胃促生长素

胃促生长素（ghrelin，lenomorelin）全名胃生长激素释放肽（growth hormone-releasing peptide），俗称飢餓素（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），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。 它被稱為飢餓素是因為它会增加进食的动力，在餐前飢餓時，飢餓素在血液中濃度最高，進食後恢复到较低水平。飢餓素可能透過增加胃的活動性和刺激胃酸分泌来帮助进食准备。 飢餓素能夠活化腦垂體前葉和下視丘弓狀核中的細胞，其中包括可引起食慾的神經肽Y神經元。飢餓素能夠刺激具有特定受體的大腦結構：飢餓素受體1A（GHSR -1A）。飢餓素同時也能夠調節神經結構中的犒賞系統、學習和記憶，睡眠-甦醒週期、味覺、犒賞行為和葡萄糖代謝。 飢餓素的首次發現是在1999年發現了飢餓素受體（稱為生長激素促分泌素受體1A或GHS-R）之後。其命名是以它能夠「促生長激素分泌」的功能來命名，源自於原始印歐語中的gʰre，意謂成長。 其GHRL基因產生的mRNA有四個外顯子，並產生五種產物：第一種是117個氨基酸的前飢餓素原。（與促胃動素原同源；兩者都是促胃動素家族的成員）。將前飢餓素原剪接後產生飢餓素原，再剪接後產生一個具有28個氨基酸的未醯化飢餓素和一個醯化飢餓素（C-Gherlin）。據推測，肥胖抑制素可能從C-ghrelin剪接而成。 飢餓素只有在飢餓素醯基轉移酶 （页面存档备份，存于互联网档案馆）（GOAT）的幫助下，結構中的辛酸在轉譯後與絲氨酸的3號位連接時才具有活性。它位於胃和胰臟中的飢餓素細胞的細胞膜上，而未辛醯化的形式則稱為去醯基飢餓素，其無法活化GHS-R受體，但具有其他作用：心臟方面的功能、刺激食慾和抑制肝臟輸出葡萄糖。同時也觀察到，辛醯基以外的側鏈也可以觸發飢餓素受體。 特別的是，已發現癸醯飢餓素在小鼠循環中的飢餓素站了一定比例，但截至2011年，其在人體中的存在尚未確定。 飢餓素細胞也被稱為胰臟的A-like cell、X-cell（X意謂功能不明）、小鼠中的X/A-like cell、胰臟中的ε細胞、人體的P/D sub 1 cell、或Gr cell（Gherlin的簡稱）。 飢餓素細胞主要存在於胃和十二指腸中，但也存在於空腸、肺、胰島、性腺、腎上腺皮質、胎盤和腎臟中。最近也有研究顯示，飢餓素能夠在大腦局部產生。 飢餓素細胞存在於胃底腺細胞中（佔細胞的20％）、幽門和小腸中，是卵圓形的顆粒性細胞，同時具有胃泌素受體，且有一些能夠產生脂肪激素nesfatin-1。飢餓素細胞在胰臟中沒有終末分化的步驟，它們作為前驅細胞，可以產生A細胞、PP細胞和β細胞。 飢餓素參與調節能量平衡（英语：Energy_homeostasis）的複雜過程，透過調節飢餓訊號來影響能量輸入;調節ATP生產、脂肪儲存、肝醣儲存及短期熱消耗等能量比例調節來影響能量輸出。能量平衡的結果最終反映在體重上，並根據代謝信號和需求進行持續監測調整。而胃腦溝通是影響能量平衡的重要途徑，有幾種溝通路徑，其中包括胃細胞內mTOR（英语：mTOR） / S6K1（英语：S6_Kinase_1 S6K1）路徑所調節的飢餓素、nesfatin（英语：Nesfatin-1）及內源性大麻素（英语：Endocannabinoid_system）胃系統彼此間的交互作用，及迷走神經的傳出入訊號。 飢餓素及合成飢餓素模擬物(生長激素促進劑（英语：Growth_hormone_secretagogue）)透過誘發含神經肽Y(NPY)（英语：Neuropeptide_Y）及刺鼠肽基因相關蛋白(AgRP)（英语：Agouti-related_peptide）的弓形核受體來增加體重及脂肪量。這些對飢餓素反應的神經元對瘦素及胰島素均敏感。而飢餓素會降低胃迷走神經傳入（英语：Afferent_nerve_fiber）的敏感性，導致較低的胃擴張程度。 除了其能量平衡的功能，飢餓素還會激活膽鹼能-多巴胺能犒賞迴路在腹側被蓋區的輸入，以及用來傳達自然犒賞的享樂和增強方面的迴路，如食物和成癮性藥物的中腦邊緣通路。該迴路上可以找到飢餓素的受體。而酒精及可口/獎勵食物是需要下視丘飢餓素訊號來提供回饋。 飢餓素與誘導食慾及進食行為有關，而血液循環中的飢餓素水平會在飯前最高、飯後最低。在人和大鼠注射飢餓素已證明會增加食物攝取，即注射量越多，食物攝取越多，但飢餓素所增加的不是進食量，而是進食的次數。飢餓素的注射還會增加動物覓食行為，同時增加嗅覺尋找能力，傾向搜集囤積食物。由於體重是透過能量平衡來調節的，飢餓素濃度與體重會呈負相關，由此飢餓素可以做為肥胖警訊。 飢餓素在血液中的濃度在pmol / l的範圍內。具有活性的飢餓素含量和總飢餓素含量都可以被測量出來 。循環中的飢餓素濃度在進食前升高，並在進食後下降，並且對於蛋白質和碳水化合物的反應比對脂質的反應更強烈。 飢餓素受體GHS-R1A（由飢餓素受體剪接而來）可以調節多項飢餓素造成的生物效應，包括：刺激生長激素的釋放、增加飢餓感、調節葡萄糖和脂質的代謝、調節腸胃蠕動和分泌、保護神經和心血管細胞以及調節免疫功能。它們大量存在於下視丘和腦垂體、迷走神經上（在傳入的細胞體和傳出的神經末梢上）以及整個胃腸道中。 整個飢餓素系統（包含dAG、AG、GHS-R、GOAT）皆具有調節葡萄糖的作用。 初步研究表明，飢餓素參與了晝夜規律的調節。雖然有文獻表示，沒有發現有力的證據顯示限制睡眠會影響飢餓素以及瘦素的濃度或能量消耗。 飢餓素對促性腺激素釋放激素（GnRH）的分泌具有抑制作用，可能導致生育力下降。 飢餓素在胎兒時期的早期肺臟產生，並具有促進肺生長的功能。 臍帶血中飢餓素的濃度也顯示，飢餓素濃度和新生兒出生體重之間的相關性。 肥胖個體血漿中的飢餓素濃度低於瘦型個體，由此顯示，飢餓素並不直接造成肥胖，只有在小胖威利症候群引起的肥胖中，高濃度的飢餓素能夠造成食物攝入量的增加。與體重過輕和正常體重的兩個對照組相比，神經性厭食症的血漿飢餓素濃度更高。體型較為削瘦的人在一天中，從午夜到黎明的這段時間的飢餓素濃度較高，這顯示肥胖者的晝夜規律系統存在缺陷。同時，癌症引起的惡體質患者也有高濃度的飢餓素。尚無足夠的證據得出支持或反對使用生長素釋放肽治療癌症相關惡體質的結論。 與體型瘦削和節食減肥的人相比，進行胃繞道手術的人不僅減少了腸道容量，甚至能夠降低體內飢餓素濃度。在此方面，尚未有研究闡明，接受胃繞道手術的人，體內的飢餓素濃度是否在減輕的體重穩定下來後就恢復正常濃度。統計也顯示，胃繞道的相關手術中，進行袖狀胃切除術（英语：Sleeve_gastrectomy）的人從長遠來看，體內飢餓素濃度能夠降低約60％。 下視丘-腦垂體-生長軸（英语：Hypothalamic–pituitary–somatotropic_axis） 生長激素促分泌素清單（英语：List_of_growth_hormone_secretagogues） 存档副本. [2024-03-10]. （原始内容存档于2024-03-10）.  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 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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". 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.