Distribution and activity of ghrelin cells in the stomach of obese subjects are controversial.
We examined samples from stomachs removed by sleeve gastrectomy in 49 obese subjects (normoglycemic, hyperglycemic and diabetic) and quantified the density of ghrelin/chromogranin endocrine cells by immunohistochemistry. Data were compared with those from 13 lean subjects evaluated by gastroscopy. In 44 cases (11 controls and 33 obese patients) a gene expression analysis of ghrelin and its activating enzyme ghrelin O-acyl transferase (GOAT) was performed. In 21 cases (4 controls and 17 obese patients) the protein levels of unacylated and acylated-ghrelin were measured by ELISA tests. In 18 cases (4 controls and 14 obese patients) the morphology of ghrelin-producing cells was evaluated by electron microscopy.
The obese group, either considered as total population or divided into subgroups, did not show any significant difference in ghrelin cell density when compared with control subjects. Inter-glandular smooth muscle fibres were increased in obese patients. In line with a positive trend of the desacylated form found by ELISA, Ghrelin and GOAT mRNA expression in obese patients was significantly increased. The unique ghrelin cell ultrastructure was maintained in all obese groups. In the hyperglycemic obese patients, the higher ghrelin expression matched with ultrastructural signs of endocrine hyperactivity, including expanded rough endoplasmic reticulum and reduced density, size and electron-density of endocrine granules. A positive correlation between ghrelin gene expression and glycemic values, body mass index and GOAT was also found. All obese patients with type 2 diabetes recovered from diabetes at follow-up after 5 months with a 16.5% of weight loss.
Given the known inhibitory role on insulin secretion of ghrelin, these results suggest a possible role for gastric ghrelin overproduction in the complex architecture that takes part in the pathogenesis of type 2 diabetes.
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Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(Dec):656–60. 9.
Tschöp M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407(Oct):908–13. 19.
Goitein D, Lederfein D, Tzioni R, Berkenstadt H, Venturero M, Rubin M. Mapping of ghrelin gene expression and cell distribution in the stomach of morbidly obese patients-a possible guide for efficient sleeve gastrectomy construction. Obes Surg. 2012;22(Apr):617–22.
Müller TD, Nogueiras R, Andermann ML, Andrews ZB, Anker SD, Argente J, et al. Ghrelin. Mol Metab. 2015;4(Jun):437–60.
Moran TH. Gut peptides in the control of food intake. Int J Obes. 2009;33(Apr):S7–10. 2005. Suppl 1.
Poher A-L, Tschöp MH, Müller TD. Ghrelin regulation of glucose metabolism. Peptides. 2018;100:236–42.
Masuda Y, Tanaka T, Inomata N, Ohnuma N, Tanaka S, Itoh Z, et al. Ghrelin stimulates gastric acid secretion and motility in rats. Biochem Biophys Res Commun. 2000;276(Oct):905–8. 5.
Asakawa A, Inui A, Kaga T, Yuzuriha H, Nagata T, Ueno N, et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology. 2001;120(Feb):337–45.
Reed JA, Benoit SC, Pfluger PT, Tschöp MH, D’Alessio DA, Seeley RJ. Mice with chronically increased circulating ghrelin develop age-related glucose intolerance. Am J Physiol Endocrinol Metab. 2008;294(Apr):E752–760.
Gray SM, Page LC, Tong J. Ghrelin regulation of glucose metabolism. J Neuroendocrinol. 2019;31(Jul):e12705.
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, et al. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab. 2002;87(Jan):240–4.
English PJ, Ghatei MA, Malik IA, Bloom SR, Wilding JPH. Food fails to suppress ghrelin levels in obese humans. J Clin Endocrinol Metab. 2002;87(Jun):2984.
Churm R, Davies JS, Stephens JW, Prior SL. Ghrelin function in human obesity and type 2 diabetes: a concise review. Obes Rev Off J Int Assoc Study Obes. 2017;18:140–8.
Basso N, Soricelli E, Castagneto-Gissey L, Casella G, Albanese D, Fava F, et al. Insulin resistance, microbiota, and fat distribution changes by a new model of vertical sleeve gastrectomy in obese rats. Diabetes. 2016;65:2990–3001.
Mani BK, Shankar K, Zigman JM. Ghrelin’s Relationship to Blood Glucose. Endocrinology. 2019;160:1247–61. 01.
Bray GA, Frühbeck G, Ryan DH, Wilding JPH. Management of obesity. Lancet Lond Engl. 2016;387(May):1947–56. 7.
González-Muniesa P, Mártinez-González M-A, Hu FB, Després J-P, Matsuzawa Y, Loos RJF. et al.Obesity.Nat Rev Dis Primer.2017;3(Jun):17034 . 15.
Bray GA, Kim KK, Wilding JPH, World Obesity Federation. Obesity: a chronic relapsing progressive disease process. A position statement of the World Obesity Federation. Obes Rev Off J Int Assoc Study Obes. 2017;18:715–23.
Cummings DE, Rubino F. Metabolic surgery for the treatment of type 2 diabetes in obese individuals. Diabetologia. 2018;61:257–64.
Miyazaki Y, Takiguchi S, Seki Y, Kasama K, Takahashi T, Kurokawa Y, et al. Clinical significance of ghrelin expression in the gastric mucosa of morbidly obese patients. World J Surg. 2013;37(Dec):2883–90.
Ritze Y, Schollenberger A, Hamze Sinno M, Bühler N, Böhle M, Bárdos G, et al. Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity. Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 2016;28:806–15.
Maksud FAN, Alves JS, Diniz MTC, Barbosa AJA. Density of ghrelin-producing cells is higher in the gastric mucosa of morbidly obese patients. Eur J Endocrinol. 2011;165(Jul):57–62.
Musella M, Di Capua F, D’Armiento M, Velotti N, Bocchetti A, Di KL. et al. No Difference in Ghrelin-Producing Cell Expression in Obese Versus Non-obese Stomach: a Prospective Histopathological Case-Control Study. Obes Surg. 2018;28(Nov):3604–10.
Abdemur A, Slone J, Berho M, Gianos M, Szomstein S, Rosenthal RJ. Morphology, localization, and patterns of ghrelin-producing cells in stomachs of a morbidly obese population. Surg Laparosc Endosc Percutan Tech. 2014;24(Apr):122–6.
Gagner M. Obesity: sleeve gastrectomy-the ideal choice for weight-loss surgery. Nat Rev Endocrinol. 2013;9(Jul):382–4.
Barresi V, Valenti G, Spampinato G, Musso N, Castorina S, Rizzarelli E, et al. Transcriptome analysis reveals an altered expression profile of zinc transporters in colorectal cancer. J Cell Biochem. 2018;119:9707–19.
Cinti F, Bouchi R, Kim-Muller JY, Ohmura Y, Sandoval PR, Masini M, et al. Evidence of β-Cell Dedifferentiation in Human Type 2 Diabetes. J Clin Endocrinol Metab. 2016;101(Mar):1044–54.
Wickham H. Intrauterine contraception: a look at devices and systems. Community Nurse. 2000;6(Oct):41–2,45.
Miettinen M. Modern soft tissue pathology: tumors and non-neoplastic conditions. Cambridge University Press; Cambridge 2010. 1117 p.
Yanagi S, Sato T, Kangawa K, Nakazato M. The Homeostatic Force of Ghrelin. Cell Metab. 2018;27:786–804. 03.
Ishii N, Tsubouchi H, Miura A, Yanagi S, Ueno H, Shiomi K, et al. Ghrelin alleviates paclitaxel-induced peripheral neuropathy by reducing oxidative stress and enhancing mitochondrial anti-oxidant functions in mice. Eur J Pharmacol. 2018;819(Jan):35–42. 15.
Sakata I, Nakamura K, Yamazaki M, Matsubara M, Hayashi Y, Kangawa K, et al. Ghrelin-producing cells exist as two types of cells, closed- and opened-type cells, in the rat gastrointestinal tract. Peptides. 2002;23(Mar):531–6.
Fakhry J, Stebbing MJ, Hunne B, Bayguinov Y, Ward SM, Sasse KC, et al. Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus. Cell Tissue Res. 2019;376(Apr):37–49. 1.
Ozkan Y, Timurkan ES, Aydin S, Sahin İ, Timurkan M, Citil C, et al. Acylated and Desacylated Ghrelin, Preptin, Leptin, and Nesfatin-1 Peptide Changes Related to the Body Mass Index [Internet]. Vol. 2013, International Journal of Endocrinology. Hindawi; 2013 [cited 2020 Jul 7]. p. e236085. https://www.hindawi.com/journals/ije/2013/236085/.
Rindi G, Necchi V, Savio A, Torsello A, Zoli M, Locatelli V, et al. Characterisation of gastric ghrelin cells in man and other mammals: studies in adult and fetal tissues. Histochem Cell Biol. 2002;117(Jun):511–9.
Sjöström L. Review of the key results from the Swedish Obese Subjects (SOS) trial - a prospective controlled intervention study of bariatric surgery. J Intern Med. 2013;273(Mar):219–34.
Gagner M, Hutchinson C, Rosenthal R. Fifth International Consensus Conference: current status of sleeve gastrectomy. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2016;12(May):750–6.
Mihalache L, Arhire LI, Giuşcă SE, Gherasim A, Niţă O, Constantinescu D, et al. Ghrelin-producing cells distribution in the stomach and the relation with Helicobacter pylori in obese patients. Rom J Morphol Embryol. 2019;60:219–25.
Gündoğan M, Çalli Demırkan N, Tekın K, Aybek H. Gastric histopathological findings and ghrelin expression in morbid obesity. Turk Patoloji Derg. 2013;29:19–26.
Veedfald S, Plamboeck A, Hartmann B, Vilsbøll T, Knop FK, Deacon CF, et al. Ghrelin secretion in humans - a role for the vagus nerve? Neurogastroenterol Motil Off J Eur Gastrointest Motil Soc. 2018;30:e13295.
Xing J, Chen JDZ. Alterations of gastrointestinal motility in obesity. Obes Res. 2004;12(Nov):1723–32.
Peiris M, Aktar R, Raynel S, Hao Z, Mumphrey MB, Berthoud H-R, et al. Effects of obesity and gastric bypass surgery on nutrient sensors, endocrine cells, and mucosal innervation of the mouse colon. Nutrients. 2018;10:1529–42.
Selim MM, Wendelschafer-Crabb G, Redmon JB, Khoruts A, Hodges JS, Koch K, et al. Gastric mucosal nerve density: a biomarker for diabetic autonomic neuropathy? Neurology. 2010;75(Sep):973–81. 14.
Kitazawa T, Kaiya H. Regulation of Gastrointestinal Motility by Motilin and Ghrelin in Vertebrates. Front Endocrinol. 2019;10:278.
Porporato PE, Filigheddu N, Reano S, Ferrara M, Angelino E, Gnocchi VF, et al. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. J Clin Investig. 2013;123(Feb):611–22.
Pradhan G, Samson SL, Sun Y. Ghrelin: much more than a hunger hormone. Curr Opin Clin Nutr Metab Care. 2013;16(Nov):619–24.
Crivellato E, Nico B, Bertelli E, Nussdorfer GG, Ribatti D. Dense-core granules in neuroendocrine cells and neurons release their secretory constituents by piecemeal degranulation (review). Int J Mol Med. 2006;18(Dec):1037–46.
Rindi G, Torsello A, Locatelli V, Solcia E. Ghrelin expression and actions: a novel peptide for an old cell type of the diffuse endocrine system. Exp Biol Med Maywood NJ. 2004;229(Nov):1007–16.
Muscogiuri G, Balercia G, Barrea L, Cignarelli A, Giorgino F, Holst JJ, et al. Gut: a key player in the pathogenesis of type 2 diabetes? Crit Rev Food Sci Nutr. 2018;58(May):1294–309. 24.
Malin S, Samat A, Wolski K, Abood B, Pothier C, Bhatt D, et al. Improved acylated ghrelin suppression at 2 years in obese patients with type 2 diabetes: effects of bariatric surgery vs standard medical therapy. Int J Obes. 2014;38(Mar):364–70. 2005.
Hotamisligil GS. Inflammation, metaflammation and immunometabolic disorders. Nature. 2017;542:177–85. 08.
Camastra S, Vitali A, Anselmino M, Gastaldelli A, Bellini R, Berta R, et al. Muscle and adipose tissue morphology, insulin sensitivity and beta-cell function in diabetic and nondiabetic obese patients: effects of bariatric surgery. Sci Rep. 2017;7:9007. 21.
Alemán JO, Iyengar NM, Walker JM, Milne GL, Da Rosa JC, Liang Y, et al. Effects of rapid weight loss on systemic and adipose tissue inflammation and metabolism in obese postmenopausal women. J Endocr Soc. 2017;1(Apr):625–37. 25
Nannipieri M, Baldi S, Mari A, Colligiani D, Guarino D, Camastra S, et al. Roux-en-Y gastric bypass and sleeve gastrectomy: mechanisms of diabetes remission and role of gut hormones. J Clin Endocrinol Metab. 2013;98(Nov):4391–9.
We thank Prof Filippo Palermo (Catania) and Prof Daniela Morale (Milano) for their assistance in evaluating the statistical data, Dr Giuseppe Grasso (Catania), Dr Valentina Merendino (Catania) and Dr Maria Cristina Zingaretti (Ancona) for their excellent technical support and Prof Riccarda Granata (Torino) for the critical reading of the paper.
PRIN 2017 to Saverio Cinti; FIR Unict 2014 and Mediterranean Foundation “G.B. Morgagni” Catania to Sergio Castorina. The sources of funding had no involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
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Castorina, S., Barresi, V., Luca, T. et al. Gastric ghrelin cells in obese patients are hyperactive. Int J Obes 45, 184–194 (2021). https://doi.org/10.1038/s41366-020-00711-3