한국발생생물학회지:발생과생식 (Development and Reproduction)

  • 제13권4호
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  • Pages.207-215
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  • 2009
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  • 2465-9525(pISSN)
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  • 2465-9541(eISSN)
한국발생생물학회 (The Korean Society of Developmental Biology)
권호 표지

포유류 생식 내분비 기능 조절에서 Ghrelin의 역할

Role of Ghrelin in the Control of Reproductive Endocrine Function

  • 이성호 (상명대학교 생명과학과)
  • Lee, Sung-Ho (Dept. of Life Science, Sangmyung University)
  • 발행 : 2009.12.31
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⟨ 이전 논문 다음 논문 ⟩

초록

시상하부-뇌하수체-생식소(hypothalamus-pituitary-gonad, HPG) 호르몬 축의 활성에 영향을 미치는 수많은 인자들은 생식 기능을 조절하고, 사춘기 개시와 폐경기 진입과 같은 뚜렷한 생식 능력의 단계 전이를 초래한다. 지방세포로부터 분비되는 다기능적 호르몬인 leptin의 발견 이후, 곧 이어 생식과 신체의 에너지 균형 사이의 긴밀한 관계에 대한 증거들이 밝혀졌다. 위장관으로부터 분비되는 또 다른 다기능 호르몬인 ghrelin은 이미 알려져 있던 growth hormone secretagogue receptor(GHSR)의 내인성 리간드이며, 에너지 항상성의 조절에서 leptin에 상응하는 물질로 알려졌다. 예상대로, ghrelin 또한 HPG 축의 활성의 조절을 통해 생식 능력을 조절함이 증명되었다. 이 논문은 ghrelin의 발견과 유전자 구조, 조직 내의 분포, 그리고 역할과 HPG 축에서의 생식 호르몬 분비 조절에 대한 포유동물의 생식에서의 ghrelin-GHSR 신호에 관한 최신 정보를 요약한 것이다. 뇌하수체에서의 POMC 유전자 발현과 유사하게, preproghrelin 유전자는 alternative splicing과 번역 후 변형(posttranslational modification)을 거치는 복잡한 레퍼토리의 전사체들과 펩티드 산물을 만들어 낸다. 에너지 항상성을 제외한 신체 생리 기능의 조절에서의 preproghrelin 유전자 산물의 역할에 관한 정보는 제한적이지만, 신진 대사와 생식 사이에서의 ghrelin의 상호작용에 관해서는 충분한 증거들이 있다. 흰쥐와 인간에서, ghrelin 수용체인 GHSRs(GHSR1a와 GHSR1b)의 분포는 본래 ghrelin의 표적으로 여겨진 시상하부와 뇌하수체뿐만 아니라 정소와 난소에서도 확인되었다. 뇌와 생식소에서도 preproghrelin 유전자 발현이 확인되었는데, 이것은 HPG 축에서 ghrelin이 국부적인 역할을 담당할 가능성을 시사한다. 비록 뇌하수체에서의 기능은 아직 확실치 않지만, ghrelin은 시상하부의 GnRH, 뇌하수체의 생식소자극호르몬과 생식소의 성 스테로이드 호르몬 분비에 대한 음성적인 조절자로서의 역할을 수행하는 것으로 보인다. 최근의 연구들은 사춘기 개시, 그리고 아마도 폐경기 진입의 조절에서 ghrelin의 관여를 시사한다. 이제 ghrelin이 '뇌-위장관' 축의 필수적인 호르몬 요인이며, 신 진 대사와 생식 사이를 연결하는 조절 물질이라는 가능성은 매우 높다. '배부름'을 반영하는 leptin 신호와는 정반대인 ghrelin 신호는 신체 에너지 균형 상태로 볼 때 '배고픔'을 표현하는 것으로 생각되며, 항상성의 유지에서 최우선 사항으로 고려되지 않는 생식으로의 에너지 투자가 이루어지지 않도록 하는데 필수적일 것으로 사료된다. 생식능력 조절에 있어서 ghrelin의 보다 명확한 작용 메커니즘과 역할에 대한 깊은 통찰력을 얻고 성공적인 생의학적 적용을 위해서는 향후 더 많은 연구들이 필요하다.

Numerous factors can affect the activities of hypothalamus-pituitary-gonad (HPG) hormonal axis, resulting in alteration of reproductive capacity or status such as onset of puberty and menopause. Soon after the finding of leptin, a multifunctional hormone secreted from adipocytes, a close relationship between reproduction and body energy balance have been manifested. Ghrelin, another multifunctional hormone from gastrointestinal tract, is an endogenous ligand of growth hormone secretagogue receptor (GHSR), and is thought to be a counterpart of leptin in the regulation of energy homeostasis. As expected, ghrelin can also modulate the reproductive capacity through the modulation of activities of HPG axis. This paper summarizes the current knowledge on the discovery, gene structures, tissue distribution and roles of ghrelin and GHSRs in mammalian reproduction in particular modulation of reproductive hormone secretion in HPG axis. Like POMC gene expression in pituitary gland, preproghrelin gene can generate a complex repertoire of transcripts which further undergo alternative splicing and posttranslational modifications. Concerning the roles of preproghrelin gene products in the control of body physiology except energy homeostasis, limited knowledge is available so far. Several lines of evidence, however, show the interplay of ghrelin between metabolism and reproduction. In rat and human, the distribution of ghrelin receptor GHSRs (GHSR1a and GHSR1b) has been confirmed not only in the hypothalamus and pituitary which were originally postulated as target of ghrelin but also in the testis and ovary. Expression of the preproghrelin gene in the brain and gonads was also verified, suggesting the local role (s) of ghrelin in HPG axis. Ghrelin might play a negative modulator in the secretions of hypothalamic GnRH, pituitary gonadotropins and gonadal steroids though the action on pituitary is still questionable. Recent studies suggest the involvement of ghrelin in regulation of puberty onset and possibly of menopause entry. It is now evident that ghrelin is a crucial hormomal component in 'brain-gut' axis, and is a strong candidate links between metabolism and reproduction. Opposite to that for leptin, ghrelin signaling is likely representing the 'hunger' state of body energy balance and is necessary to avoid the energy investment into reproduction which has not a top priority in maintaining homeostasis. Further researches are needed to gain a deep insight into the more precise action mechanism and role of ghrelin in reproduction, and to guarantee the successful biomedical applications.

키워드

참고문헌

  1. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, Suda M, Koh T, Natsui K, Toyooka S, Shirakami G, Usui T, Shimatsu A, Doi K, Hosoda H, Kojima M, Kangawa K, Nakao K (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. https://doi.org/10.1210/jc.86.10.4753
  2. Bang AS, Soule SG, Yandle TG, Richards AM, Pemberton CJ (2007) Characterisation of proghrelin peptides in mammalian tissue and plasma. J Endocrinol 192:313- 323. https://doi.org/10.1677/JOE-06-0021
  3. Barreiro ML, Gaytan F, Caminos JE, Pinilla L, Casanueva FF, Aguilar E, Dieguez C, Tena-Sempere M (2002) Cellular location and hormonal regulation of ghrelin expression in rat testis. Biol Reprod 67:1768-1776. https://doi.org/10.1095/biolreprod.102.006965
  4. Barreiro ML, Suominen JS, Gaytan F, Pinilla L, Chopin LK, Casanueva FF, Dieguez C, Aguilar E, Toppari J, Tena-Sempere M (2003) Developmental, stage-specific, and hormonally regulated expression of growth hormone secretagogue receptor messenger RNA in rat testis. Biol Reprod 68:1631-1640. https://doi.org/10.1095/biolreprod.102.008862
  5. Barreiro ML, Gaytan F, Castellano JM, Suominen JS, Roa J, Gaytan M, Aguilar E, Dieguez C, Toppari J, Tena- Sempere M (2004) Ghrelin inhibits the proliferative activity of immature Leydig cells in vivo and regulates stem cell factor messenger ribonucleic acid expression in rat testis. Endocrinology 145:4825-4834. https://doi.org/10.1210/en.2004-0732
  6. Bluher S, Mantzoros CS (2007) Leptin in reproduction. Curr Opin Endocrinol Diabetes Obes 14:458-464. https://doi.org/10.1097/MED.0b013e3282f1cfdc
  7. Bowers CY, Momany F, Reynolds GA, Chang D, Hong A, Chang K (1980) Structure-activity relationships of a synthetic pentapeptide that specifically releases growth hormone in vitro. Endocrinology 106:663-667. https://doi.org/10.1210/endo-106-3-663
  8. Bowers CY, Momany FA, Reynolds GA, 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. https://doi.org/10.1210/endo-114-5-1537
  9. Caminos JE, Tena-Sempere M, Gaytan F, Sanchez-Criado JE, Barreiro ML, Nogueiras R, Casanueva FF, Aguilar E, Dieguez C (2003) Expression of ghrelin in the cyclic and pregnant rat ovary. Endocrinology 144:1594-1602. https://doi.org/10.1210/en.2002-221058
  10. Casanueva FF, Dieguez C (1999) Growth hormone secretagogues: physiological role and clinical utility. Trends Endocrinol Metab 10:30-38. https://doi.org/10.1016/S1043-2760(98)00116-7
  11. Chen C (2000) Growth hormone secretagogue actions on the pituitary gland: multiple receptors for multiple ligands- Clin Exp Pharmacol Physiol 27:323-329. https://doi.org/10.1046/j.1440-1681.2000.03258.x
  12. Christo K, Cord J, Mendes N, Miller KK, Goldstein MA, Klibanski A, Misra M (2008) Acylated ghrelin and leptin in adolescent athletes with amenorrhea, eumenorrheic athletes and controls: a cross-sectional study. Clin Endocrinol 69:628-633. https://doi.org/10.1111/j.1365-2265.2008.03237.x
  13. Cowley MA, Smith RG, Diano S, Tschöp M, Pronchuk N, Grove KL, Strasburger CJ, Bidlingmaier M, Esterman M, Heiman ML, Garcia-Segura LM, Nillni EA, Mendez P, Low MJ, Sotonyi P, Friedman JM, Liu H, Pinto S, Colmers WF, Cone RD, Horvath TL (2003) The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37:649-661. https://doi.org/10.1016/S0896-6273(03)00063-1
  14. Crown A, Clifton DK, Steiner RA (2007) Neuropeptide signaling in the integration of metabolism and reproduction. Neuroendocrinology 86:175-182. https://doi.org/10.1159/000109095
  15. Cunha SR, Mayo KE (2002) Ghrelin and growth hormone (GH) secretagogues potentiate GH-releasing hormone (GHRH)-induced cyclic adenosine 3',5'-monophosphate production in cells expressing transfected GHRH and GH secretagogue receptors. Endocrinology 143:4570-4582. https://doi.org/10.1210/en.2002-220670
  16. de Luis DA, Perez Castrillón JL, Duenas A (2009) Leptin and obesity. Minerva Med 100:229-236.
  17. Fernandez-Fernández R, Tena-Sempere M, Navarro VM, Barreiro ML, Castellano JM, Aguilar E, Pinilla L (2005a) Effects of ghrelin upon gonadotropin-releasing hormone and gonadotropin secretion in adult female rats: in vivo and in vitro studies. Neuroendocrinology 82:245-255. https://doi.org/10.1159/000092753
  18. Fernandez-Fernandez R, Navarro VM, Barreiro ML, Vigo EM, Tovar S, Sirotkin AV, Casanueva FF, Aguilar E, Dieguez C, Pinilla L, Tena-Sempere M (2005b) Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat. Endocrinology 146:3018- 3025. https://doi.org/10.1210/en.2004-1622
  19. Fernandez-Fernandez R, Martini AC, Navarro VM, Castellano JM, Dieguez C, Aguilar E, Pinilla L, Tena-Sempere M (2006) Novel signals for the integration of energy balance and reproduction. Mol Cell Endocrinol 254-255: 127-132. https://doi.org/10.1016/j.mce.2006.04.026
  20. Fernandez-Fernandez R, Tena-Sempere M, Roa J, Castellano JM, Navarro VM, Aguilar E, Pinilla L (2007) Direct stimulatory effect of ghrelin on pituitary release of LH through a nitric oxide-dependent mechanism that is modulated by estrogen. Reproduction 133:1223-1232. https://doi.org/10.1530/REP-06-0227
  21. Furuta M, Funabashi T, Kimura F (2001) Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochem Biophys Res Commun 288:780-785. https://doi.org/10.1006/bbrc.2001.5854
  22. Gaytan F, Barreiro ML, Chopin LK, Herington AC, Morales C, Pinilla L, Casanueva FF, Aguilar E, Dieguez C, Tena-Sempere M (2003) Immunolocalization of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in the cyclic human ovary. J Clin Endocrinol Metab 88:879-887. https://doi.org/10.1210/jc.2002-021196
  23. Gaytan F, Barreiro ML, Caminos JE, Chopin LK, Herington AC, Morales C, Pinilla L, Paniagua R, Nistal M, Casanueva FF, Aguilar E, Dieguez C, Tena-Sempere M (2004) Expression of ghrelin and its functional receptor, the type 1a growth hormone secretagogue receptor, in normal human testis and testicular tumors. J Clin Endocrinol Metab 89:400-409. https://doi.org/10.1210/jc.2003-031375
  24. Ghelardoni S, Carnicelli V, Frascarelli S, Ronca-Testoni S, Zucchi R (2006) Ghrelin tissue distribution: comparison between gene and protein expression. J Endocrinol Invest 29:115-121.
  25. Goto M, Arima H, Watanabe M, Hayashi M, Banno R, Sato I, Nagasaki H, Oiso Y (2006) Ghrelin increases neuropeptide Y and agouti-related peptide gene expression in the arcuate nucleus in rat hypothalamic organotypic cultures. Endocrinology 147:5102-5109. https://doi.org/10.1210/en.2006-0104
  26. Greenman Y, Rouach V, Limor R, Gilad S, Stern N (2009) Testosterone is a strong correlate of ghrelin levels in men and postmenopausal women. Neuroendocrinology 89:79-85. https://doi.org/10.1159/000151768
  27. Guan JL, Okuda H, Takenoya F, Kintaka Y, Yagi M, Wang L, Seki M, Hori Y, Kageyama H, Shioda S (2008) Synaptic relationships between proopiomelanocortinand ghrelin-containing neurons in the rat arcuate nucleus. Regul Pept 145:128-132. https://doi.org/10.1016/j.regpep.2007.09.028
  28. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, Smith RG, Van der Ploeg LH, Howard AD (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 48:23-29. https://doi.org/10.1016/S0169-328X(97)00071-5
  29. Han XF, Zhu YL, Hernandez M, Keating DJ, Chen C (2005) Ghrelin reduces voltage-gated potassium currents in GH3 cells via cyclic GMP pathways. Endocrine 28:217-224. https://doi.org/10.1385/ENDO:28:2:217
  30. Herrid M, O'Shea T, McFarlane JR (2008) Ontogeny of leptin and its receptor expression in mouse testis during the postnatal period. Mol Reprod Dev 75:874- 880. https://doi.org/10.1002/mrd.20796
  31. Hosoda H, Kojima M, Matsuo H, Kangawa K (2000) Purification and characterization of rat des-Gln14-Ghrelin, a second endogenous ligand for the growth hormone secretagogue receptor. J Biol Chem 275:21995-2000. https://doi.org/10.1074/jbc.M002784200
  32. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, Hamelin M, Hreniuk DL, Palyha OC, Anderson J, Paress PS, Diaz C, Chou M, Liu KK, McKee KK, Pong SS, Chaung LY, Elbrecht A, Dashkevicz M, Heavens R, Rigby M, Sirinathsinghji DJ, Dean DC, Melillo DG, Patchett AA, Nargund R, Griffin PR, DeMartino JA, Gupta SK, Schaeffer JM, Smith RG, Van der Ploeg LH (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 273:974-977. https://doi.org/10.1126/science.273.5277.974
  33. Iqbal J, Kurose Y, Canny B, Clarke I (2006) Effects of central infusion of ghrelin on food intake and plasma levels of growth hormone, luteinizing hormone, prolactin, and cortisol secretion in sheep. Endocrinology 147: 510-519. https://doi.org/10.1210/en.2005-1048
  34. Kanamoto N, Akamizu T, Tagami T, Hataya Y, Moriyama K, Takaya K, Hosoda H, Kojima M, Kangawa K, Nakao K (2004) Genomic structure and characterization of the 5'-flanking region of the human ghrelin gene. Endocrinology 145:4144-4153. https://doi.org/10.1210/en.2003-1718
  35. Kluge M, Uhr M, Bleninger P, Yassouridis A, Steiger A (2009) Ghrelin suppresses secretion of FSH in males. Clin Endocrinol 70:920-923. https://doi.org/10.1111/j.1365-2265.2008.03440.x
  36. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (1999) Ghrelin is a growth-hormonereleasing acylated peptide from stomach. Nature 402: 656-660. https://doi.org/10.1038/45230
  37. Kok P, Paulo RC, Cosma M, Mielke KL, Miles JM, Bowers CY, Veldhuis JD (2008) Estrogen supplementation selectively enhances hypothalamo-pituitary sensitivity to ghrelin in postmenopausal women. J Clin Endocrinol Metab 93:4020-4026. https://doi.org/10.1210/jc.2008-0522
  38. Lanfranco F, Bonelli L, Baldi M, Me E, Broglio F, Ghigo E (2008) Acylated ghrelin inhibits spontaneous luteinizing hormone pulsatility and responsiveness to naloxone but not that to gonadotropin-releasing hormone in young men: evidence for a central inhibitory action of ghrelin on the gonadal axis. J Clin Endocrinol Metab 93: 3633-3639. https://doi.org/10.1210/jc.2008-0049
  39. Lauwers E, Landuyt B, Arckens L, Schoofs L, Luyten W (2006) Obestatin does not activate orphan G proteincoupled receptor GPR39. Biochem Biophys Res Commun 351:21-25. https://doi.org/10.1016/j.bbrc.2006.09.141
  40. Leite-Moreira AF, Soares JB (2007) Physiological, pathological and potential therapeutic roles of ghrelin. Drug Discov Today 12:276-88. https://doi.org/10.1016/j.drudis.2007.02.009
  41. Leung PK, Chow KB, Lau PN, Chu KM, Chan CB, Cheng CH, Wise H (2007) The truncated ghrelin receptor polypeptide (GHS-R1b) acts as a dominant-negative mutant of the ghrelin receptor. Cell Signal 19:1011- 1022. https://doi.org/10.1016/j.cellsig.2006.11.011
  42. Loffler S, Aust G, Kohler U, Spanel-Borowski K (2001) Evidence of leptin expression in normal and polycystic human ovaries. Mol Hum Reprod 7:1143-1149. https://doi.org/10.1093/molehr/7.12.1143
  43. Lu S, Guan JL, Wang QP, Uehara K, Yamada S, Goto N, Date Y, Nakazato M, Kojima M, Kangawa K, Shioda S (2002) Immunocytochemical observation of ghrelincontaining neurons in the rat arcuate nucleus. Neurosci Lett 321:157-160. https://doi.org/10.1016/S0304-3940(01)02544-7
  44. Martos-Moreno GA, Chowen JA, Argente J (2009) Metabolic signals in human puberty: Effects of over and undernutrion. Mol Cell Endocrinol in press.
  45. Mircea CN, Lujan ME, Pierson RA (2009) Metabolic fuel and clinical implications for female reproduction. J Obstet Gynaecol Can 29:887-902.
  46. Pelleymounter MA, Cullen MJ, Baker MB, Hecht R, Winters D, Boone T, Collins F (1995) Effects of the obese gene product on body weight regulation in ob/ob mice. Science 269:540-543. https://doi.org/10.1126/science.7624776
  47. Pinelli G, Tagliabue A (2007) Nutrition and fertility. Minerva Gastroenterol Dietol 53:375-582.
  48. Plant TM (2008) Hypothalamic control of the pituitarygonadal axis in higher primates: key advances over the last two decades. J Neuroendocrinol 20:719-726. https://doi.org/10.1111/j.1365-2826.2008.01708.x
  49. Rindi G, Necchi V, Savio A, Torsello A, Zoli M, Locatelli V, Raimondo F, Cocchi D, 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. https://doi.org/10.1007/s00418-002-0415-1
  50. Sam S, Frohman LA (2008) Normal physiology of hypothalamic pituitary regulation. Endocrinol Metab Clin North Am 37:1-22. https://doi.org/10.1016/j.ecl.2007.10.007
  51. Sato T, Fukue Y, Teranishi H, Yoshida Y, Kojima M (2005) Molecular forms of hypothalamic ghrelin and its regulation by fasting and 2-deoxy-d-glucose administration. Endocrinology 146:2510-2516. https://doi.org/10.1210/en.2005-0174
  52. Seim I, Collet C, Herington AC, Chopin LK (2007) Revised genomic structure of the human ghrelin gene and identification of novel exons, alternative splice variants and natural antisense transcripts. BMC Genomics 8:298. https://doi.org/10.1186/1471-2164-8-298
  53. Soriano-Guillen L, Barrios V, Chowen JA, Sanchez I, Vila S, Quero J, Argente J (2004) Ghrelin levels from fetal life through early adulthood: relationship with endocrine and metabolic and anthropometric measures. J Pediatr 144:30-35. https://doi.org/10.1016/j.jpeds.2003.08.050
  54. Tena-Sempere M, Barreiro ML, Gonzalez LC, Gaytan F, Zhang FP, Caminos JE, Pinilla L, Casanueva FF, Dieguez C, Aguilar E (2002) Novel expression and functional role of ghrelin in rat testis. Endocrinology 143:717-725. https://doi.org/10.1210/en.143.2.717
  55. Tsutsumi R, Webster NJ (2009) GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocr J 56:729-737. https://doi.org/10.1507/endocrj.K09E-185
  56. van der Lely AJ, Tschop M, Heiman ML, Ghigo E (2004) Biological, physiological, pathophysiological, and pharmacological aspects of ghrelin. Endocr Rev 25:426-457. https://doi.org/10.1210/er.2002-0029
  57. Viani I, Vottero A, Tassi F, Cremonini G, Sartori C, Bernasconi S, Ferrari B, Ghizzoni L (2008) Ghrelin inhibits steroid biosynthesis by cultured granulosa-lutein cells. J Clin Endocrinol Metab 93:1476-1481. https://doi.org/10.1210/jc.2007-2063
  58. Vulliemoz NR, Xiao E, Xia-Zhang L, Germond M, Rivier J, Ferin M (2004) Decrease in luteinizing hormone pulse frequency during a five-hour peripheral ghrelin infusion in the ovariectomized rhesus monkey. J Clin Endocrinol Metab 89:5718-5723. https://doi.org/10.1210/jc.2004-1244
  59. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL (2008) Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell 132:387-396. https://doi.org/10.1016/j.cell.2008.01.017
  60. Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ (2005) Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310:996-999. https://doi.org/10.1126/science.1117255