胃促生长素

胃促生长素^[1][2]（ghrelin，lenomorelin）全名胃生长激素释放肽（growth hormone-releasing peptide）^[3]，俗称饥饿素（hunger hormone），是一种主要由胃肠道（尤其是胃）的肠内分泌细胞（英语：Enteroendocrine cell）（P/D1细胞（英语：P/D1 cell））产生的激素，属一种多功能脑肠肽（胃肠道神经肽）^[4][5]，能诱导生长激素的释放、胃肠道功能调节、摄食、抑制炎症反应，并维持能量正平衡的作用。

它被称为饥饿素是因为它会增加进食的动力^[5]，在餐前饥饿时，饥饿素在血液中浓度最高，进食后恢复到较低水平^[5][6]。饥饿素可能透过增加胃的活动性和刺激胃酸分泌来帮助进食准备^[5][7]。

饥饿素能够激活脑垂体前叶和下丘脑弓状核中的细胞，^[5][8]其中包括可引起食欲的神经肽Y神经元。^[5][9]饥饿素能够刺激具有特定受体的大脑结构：饥饿素受体1A（GHSR -1A）。^[5][10]饥饿素同时也能够调节神经结构中的犒赏系统^[11]、学习和记忆，睡眠-苏醒周期、味觉、犒赏行为和葡萄糖代谢。^[5][12][13]

历史与命名

饥饿素的首次发现是在1999年^[5]发现了饥饿素受体（称为生长激素促分泌素受体1A或GHS-R）之后。其命名是以它能够“促生长激素分泌”的功能来命名，源自于原始印欧语中的gʰre，意谓成长。^[5]

基因、转录产物与构造

其GHRL基因产生的mRNA有四个外显子，并产生五种产物：第一种是117个氨基酸的前饥饿素原。（与促胃动素原同源；两者都是促胃动素家族的成员）。将前饥饿素原剪接后产生饥饿素原，再剪接后产生一个具有28个氨基酸的未酰化饥饿素和一个酰化饥饿素（C-Gherlin）。据推测，肥胖抑制素可能从C-ghrelin剪接而成。^[14]

饥饿素只有在饥饿素酰基转移酶 （页面存档备份，存于互联网档案馆）（GOAT）的帮助下，结构中的辛酸在翻译后与丝氨酸的3号位连接时才具有活性。它位于胃和胰脏中的饥饿素细胞的细胞膜上^[15]，而未辛酰化的形式则称为去酰基饥饿素，其无法激活GHS-R受体，但具有其他作用：心脏方面的功能^[16]、刺激食欲^[17]和抑制肝脏输出葡萄糖^[18]。同时也观察到，辛酰基以外的侧链也可以触发饥饿素受体^[19]。 特别的是，已发现癸酰饥饿素在小鼠循环中的饥饿素站了一定比例，但截至2011年，其在人体中的存在尚未确定。^[20]

前饥饿素原(蓝色和绿色的部分)及饥饿素(绿色部分)

饥饿素细胞

别名

饥饿素细胞也被称为胰脏的A-like cell、X-cell（X意谓功能不明）、小鼠中的X/A-like cell、胰脏中的ε细胞、人体的P/D sub 1 cell、或Gr cell（Gherlin的简称）^[21]。

位置

饥饿素细胞主要存在于胃^[22]和十二指肠中，但也存在于空肠、肺、胰岛^[23]、性腺、肾上腺皮质、胎盘和肾脏中。最近也有研究显示，饥饿素能够在大脑局部产生^[24]。

特色

饥饿素细胞存在于胃底腺细胞中（占细胞的20％）^[25]、幽门和小肠中，是卵圆形的颗粒性细胞^[26]，同时具有胃泌素受体^[27]，且有一些能够产生脂肪激素nesfatin-1^[28]。饥饿素细胞在胰脏中没有终末分化的步骤，它们作为前驱细胞，可以产生A细胞、PP细胞和β细胞。^[29]

作用的功能与机制

饥饿素参与调节能量平衡（英语：Energy_homeostasis）的复杂过程，透过调节饥饿讯号来影响能量输入;调节ATP生产、脂肪储存、肝糖储存及短期热消耗等能量比例调节来影响能量输出。能量平衡的结果最终反映在体重上，并根据代谢信号和需求进行持续监测调整。而胃脑沟通是影响能量平衡的重要途径，有几种沟通路径，其中包括胃细胞内mTOR（英语：mTOR） / S6K1（英语：S6_Kinase_1 S6K1）路径所调节的饥饿素、nesfatin（英语：Nesfatin-1）及内源性大麻素（英语：Endocannabinoid_system）胃系统彼此间的交互作用，^[30]及迷走神经的传出入讯号。

饥饿素及合成饥饿素模拟物(生长激素促进剂（英语：Growth_hormone_secretagogue）)透过诱发含神经肽Y(NPY)（英语：Neuropeptide_Y）及刺鼠肽基因相关蛋白(AgRP)（英语：Agouti-related_peptide）^[31][9]的弓形核^[8]受体来增加体重及脂肪量。^[32][33][34]这些对饥饿素反应的神经元对瘦素及胰岛素均敏感。^[35]而饥饿素会降低胃迷走神经传入（英语：Afferent_nerve_fiber）的敏感性，导致较低的胃扩张程度。^[36]

除了其能量平衡的功能，饥饿素还会激活胆碱能-多巴胺能犒赏回路在腹侧被盖区的输入，以及用来传达自然犒赏的享乐和增强方面的回路，^[37]如食物和成瘾性药物^[35][38][39]的中脑边缘通路。^[40]该回路上可以找到饥饿素的受体。^[37][11]而酒精^[41]及可口/奖励食物^[42][43]是需要下丘脑饥饿素讯号来提供回馈。

饥饿素与诱导食欲及进食行为有关，而血液循环中的饥饿素水平会在饭前最高、饭后最低。^[44][45]在人和大鼠注射饥饿素已证明会增加食物摄取，即注射量越多，食物摄取越多^[46]，但饥饿素所增加的不是进食量，而是进食的次数。^[47]饥饿素的注射还会增加动物觅食行为，同时增加嗅觉寻找能力，倾向搜集囤积食物。由于体重是透过能量平衡来调节的，饥饿素浓度与体重会呈负相关，由此饥饿素可以做为肥胖警讯。^[7]

血液中浓度

饥饿素在血液中的浓度在pmol / l的范围内。具有活性的饥饿素含量和总饥饿素含量都可以被测量出来^[48] 。循环中的饥饿素浓度在进食前升高，并在进食后下降^[44]，并且对于蛋白质和碳水化合物的反应比对脂质的反应更强烈。^[20]

饥饿素受体

饥饿素受体GHS-R1A（由饥饿素受体剪接而来）可以调节多项饥饿素造成的生物效应，包括：刺激生长激素的释放、增加饥饿感、调节葡萄糖和脂质的代谢、调节肠胃蠕动和分泌、保护神经和心血管细胞以及调节免疫功能。^[49]它们大量存在于下丘脑和脑垂体、迷走神经上（在传入的细胞体和传出的神经末梢上）以及整个胃肠道中。^[15]

作用地点

葡萄糖代谢

整个饥饿素系统（包含dAG、AG、GHS-R、GOAT）皆具有调节葡萄糖的作用。^[50]

睡眠

初步研究表明，饥饿素参与了昼夜规律的调节^[5]。虽然有文献表示，没有发现有力的证据显示限制睡眠会影响饥饿素以及瘦素的浓度或能量消耗。^[51]

生殖系统

饥饿素对促性腺激素释放激素（GnRH）的分泌具有抑制作用，可能导致生育力下降。^[52]

胎儿和新生儿

饥饿素在胎儿时期的早期肺脏产生，并具有促进肺生长的功能。^[53] 脐带血中饥饿素的浓度也显示，饥饿素浓度和新生儿出生体重之间的相关性。^[48]

厌食症和肥胖

肥胖个体血浆中的饥饿素浓度低于瘦型个体^[5][54]，由此显示，饥饿素并不直接造成肥胖，只有在小胖威利综合症引起的肥胖中，高浓度的饥饿素能够造成食物摄入量的增加^[55][55]。与体重过轻和正常体重的两个对照组相比，神经性厌食症的血浆饥饿素浓度更高^[56][57][58]。体型较为削瘦的人在一天中，从午夜到黎明的这段时间的饥饿素浓度较高，这显示肥胖者的昼夜规律系统存在缺陷^[59]。同时，癌症引起的恶体质患者也有高浓度的饥饿素^[60]。尚无足够的证据得出支持或反对使用生长素释放肽治疗癌症相关恶体质的结论^[61]。

相关疾病的控管与治疗

胃绕道手术

与体型瘦削和节食减肥的人相比，进行胃绕道手术的人不仅减少了肠道容量，甚至能够降低体内饥饿素浓度。^[5][62]在此方面，尚未有研究阐明，接受胃绕道手术的人，体内的饥饿素浓度是否在减轻的体重稳定下来后就恢复正常浓度。^[63]统计也显示，胃绕道的相关手术中，进行袖状胃切除术（英语：Sleeve_gastrectomy）的人从长远来看，体内饥饿素浓度能够降低约60％。^[64]

参见

• 下丘脑-脑垂体-生长轴（英语：Hypothalamic–pituitary–somatotropic_axis）
• 生长激素促分泌素清单（英语：List_of_growth_hormone_secretagogues）

参考文献

1. 存档副本. [2024-03-10]. （原始内容存档于2024-03-10）.
2. 曹曙光,郑君杰,薛战雄.胃促生长素与消化道运动[J].国际消化病杂志,2007,27(4):290-292
3. 王馨苒, 贾许杨, 杜磊, 等. 胃生长激素释放肽调控食欲的机制及临床应用前景 [J] . 中华内分泌代谢杂志, 2023, 39(3) : 283-288. DOI: 10.3760/cma.j.cn311282-20220709-00421.
4. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K (December 1999). "Ghrelin is a growth-hormone-releasing acylated peptide from stomach". Nature. 402 (6762): 656–60. Bibcode:1999Natur.402..656K. doi:10.1038/45230. PMID 10604470.
5. Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. (June 2015). "Ghrelin". Molecular Metabolism. 4 (6): 437–60. doi:10.1016/j.molmet.2015.03.005. PMC 4443295. PMID 26042199.
6. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS (August 2001). "A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans". Diabetes. 50 (8): 1714–9. doi:10.2337/diabetes.50.8.1714. PMID 11473029.
7. Schwartz MW, Woods SC, Porte D, Seeley RJ, Baskin DG (April 2000). "Central nervous system control of food intake". Nature. 404 (6778): 661–71. doi:10.1038/35007534. PMID 10766253.
8. Dickson SL, Leng G, Robinson IC (March 1993). "Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons". Neuroscience. 53 (2): 303–6. doi:10.1016/0306-4522(93)90197-n. PMID 8492908.
9. Dickson SL, Luckman SM (February 1997). "Induction of c-fos messenger ribonucleic acid in neuropeptide Y and growth hormone (GH)-releasing factor neurons in the rat arcuate nucleus following systemic injection of the GH secretagogue, GH-releasing peptide-6". Endocrinology. 138 (2): 771–7. doi:10.1210/endo.138.2.4907. PMID 9003014.
10. Howard AD, Feighner SD, Cully DF, Arena JP, Liberator PA, Rosenblum CI, et al. (August 1996). "A receptor in pituitary and hypothalamus that functions in growth hormone release". Science. 273 (5277): 974–7. Bibcode:1996Sci...273..974H. doi:10.1126/science.273.5277.974. PMID 8688086.
11. Nestler EJ, Hyman SE, Holtzman DM, Malenka RC (2015). "Neural and Neuroendocrine Control of the Internal Milieu". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. pp. 245–267. ISBN 9780071827690.
12. Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (June 2011). "The role of the central ghrelin system in reward from food and chemical drugs". Molecular and Cellular Endocrinology. 340 (1): 80–7. doi:10.1016/j.mce.2011.02.017. hdl:2077/26318. PMID 21354264.
13. Le Moal M (2002). "Mesocorticolimbic Dopaminergic Neurons". In Davis KL, Charney D, Coyle JT, Nemeroff C (eds.). Neuropsychopharmacology : the fifth generation of progress : an official publication of the American College of Neuropsychopharmacology (5th ed.). Philadelphia, Pa.: Lippincott Williams & Wilkins. ISBN 978-0781728379.
14. Seim I, Amorim L, Walpole C, Carter S, Chopin LK, Herington AC (January 2010). "Ghrelin gene-related peptides: multifunctional endocrine / autocrine modulators in health and disease". Clinical and Experimental Pharmacology & Physiology. 37 (1): 125–31. doi:10.1111/j.1440-1681.2009.05241.x. PMID 19566830.
15. Castañeda TR, Tong J, Datta R, Culler M, Tschöp MH (January 2010). "Ghrelin in the regulation of body weight and metabolism". Frontiers in Neuroendocrinology. 31 (1): 44–60. doi:10.1016/j.yfrne.2009.10.008. PMID 19896496.
16. Bedendi I, Alloatti G, Marcantoni A, Malan D, Catapano F, Ghé C, et al. (August 2003). "Cardiac effects of ghrelin and its endogenous derivatives des-octanoyl ghrelin and des-Gln14-ghrelin" (PDF). European Journal of Pharmacology. 476 (1–2): 87–95. doi:10.1016/S0014-2999(03)02083-1. hdl:2318/125949. PMID 12969753.
17. Toshinai K, Yamaguchi H, Sun Y, Smith RG, Yamanaka A, Sakurai T, et al. (May 2006). "Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor". Endocrinology. 147 (5): 2306–14. doi:10.1210/en.2005-1357. PMID 16484324.
18. Gauna C, Delhanty PJ, Hofland LJ, Janssen JA, Broglio F, Ross RJ, et al. (February 2005). "Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes". The Journal of Clinical Endocrinology and Metabolism. 90 (2): 1055–60. doi:10.1210/jc.2004-1069. PMID 15536157.
19. Korbonits M, Goldstone AP, Gueorguiev M, Grossman AB (April 2004). "Ghrelin--a hormone with multiple functions". Frontiers in Neuroendocrinology. 25 (1): 27–68. doi:10.1016/j.yfrne.2004.03.002. PMID 15183037.
20. Stengel A, Taché Y (June 2011). "Interaction between gastric and upper small intestinal hormones in the regulation of hunger and satiety: ghrelin and cholecystokinin take the central stage". Current Protein & Peptide Science. 12 (4): 293–304. doi:10.2174/138920311795906673. PMC 3670092. PMID 21428875.
21. Zigman JM, Nakano Y, Coppari R, Balthasar N, Marcus JN, Lee CE, et al. (December 2005). "Mice lacking ghrelin receptors resist the development of diet-induced obesity". The Journal of Clinical Investigation. 115 (12): 3564–72. doi:10.1172/JCI26002. PMC 1297251. PMID 16322794.
22. Ariyasu H, Takaya K, Tagami T, Ogawa Y, Hosoda K, Akamizu T, et al. (October 2001). "Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans". The Journal of Clinical Endocrinology and Metabolism. 86 (10): 4753–8. doi:10.1210/jcem.86.10.7885. PMID 11600536.
23. Suckale J, Solimena M (May 2008). "Pancreas islets in metabolic signaling--focus on the beta-cell". Frontiers in Bioscience. 13 (13): 7156–71. doi:10.2741/3218. PMID 18508724.
24. Ferrini F, Salio C, Lossi L, Merighi A (March 2009). "Ghrelin in central neurons". Current Neuropharmacology. 7 (1): 37–49. doi:10.2174/157015909787602779. PMC 2724662. PMID 19721816.
25. Simonsson M, Eriksson S, Håkanson R, Lind T, Lönroth H, Lundell L, et al. (November 1988). "Endocrine cells in the human oxyntic mucosa. A histochemical study". Scandinavian Journal of Gastroenterology. 23 (9): 1089–99. doi:10.3109/00365528809090174. PMID 2470131.
26. Grube D, Forssmann WG (November 1979). "Morphology and function of the entero-endocrine cells". Hormone and Metabolic Research = Hormon- und Stoffwechselforschung = Hormones et Metabolisme. 11 (11): 589–606. doi:10.1055/s-0028-1092785. PMID 94030.
27. Fukumoto K, Nakahara K, Katayama T, Miyazatao M, Kangawa K, Murakami N (September 2008). "Synergistic action of gastrin and ghrelin on gastric acid secretion in rats". Biochemical and Biophysical Research Communications. 374 (1): 60–3. doi:10.1016/j.bbrc.2008.06.114. PMID 18611393.
28. Inhoff T, Stengel A, Peter L, Goebel M, Taché Y, Bannert N, et al. (February 2010). "Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats". Peptides. 31 (2): 257–62. doi:10.1016/j.peptides.2009.11.024. PMC 4043136. PMID 19961888.
29. Arnes L, Hill JT, Gross S, Magnuson MA, Sussel L (2012). "Ghrelin expression in the mouse pancreas defines a unique multipotent progenitor population". PLOS ONE. 7 (12): e52026. Bibcode:2012PLoSO...752026A. doi:10.1371/journal.pone.0052026. PMC 3520898. PMID 23251675.
30. Folgueira C, Seoane LM, Casanueva FF (2014). "The brain-stomach connection". In Delhanty PJD, van der Lely AJ (eds.). How Gut and Brain Control Metabolism. Frontiers of Hormone Research. 42. Basel: Karger. pp. 83–92. doi:10.1159/000358316. ISBN 978-3-318-02638-2. PMID 24732927.
31. Chen HY, Trumbauer ME, Chen AS, Weingarth DT, Adams JR, Frazier EG, et al. (June 2004). "Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein". Endocrinology. 145 (6): 2607–12. doi:10.1210/en.2003-1596. PMID 14962995.
32. Lall S, Tung LY, Ohlsson C, Jansson JO, Dickson SL (January 2001). "Growth hormone (GH)-independent stimulation of adiposity by GH secretagogues". Biochemical and Biophysical Research Communications. 280 (1): 132–8. doi:10.1006/bbrc.2000.4065. PMID 11162489.
33. Tschöp M, Smiley DL, Heiman ML (October 2000). "Ghrelin induces adiposity in rodents". Nature. 407 (6806): 908–13. Bibcode:2000Natur.407..908T. doi:10.1038/35038090. PMID 11057670.
34. Chebani Y, Marion C, Zizzari P, Chettab K, Pastor M, Korostelev M, et al. (April 2016). "Enhanced responsiveness of Ghsr Q343X rats to ghrelin results in enhanced adiposity without increased appetite" (PDF). Science Signaling. 9 (424): ra39. doi:10.1126/scisignal.aae0374. PMID 27095593.
35. Hewson AK, Tung LY, Connell DW, Tookman L, Dickson SL (December 2002). "The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic". Diabetes. 51 (12): 3412–9. doi:10.2337/diabetes.51.12.3412. PMID 12453894.
36. Page AJ, Slattery JA, Milte C, Laker R, O'Donnell T, Dorian C, et al. (May 2007). "Ghrelin selectively reduces mechanosensitivity of upper gastrointestinal vagal afferents". American Journal of Physiology. Gastrointestinal and Liver Physiology. 292 (5): G1376-84. doi:10.1152/ajpgi.00536.2006. PMID 17290011.
37. Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E (June 2011). "The role of the central ghrelin system in reward from food and chemical drugs". Molecular and Cellular Endocrinology. 340 (1): 80–7. doi:10.1016/j.mce.2011.02.017. hdl:2077/26318. PMID 21354264. Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link".
38. Jerlhag E, Egecioglu E, Dickson SL, Andersson M, Svensson L, Engel JA (March 2006). "Ghrelin stimulates locomotor activity and accumbal dopamine-overflow via central cholinergic systems in mice: implications for its involvement in brain reward". Addiction Biology. 11 (1): 45–54. doi:10.1111/j.1369-1600.2006.00002.x. PMID 16759336.
39. Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA (March 2007). "Ghrelin administration into tegmental areas stimulates locomotor activity and increases extracellular concentration of dopamine in the nucleus accumbens". Addiction Biology. 12 (1): 6–16. doi:10.1111/j.1369-1600.2006.00041.x. PMID 17407492.
40. Naleid AM, Grace MK, Cummings DE, Levine AS (November 2005). "Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens". Peptides. 26 (11): 2274–9. doi:10.1016/j.peptides.2005.04.025. PMID 16137788.
41. Jerlhag E, Egecioglu E, Landgren S, Salomé N, Heilig M, Moechars D, et al. (July 2009). "Requirement of central ghrelin signaling for alcohol reward". Proceedings of the National Academy of Sciences of the United States of America. 106 (27): 11318–23. Bibcode:2009PNAS..10611318J. doi:10.1073/pnas.0812809106. PMC 2703665. PMID 19564604.
42. Egecioglu E, Jerlhag E, Salomé N, Skibicka KP, Haage D, Bohlooly-Y M, et al. (July 2010). "Ghrelin increases intake of rewarding food in rodents". Addiction Biology. 15 (3): 304–11. doi:10.1111/j.1369-1600.2010.00216.x. PMC 2901520. PMID 20477752.
43. Skibicka KP, Hansson C, Egecioglu E, Dickson SL (January 2012). "Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression". Addiction Biology. 17 (1): 95–107. doi:10.1111/j.1369-1600.2010.00294.x. PMC 3298643. PMID 21309956.
44. Tolle V, Bassant MH, Zizzari P, Poindessous-Jazat F, Tomasetto C, Epelbaum J, Bluet-Pajot MT (April 2002). "Ultradian rhythmicity of ghrelin secretion in relation with GH, feeding behavior, and sleep-wake patterns in rats". Endocrinology. 143 (4): 1353–61. doi:10.1210/endo.143.4.8712. PMID 11897692.
45. Cummings DE, Frayo RS, Marmonier C, Aubert R, Chapelot D (August 2004). "Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues". American Journal of Physiology. Endocrinology and Metabolism. 287 (2): E297-304. doi:10.1152/ajpendo.00582.2003. PMID 15039149.
46. Wren AM, Small CJ, Ward HL, Murphy KG, Dakin CL, Taheri S, et al. (November 2000). "The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion". Endocrinology. 141 (11): 4325–8. doi:10.1210/endo.141.11.7873. PMID 11089570.
47. Faulconbridge LF, Cummings DE, Kaplan JM, Grill HJ (September 2003). "Hyperphagic effects of brainstem ghrelin administration". Diabetes. 52 (9): 2260–5. doi:10.2337/diabetes.52.9.2260. PMID 12941764.
48. Yokota I, Kitamura S, Hosoda H, Kotani Y, Kangawa K (April 2005). "Concentration of the n-octanoylated active form of ghrelin in fetal and neonatal circulation". Endocrine Journal. 52 (2): 271–6. doi:10.1507/endocrj.52.271. PMID 15863960.
49. Yin Y, Li Y, Zhang W (March 2014). "The growth hormone secretagogue receptor: its intracellular signaling and regulation". International Journal of Molecular Sciences. 15 (3): 4837–55. doi:10.3390/ijms15034837. PMC 3975427. PMID 24651458.
50. Heppner KM, Tong J (July 2014). "Mechanisms in endocrinology: regulation of glucose metabolism by the ghrelin system: multiple players and multiple actions". European Journal of Endocrinology. 171 (1): R21-32. doi:10.1530/EJE-14-0183. PMID 24714083.
51. Zhu B, Shi C, Park CG, Zhao X, Reutrakul S (June 2019). "Effects of sleep restriction on metabolism-related parameters in healthy adults: A comprehensive review and meta-analysis of randomized controlled trials". Sleep Medicine Reviews. 45: 18–30. doi:10.1016/j.smrv.2019.02.002. PMID 30870662.
52. Comninos AN, Jayasena CN, Dhillo WS (2014). "The relationship between gut and adipose hormones, and reproduction". Human Reproduction Update. 20 (2): 153–74. doi:10.1093/humupd/dmt033. PMID 24173881.
53. Santos M, Bastos P, Gonzaga S, Roriz JM, Baptista MJ, Nogueira-Silva C, et al. (April 2006). "Ghrelin expression in human and rat fetal lungs and the effect of ghrelin administration in nitrofen-induced congenital diaphragmatic hernia". Pediatric Research. 59 (4 Pt 1): 531–7. doi:10.1203/01.pdr.0000202748.66359.a9. PMID 16549524.
54. Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. (January 2002). "Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion". The Journal of Clinical Endocrinology and Metabolism. 87 (1): 240–4. doi:10.1210/jcem.87.1.8129. PMID 11788653.
55. Goldstone AP, Thomas EL, Brynes AE, Castroman G, Edwards R, Ghatei MA, et al. (April 2004). "Elevated fasting plasma ghrelin in prader-wili syndrome adults is not solely explained by their reduced visceral adiposity and insulin resistance". The Journal of Clinical Endocrinology and Metabolism. 89 (4): 1718–26. doi:10.1210/jc.2003-031118. PMID 15070936.
56. Misra M, Klibanski A (July 2014). "Endocrine consequences of anorexia nervosa". The Lancet. Diabetes & Endocrinology. 2 (7): 581–92. doi:10.1016/S2213-8587(13)70180-3. PMC 4133106. PMID 24731664.
57. Tolle V, Kadem M, Bluet-Pajot MT, Frere D, Foulon C, Bossu C, et al. (January 2003). "Balance in ghrelin and leptin plasma levels in anorexia nervosa patients and constitutionally thin women". The Journal of Clinical Endocrinology and Metabolism. 88 (1): 109–16. doi:10.1210/jc.2002-020645. PMID 12519838.
58. Germain N, Galusca B, Le Roux CW, Bossu C, Ghatei MA, Lang F, et al. (April 2007). "Constitutional thinness and lean anorexia nervosa display opposite concentrations of peptide YY, glucagon-like peptide 1, ghrelin, and leptin". The American Journal of Clinical Nutrition. 85 (4): 967–71. doi:10.1093/ajcn/85.4.967. PMID 17413094.
59. Yildiz BO, Suchard MA, Wong ML, McCann SM, Licinio J (July 2004). "Alterations in the dynamics of circulating ghrelin, adiponectin, and leptin in human obesity". Proceedings of the National Academy of Sciences of the United States of America. 101 (28): 10434–9. Bibcode:2004PNAS..10110434Y. doi:10.1073/pnas.0403465101. PMC 478601. PMID 15231997.
60. Garcia JM, Garcia-Touza M, Hijazi RA, Taffet G, Epner D, Mann D, et al. (May 2005). "Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia". The Journal of Clinical Endocrinology and Metabolism. 90 (5): 2920–6. doi:10.1210/jc.2004-1788. PMID 15713718.
61. Khatib MN, Shankar AH, Kirubakaran R, Gaidhane A, Gaidhane S, Simkhada P, Quazi Syed Z (February 2018). "Ghrelin for the management of cachexia associated with cancer". The Cochrane Database of Systematic Reviews. 2: CD012229. doi:10.1002/14651858.cd012229.pub2. PMC 6491219. PMID 29489032.
62. Cummings DE, Weigle DS, Frayo RS, Breen PA, Ma MK, Dellinger EP, Purnell JQ (May 2002). "Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery". The New England Journal of Medicine. 346 (21): 1623–30. doi:10.1056/NEJMoa012908. PMID 12023994.
63. Cummings DE, Shannon MH (July 2003). "Ghrelin and gastric bypass: is there a hormonal contribution to surgical weight loss?". The Journal of Clinical Endocrinology and Metabolism. 88 (7): 2999–3002. doi:10.1210/jc.2003-030705. PMID 12843132.
64. Bohdjalian A, Langer FB, Shakeri-Leidenmühler S, Gfrerer L, Ludvik B, Zacherl J, Prager G (May 2010). "Sleeve gastrectomy as sole and definitive bariatric procedure: 5-year results for weight loss and ghrelin". Obesity Surgery. 20 (5): 535–40. doi:10.1007/s11695-009-0066-6. PMID 20094819.