R 1a shares 96% and 93% sequence identity with rat and pig receptors, respectively. The existence of this receptor can be traced to animals in the pre-Cambrian era because amino acid sequences highly similar to those in the human GHS-R 1a have been detected in teleost fish.42 These observations indicate that the GHS-R 1a is highly conserved across species and likely has an essential biological function. This receptor is largely confined to somatotroph cells in the pituitary gland and to several hypothalamic nuclei (eg, the supraoptic, arcuate, and paraventricular nuclei) in humans and rats.21,36,37,43 Messenger RNA encoding GHS-R 1a has been detected in the pituitary gland, indicating that GHSs can act directly on somatotrophs to stimulate GH release. This is in accordance with an earlier observation44 that GHSs are able to directly stimulate GH release from rat pituitary cells in vitro. The hypothalamic localization of the GHS-R 1a, especially in the supraoptic and paraventricular nuclei, supports the notion that GHSs may also indirectly regulate GH release by interacting with GHRH-producing neurons, somatostatin-producing neurons, or both, in the hypothalamus.45 The GHS-R 1a is also expressed in other areas of the brain and certain peripheral tissues,46 indicating that GHSs may also be involved in other physiologic functions.37,47 The importance of the widespread expression of GHS-R 1b in endocrine and nonendocrine tissues has not been determined.36,48

The GHS-Rs are distinct from the GHRH receptor 36,37,40. Although binding of GHRH to the GHRH receptor increases cAMP in somatotroph cells and stimulates GH release via activation of the kinase A pathway, binding of ghrelin and synthetic GHSs to the GHS-R 1a activates the phospholipase C signaling pathway, leading to an increase in inositol triphosphate and protein kinase C activation, followed in turn by release of calcium from intracellular stores.39 Unlike GHS-R 1a, GHS-R 1b does not bind ghrelin or synthetic GHSs, and its function awaits clarification.36,40,48

Ghrelin

The 1999 discovery of the endogenous or natural ligand of the GHS-R, termed ghrelin (ghre is the proto—Indo-European root of the word grow, and relin indicates release), provided a new dimension to GH research.8 Ghrelin causes release of GH in vitro and in vivo. The 28-amino acid peptide was isolated from the stomach, where its expression is higher than in any other tissue.8 Although this source may initially seem strange, it should be remembered that most circulating somatostatin is synthesized in the intestines and pancreas and that GHRH was first isolated not from the hypothalamus but from a pancreatic tumor.49 Thus, the 3 neurohormones (ie, somatostatin, GHRH, and ghrelin) responsible for regulation of GH secretion are highly expressed in gastrointestinal tissues.

In humans, rats, and domestic animals, expression of ghrelin mRNA and the ghrelin peptide is primarily detected in the enteroendocrine or X-A—like cells of the fundic glands in the stomach,27,50 which have been renamed Ghr-cells. The cells containing ghrelin do not communicate with the lumen of the fundic gland but, like all enteroendocrine cells, are positioned adjacent to capillaries, indicating that their primary action is secretion of hormone into plasma and not into the intestinal lumen.51

The degree of structural heterogeneity of ghrelin among species appears to be minor, suggesting that there is little functional heterogeneity. Such preservation of structure also reflects the physiologic relevance of the peptide.49,50 For example, human and rat ghrelin differ in only 2 amino acids (Table 1).52 Alternative splicing of mRNA segments encoding ghrelin yields 2 different peptides, ghrelin and des-Gln14-ghrelin.53 The latter is homologous with ghrelin except for the absence of a single glutamine residue. Des-Gln14-ghrelin is expressed in the stomach in low quantities,47 but like ghrelin, it increases the intracellular concentration of calcium in cells that express the GHS-R 1a and increases plasma GH concentrations.8,53

Table 1—

Primary structure of ghrelin in domestic mammalian species.

1234567891011121314151617 192021222324252627 Species
GSSFLSPEHQRVQQRKE KKPPAKLQP Human
GSSFLSPEHQKTQQRKE KKPPAKLQP Gerbil
GSSFLSPEHQKAQQRKE KKPPAKLQP Mouse
GSSFLSPEHQKAQQRKE KKPPAKLQP Rat
GSSFLSPEHQKLQQRKE KKPPAKLQP Dog
GSSFLSPEHQKVQQRKE KKPAAKLKP Pig
GSSFLSPEHQKLQQRKE KKPSGRLKP Cattle
GSSFLSPEHQKLQQRKE KKPSGRLKP Sheep
GSSFLSPTYKNIQQQKD RKPTARLHR Chicken

(Adapted from van der Lely et al.52 Reprinted with permission [copyright 2004, The Endocrine Society].)

Before being secreted, n-octanoic acid is added to the third serine residue of ghrelin and des-Gln14-ghrelin (Figure 1).52 This acylation step, unique to mammalian species, is essential for binding to and activating the GHS-R 1a54 and hence for the peptide's GH-releasing action. Acylation is most likely also necessary for the other endocrine actions of the ghrelin molecule.47,55 Addition of the n-octanoyl group confers a hydrophobic property to the N terminus of the peptide. It has been suggested that the octanoylation of ghrelin is critical to the peptide's ability to cross the blood-brain barrier. It may also facilitate distribution of the peptide in the brain, although there are presently no data to support this speculation.56 Nonacylated ghrelin is found in far greater quantities in human serum than acylated ghrelin, but appears to lack endocrine activity. However, this peptide does have certain nonendocrine cardiovascular and antiproliferative effects, which are likely mediated by binding to a novel and as-yet unidentified GHS-R subtye.57 Nonacylated ghrelin inhibits proliferation of human prostate cancer cell lines and neoplastic cell growth in thyroid, breast, and lung tumors. Cardioprotective and negative inotropic effects have also been described.51,57

Figure 1—
Figure 1—

Illustration of acylation of the ghrelin molecule. A hydroxyl group on the serine residue at position 3 of the ghrelin molecule is octanoylated. This esterification is unique to mammals and is essential for ghrelin binding to and activating GHS-R 1a and, consequently, for the GH-releasing action of ghrelin. The other endocrine actions of ghrelin are also likely dependent on acylation of the peptide. (Adapted from van der Lely et al.52 Reprinted with permission [copyright 2004, The Endocrine Society].)

Citation: American Journal of Veterinary Research 67, 1; 10.2460/ajvr.67.1.180

Lower concentrations of ghrelin have been detected in various other tissues, including the intestines,51 pituitary gland,58 hypothalamus,8,51 kidney,59 placenta,60 heart,49 testis,61 thyroid gland,62 pancreas,63 lung,64 ovary,65 immune system,66 and neoplastic tissue.46 The physiologic importance of ghrelin as a paracrine factor in these tissues is under investigation, but an endocrine role for non-stomach-derived ghrelin is thought to be unlikely. Removal of the stomach in humans and rats decreases the plasma concentration of ghrelin by approximately 65% and 80%, respectively.51,67 However, plasma ghrelin concentrations gradually increase after gastrectomy.68 These findings indicate that the stomach is the major source of circulating ghrelin but that other tissues may increase secretion of ghrelin in a compensatory manner.69

Endocrine Effects of Ghrelin

Ghrelin has pronounced, dose-related GH-releasing actions that are more marked in humans than in other mammals.8,21,27–29,31,51,70–73 The GH-releasing activity of ghrelin is greater in vivo than in vitro because ghrelin and GHRH act synergistically, consistent with the fact that their actions are at least partially mediated via different mechanisms.21,74 Nevertheless, GHRH activity is required for full expression of ghrelin's GH-releasing activity.21,74 The GH response to ghrelin is partially inhibited by GHRH receptor antagonists and disruption of communication between the hypothalamus and pituitary gland,75,76 supporting the assumption that the effect of ghrelin on GH secretion is primarily mediated by GHRH-secreting neurons at the level of thehypothalamus.21,74,76,77

In anesthetized rats, ghrelin administered IV stimulates GH release without affecting secretion of other adenohypophyseal hormones.8 Also, in cultured rat pituitary cells, ghrelin stimulates GH release in a dose-dependent manner without affecting the release of other pituitary hormones, even at high concentrations.8 However, in healthy humans, ghrelin is not specific for GH release because it also has stimulatory effects on lactotroph and corticotroph cells.31,72,78,79 The effect of ghrelin on PRL secretion is independent of gender and age and likely results from direct stimulation of somatomammotrophs.72,78,80,81 In dogs28,29 and rats,8 synthetic GHSs do not stimulate PRL release. This species-related difference may be explained by differences in the number of somatomammotrophs in various species, with humans having a high proportion of those cells.32,82 The mechanism by which ghrelin stimulates the pituitary-adrenocortical axis is still unknown, but it is thought to be mediated via the hypothalamus because the stimulatory effect is lost after sectioning of the pituitary stalk.83 Ghrelin may also interact with hypothalamic peptides that control ACTH release, probably via arginine vasopressin.55,84,85

Orexigenic Actions and Role in Energy Homeostasis

Evidence for involvement of ghrelin in regulation of appetite was first detected in humans. Healthy human volunteers reported hunger after administration of ghrelin in a clinical study in which GH release was analyzed.86 In rodents, ghrelin stimulates food intake and increases body weight while reducing mobilization of adipose stores.87–89 The effects of ghrelin on food intake are likely mediated through mechanisms other than those implicated in GH regulation, compatible with the concept of distinct GHS-R subtypes.87,90

Adipocytes traditionally have been viewed as energy depots in which triglycerides are stored during feeding and that release fatty acids during fasting to provide fuel for other tissues. However, it is now known that adipose tissue has major integrative physiologic functions, including secretion of numerous proteins.91,92 The realization that adipose tissue has endocrine functions has important implications for our understanding of the associations between excessive body fat and pathologic states such as insulin resistance and type 2 diabetes mellitus.92

An important finding that linked central regulation of metabolism to mobilization of peripheral energy stores was the discovery of the adipose hormone, leptin (from the Greek root leptos, meaning thin). Leptin, a peptide hormone discovered in 1994, is produced principally by white adipose tissue.93 Leptin crosses the blood-brain barrier to act via receptors in the arcuate nucleus of the hypothalamus to inhibit release of orexigenic neuropeptides and stimulate release of anorexigenic neuropeptides.91,94 A direct relationship exists between plasma leptin concentrations and percentage body fat. Plasma leptin concentrations in humans are generally proportional to adipose mass. Decreases in leptin concentrations occur in conditions characterized by loss of adipose mass, such as anorexia nervosa, diet- or exercise-induced weight loss, or starvation. Concentrations of circulating leptin decrease rapidly within 12 hours after initiation of starvation, whereas concentrations increase in response to overfeeding. Thus, plasma leptin concentrations reflect adipose tissue mass and provide a signal that informs the CNS about the body's energy reserves.91

The similarities and complementary actions between leptin and ghrelin are intriguing. The effects of ghrelin on metabolism appear to be the opposite to those of leptin.47,87,95,96 Leptin reduces food intake and selectively reduces fat mass without altering lean body mass.97 Ghrelin, in contrast, increases food intake and selectively enhances fat mass.87

Ghrelin stimulates food intake in rodents when administered via central or peripheral routes (ie, intracerebroventricularly or SC), although the effect is more powerful after central administration.87 There is evidence that the appetite-stimulating effects of ghrelin are mediated by secretion of 2 potent orexigenic hypothalamic hormones (neuropeptide Y and agouti-related peptide) and by inhibition of pro-opiomelanocortin and α-melanocyte–stimulating hormone.98–101 Furthermore, the orexigenic action of ghrelin is eliminated when the effects of neuropeptide Y and agouti-related peptide are antagonized.99 By stimulating the release of orexigenic peptides and neuro-transmitters, ghrelin mediates a novel circuit regulating energy homeostasis.101–105

In humans and rats, concentrations of circulating ghrelin decrease in chronic (obesity)106 and acute (caloric intake)107 states of positive energy balance, whereas ghrelin concentrations increase in states of negative energy balance (eg, fasting).87 In cattle, plasma ghrelin concentrations are low 1 hour after feeding and then return to the prefeeding concentration.27 In sheep, the preprandial ghrelin surge is higher in animals fed twice daily than in animals fed 4 times daily, indicating that different feeding regimens influence ghrelin concentrations.108 The preprandial increase and postprandial decrease in plasma ghrelin concentrations suggest a possible role for ghrelin as a hunger signal that triggers meal initiation.107 Because ghrelin is a potent stimulator of GH release, these observations are in accordance with the low plasma GH concentrations associated with obesity109 and the high concentrations observed in the malnourished and fasting states.110

It may be concluded that nutritional state is an important determinant of plasma ghrelin concentration.111 Ghrelin peptide reaches ghrelin receptors in the hypothalamo-pituitary region via the general circulation, where it stimulates GH release and regulates energy homeostasis. It is unclear whether ghrelin must cross the blood-brain barrier to influence the activity of these central structures.52 In the general circulation, ghrelin is bound to high-density lipoproteins in the serum and presumably to other proteins, such as albumin. Ghrelin may also signal the brain directly, by activating the afferent portion of the vagal nervous system as either an endocrine or a paracrine signal, at the level of the stomach. Ghrelin-responsive GHS-Rs are expressed on gastric vagal nerves, and vagotomy prevents some of the effects of ghrelin on energy balance. On the other hand, the extent and direction of ghrelin transport across the blood-brain barrier may be determined by its unique primary structure.112 There is debate among scientists concerning the routes by which ghrelin in the peripheral circulation activates receptors in the CNS of different species.

Gastric Prokinetic Action

Ghrelin induces strong prokinetic activity in the stomach.113,114 The peptide dramatically accelerates gastric and intestinal emptying in rats, and circulating ghrelin concentrations are correlated with gastric emptying time in humans.113 In addition, ghrelin stimulates gastric acid secretion.114

In that context, structural and functional similarities exist between ghrelin and motilin.115 In addition to prokinetic effects on the gastrointestinal tract, both peptides have orexigenic properties116 and stimulatory effects on pituitary GH release.117 The G-protein–coupled receptors of ghrelin and motilin also have a high degree of structural homology.118 In contrast to ghrelin, motilin is primarily expressed in the small intestine.119 Motilin stimulates motor activity in the gastric antrum and proximal portion of the duodenum and plays a key role in the regulation of motili-ty between meals.120

The gastrokinetic effects of ghrelin and motilin may prove beneficial in the treatment of postoperative gastric ileus. In humans and other mammalian species, abdominal surgery and attendant manipulation of the viscera inhibit gastric emptying and digestive motor activity, which may result in postoperative ileus. Attempts to stimulate smooth muscle activity with prokinetics (eg, cisapride and acetylcholine) are often unsuccessful.114 In rats, ghrelin reverses postoperative gastric ileus.113

Effects on the Endocrine Pancreas

Ghrelin and GHS-R 1a mRNA are expressed in endocrine cells of the pancreas.37,48,121,122 Expression of ghrelin has been reported in the pancreatic α-cells,121 although other investigators have reported that ghrelin is expressed in the pancreatic beta cells.63 Ghrelin is not co-expressed with any known islet-derived hormone; thus, ghrelin-producing cells may be a newly recognized type of islet cell.123

Published information regarding the effect of ghrelin on insulin secretion in humans and rats is conflicting,121,124,125 but most findings suggest that there is a negative association between ghrelin concentrations and insulin secretion.106,107,121,126,127 In humans, ghrelin induces a significant increase in plasma glucose concentrations and a decrease in insulin secretion.55,126 Coupled with the observation that treatment with GHSs, particularly the nonpeptidyl derivatives, induces hyperglycemia and insulin resistance in the elderly and in obese human patients, those findings suggest that ghrelin has an important role in the regulation of insulin secretion and glucose metabolism.128,129

In healthy humans, hyperglycemia suppresses both baseline plasma concentrations of GH and GH release induced by GHRH.130 The mechanism of the hyperglycemia-induced decrease in circulating GH is unclear. Acute hyperglycemia substantially decreases plasma ghrelin concentrations in healthy humans.131 Because ghrelin markedly stimulates GH secretion, the hyperglycemia-induced suppression of GH release may be caused, at least partly, by the decrease in plasma ghrelin concentrations.131

Cardiovascular Effects

Ghrelin receptors are widely distributed in cardiovascular tissues. In humans and rats, GHS-R 1a mRNA has been detected primarily in the heart, coronary arteries, and aorta.48,132 Ghrelin is synthesized and secreted by isolated human cardiomyocytes, in which it likely has paracrine or autocrine effects and may protect the cells from apoptosis.133

Growth hormone improves cardiac performance in experimentally induced heart failure.134,135 In 1 study,81 prolonged treatment with GHSs protected aged rats against cardiovascular damage and improved cardiac performance after myocardial infarction, and enhanced left ventricular contractility in pigs with dilated cardiomyopathy. Long-term ghrelin administration improves cardiac contractility and cardiac output and reduces systemic vascular resistance in humans with chronic heart failure.132 Furthermore, it induces myocardial growth, improving the structure and function of the left ventricle.136,137 Interestingly, hexarelin, acylated ghrelin, and even unacylated ghrelin all prevent doxorubicin-induced death in cultured cardiomyocytes.138 Because unacylated ghrelin does not activate the GHS-R 1a,54 these data indicate that another subtype of GHS-R exists in cardiac tissue and that unacylated ghrelin has some biological activity.81 Thus, long-term administration of ghrelin may become a treatment strategy for patients with heart failure.136

Antiproliferative Effects

Growth hormone secretagogue receptors are also found in human neoplastic tissues, such as mammary gland tumors and thyroid carcinoma cells.139,140 Ghrelin and GHSs inhibit cell proliferation in thyroid tumor cells140,141 and breast cancer cells.138 Nonacylated ghrelin also exerts antiproliferative actions.139 Because unacyl-ated ghrelin is unable to bind to the GHS-R 1a, these data suggest that the antiproliferative effects of acylated and unacylated ghrelin on cancer cells are mediated via a GHS-R subtype that is different from GHS-R 1a.142

Conclusion

The isolation and characterization of ghrelin are landmarks in GH research and represent a major advancement in our understanding of GH regulation. Ghrelin is a gastric peptide that is active in the CNS, where it is involved in regulation of GH secretion and control of food intake. The widespread expression of GHS-Rs in central and peripheral tissues suggests that ghrelin may have many endocrine, paracrine, and possibly autocrine effects. Future challenges lie in improving our ability to diagnose and treat the different diseases associated with altered GH secretion. For example, the potential use of ghrelin in GH deficiency warrants investigation. In addition, ghrelin or ghrelin analogs may be useful in pathologic catabolic states such as wound and fracture healing, osteoporosis, severe burns, sepsis, excessive inflammation, multiple organ failure, and weakness in critically ill patients, all conditions in which the administration of moderate doses of GH has been effective.143,144 The orexigenic actions of ghrelin and its analogs may be harnessed to treat the pathologic forms of anorexia that accompany cancer and aging.145 Whether ghrelin antagonists can be used to reduce food intake and be developed as a treatment for obesity remains to be investigated.

GHS-R 1a

GH secretagogue receptor type 1a

GH

Growth hormone

GHRH

GH-releasing hormone

IGF

Insulin-like growth factor

GHRP-6

GH-releasing peptide-6

GHS

GH secretagogue

PRL

Prolactin

GHS-R

GHS receptor

References

  • 1

    Plotsky PMVale W. Patterns of growth hormone-releasing factor and somatostatin secretion into the hypophysial-portal circulation of the rat. Science 1985; 230: 461463.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2

    Tannenbaum GSLing N. The interrelationship of growth hormone releasing factor and somatostatin in generation of the ultradian rhythm of growth hormone secretion. Endocrinology 1984; 115: 19521957.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3

    Kooistra HSden Hertog EOkkens AC, et al.Pulsatile secretion pattern of growth hormone during the luteal phase and mid-anoestrus in beagle bitches. J Reprod Fertil 2000; 119: 217222.

    • Search Google Scholar
    • Export Citation
  • 4

    Frohman LADowns TRChomzsynski P. Regulation of growth hormone secretion. Front Neuroendocrinol 1992; 13: 344405.

  • 5

    Ho KYVeldhuis JDJohnson ML. Fasting enhances growth hormone secretion and amplifies the complex rhythms of growth hormone secretion in man. J Clin Invest 1988; 81: 968975.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6

    Van Cauter EPlat LCopinschi G. Interrelations between sleep and the somatotropic axis. Sleep 1998; 21: 553566.

  • 7

    Vigneri RSquatrito SPezzino V, et al.Growth hormone levels in diabetes: correlation with the clinical control of the disease. Diabetes 1976; 25: 167172.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8

    Kojima MHosoda HDate Y, et al.Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656660.

  • 9

    Wallis M. The molecular evolution of pituitary growth hormone, prolactin and placental lactogen: a protein family showing variable rates of evolution. J Mol Evol 1981; 17: 1018.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10

    Xu BCWang XDarus CJ, et al.Growth hormone promotes the association of transcription factor STAT5 with the growth hormone receptor. J Biol Chem 1996; 271: 1976819773.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11

    Barnard RWaters MJ. The serum growth hormone binding protein: pregnant with possibilities. J Endocrinol 1997; 153: 114.

  • 12

    Eigenmann JEPatterson DFFroesch ER. Body size parallels insulin-like growth factor I levels but not growth hormone secretory capacity. Acta Endocrinol (Copenh) 1984; 106: 448453.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13

    Casanueva FF. Physiology of growth hormone secretion and action. Endocrinol Metab Clin North Am 1992; 21: 483517.

  • 14

    Carrel ALAllen DB. Effects of growth hormone on body composition and bone metabolism. Endocrine 2000; 12: 163172.

  • 15

    Daughaday WHHall KRaben MS, et al.Somatomedin: proposed designation for sulphation factor. Nature 1972; 235: 107.

  • 16

    Tamura KKobayashi MIshii Y, et al.Primary structure of rat insulin-like growth factor-I and its biological activities. J Biol Chem 1989; 264: 56165621.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 17

    Ceda GPDavis RGRosenfeld RG, et al.The growth hormone (GH)-releasing hormone (GHRH)-GH-somatomedin axis: evidence for rapid inhibition of GHRH-elicited GH release by insulin-like growth factors I and II. Endocrinology 1987; 120: 16581662.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18

    Pelligrini EBluet-Pajot MTMounier F, et al.Central administration of a growth hormone (GH) receptor mRNA antisense increases GH pulsatility and decreases hypothalamic somatostatin expression in rats. J Neurosci 1996; 16: 81408148.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19

    Bowers CYChang JMomany FA, et al.Effect of the enkephalins and enkephalin analogs on release of pituitary hormones in vitro. Mol Endocrinol 1977;287292.

    • Search Google Scholar
    • Export Citation
  • 20

    Bowers CYMomany FAReynolds GA, et al.On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology 1984; 114: 15371545.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21

    Smith RGVan der Ploeg LHHoward AD, et al.Peptidomimetic regulation of growth hormone secretion. Endocr Rev 1997; 18: 621645.

  • 22

    Ghigo EArvat EGianotti L, et al.Growth hormone-releasing activity of hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal, and oral administration in man. J Clin Endocrinol Metab 1994; 78: 693698.

    • Search Google Scholar
    • Export Citation
  • 23

    Chapman IMBach MAVan Cauter E, et al.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 1996; 81: 42494257.

    • Search Google Scholar
    • Export Citation
  • 24

    Casanueva FFDieguez C. Growth hormone secretagogues: physiological role and clinical utility. Trends Endocrinol Metab 1999; 10: 3038.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25

    Laron Z. Growth hormone secretagogues. Clinical experience and therapeutic potential. Drugs 1995; 50: 595601.

  • 26

    Jacks TSmith RJudith F, et al.MK-0677, a potent, novel, orally active growth hormone (GH) secretagogue: GH, insulin-like growth factor I, and other hormonal responses in beagles. Endocrinology 1996; 137: 52845289.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27

    Hayashida TMurakami KMogi K, et al.Ghrelin in domestic animals: distribution in stomach and its possible role. Domest Anim Endocrinol 2001; 21: 1724.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28

    Bhatti SFMDe Vliegher SPVan Ham L, et al.Effects of growth hormone–releasing peptides in healthy dogs and in dogs with pituitary-dependent hyperadrenocorticism. Mol Cell Endocrinol 2002; 197: 97103.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29

    Bhatti SFMDuchateau LVan Ham LML, et al.Effects of growth hormone secretagogues on the release of adenohypophyseal hormones in young and old healthy dogs. Vet J 2006;in press.

    • Search Google Scholar
    • Export Citation
  • 30

    Massoud AFHindmarsh PCBrook DGD. Hexarelin-induced growth hormone, cortisol and prolactin release: a dose-response study. J Clin Endocrinol Metab 1996; 81: 43384341.

    • Search Google Scholar
    • Export Citation
  • 31

    Arvat EMaccario MDi Vito L, et al.Endocrine activities of ghrelin, a natural growth hormone secretagogue (GHS), in humans: comparison and interactions with hexarelin, a nonnatural peptidyl GHS, and GH-releasing hormone. J Clin Endocrinol Metab 2001; 86: 11691174.

    • Search Google Scholar
    • Export Citation
  • 32

    Raun KHansen BSJohansen NL, et al.Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol 1998; 139: 552561.

  • 33

    Broglio FKoetsveld PVPBenso A, et al.Ghrelin secretion is inhibited by either somatostatin or cortistatin in humans. J Clin Endocrinol Metab 2002; 87: 48294832.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 34

    Guillemin RBrazeau PBohlen P, et al.Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science 1982; 218: 585587.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 35

    Rivier JSpiess JThorner MO, et al.Characterisation of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature 1982; 300: 276278.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 36

    Howard ADFeighner SDCully DF, et al.A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996; 273: 974977.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37

    Guan XMYu HPalyha OC, et al.Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 1997; 48: 2329.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 38

    Bowers CYReynolds GADurham D, et al.Growth hormone (GH)-releasing peptide stimulates GH release in normal men and acts synergistically with GH-releasing hormone. J Clin Endocrinol Metab 1990; 70: 975982.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 39

    Pong S-SChaung L-YPDean DC, et al.Identification of a new G-protein-linked receptor for growth hormone secretagogues. Mol Endocrinol 1996; 10: 5761.

    • Search Google Scholar
    • Export Citation
  • 40

    McKee KKTan CPPalyha OC, et al.Cloning and characterization of two human G protein-coupled receptor genes (GPR38 and GPR39) related to the growth hormone secretagogue and neurotensin receptors. Genomics 1997; 46: 426434.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 41

    McKee KKPalyha OCFeighner SD, et al.Molecular analysis of rat pituitary and hypothalamic growth hormone secretagogue receptors. Mol Endocrinol 1997; 11: 415423.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 42

    Palyha OCFeighner SDTan CP, et al.Ligand activation domain of human orphan growth hormone (GH) secretagogue receptor (GHS-R) conserved from Pufferfish to humans. Mol Endocrinol 2000; 14: 160169.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 43

    Shuto YShibasaki TWada K, et al.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 2001; 68: 991996.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 44

    Cheng KChan WWButler B, et al.Stimulation of growth hormone release from rat primary pituitary cells by L-692,429, a novel non-peptidyl GH secretagogue. Endocrinology 1993; 132: 27292731.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 45

    Dickson SLLeng GDyball RE, et al.Central actions of peptide and non-peptide growth hormone secretagogues in the rat. Neuroendocrinology 1995; 61: 3643.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 46

    Papotti MGhé CCassoni P, et al.Growth hormone secretagogue binding sites in peripheral human tissues. J Clin Endocrinol Metab 2000; 85: 38033807.

    • Search Google Scholar
    • Export Citation
  • 47

    Kojima MHosoda HKangawa K. Purification and distribution of ghrelin: the natural ligand for the growth hormone secretagogue receptor. Horm Res 2001; 56: 9397.

    • Search Google Scholar
    • Export Citation
  • 48

    Gnanapavan SKola BBustin SA, et al.The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 49

    Casanueva FFDieguez C. Ghrelin: the link connecting growth with metabolism and energy homeostasis. Rev Endocr Metab Disord 2002; 3: 325338.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 50

    Tomasetto CWendling CRio M-C, et al.Identification of cDNA encoding motilin related peptide/ghrelin precursor from dog fundus. Peptides 2001; 22: 20552059.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 51

    Date YKojima MHosoda H, et al.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 2000; 141: 42554261.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 52

    van der Lely AJTschop MHeiman ML, et al.Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 2004; 25: 426457.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 53

    Hosoda HKojima MMatsuo H, et al.Purification and characterization of rat des-Gln 14-ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 2000; 275: 2199522000.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 54

    Bednarek MAFeighner SDPong SS, et al.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 2000; 43: 43704376.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 55

    Broglio FGottero CArvat E, et al.Endocrine and nonendocrine actions of ghrelin. Horm Res 2003; 59: 109117.