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Review ArticleReview Article

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

Chih-Yen Chen, Akihiro Asakawa, Mineko Fujimiya, Shou-Dong Lee and Akio Inui
Pharmacological Reviews December 2009, 61 (4) 430-481; DOI: https://doi.org/10.1124/pr.109.001958
Chih-Yen Chen
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei (C.-Y.C, S.-D.L.), and Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (C.-Y.C, S.-D.L.); Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan (M.F.); and Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (A.A., A.I.)
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Akihiro Asakawa
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei (C.-Y.C, S.-D.L.), and Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (C.-Y.C, S.-D.L.); Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan (M.F.); and Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (A.A., A.I.)
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Mineko Fujimiya
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei (C.-Y.C, S.-D.L.), and Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (C.-Y.C, S.-D.L.); Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan (M.F.); and Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (A.A., A.I.)
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Shou-Dong Lee
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei (C.-Y.C, S.-D.L.), and Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (C.-Y.C, S.-D.L.); Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan (M.F.); and Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (A.A., A.I.)
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Akio Inui
Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei (C.-Y.C, S.-D.L.), and Division of Gastroenterology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan (C.-Y.C, S.-D.L.); Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan (M.F.); and Department of Psychosomatic Internal Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan (A.A., A.I.)
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Abstract

A breakthrough using “reverse pharmacology” identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of O-n-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin O-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes.

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  • This article is available online at http://pharmrev.aspetjournals.org.

    doi:10.1124/pr.109.001958.

  • © 2009 by The American Society for Pharmacology and Experimental Therapeutics
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Pharmacological Reviews: 61 (4)
Pharmacological Reviews
Vol. 61, Issue 4
1 Dec 2009
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Review ArticleReview Article

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

Chih-Yen Chen, Akihiro Asakawa, Mineko Fujimiya, Shou-Dong Lee and Akio Inui
Pharmacological Reviews December 1, 2009, 61 (4) 430-481; DOI: https://doi.org/10.1124/pr.109.001958

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Review ArticleReview Article

Ghrelin Gene Products and the Regulation of Food Intake and Gut Motility

Chih-Yen Chen, Akihiro Asakawa, Mineko Fujimiya, Shou-Dong Lee and Akio Inui
Pharmacological Reviews December 1, 2009, 61 (4) 430-481; DOI: https://doi.org/10.1124/pr.109.001958
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  • Article
    • Abstract
    • I. Introduction: Discovery of Growth Hormone Secretagogue Receptor, Ghrelin Gene Products (Acyl Ghrelin, Des-Acyl Ghrelin, and Obestatin), and Ghrelin O-acyltransferase
    • II. Normal Physiology of Acyl Ghrelin and Regulation of Its Expression and Interactions
    • III. Normal Physiology of Des-Acyl Ghrelin and Regulation of Its Expression and Interactions
    • IV. Normal Physiology of Obestatin and Regulation of Its Expression and Interactions
    • V. Normal Physiology, Expression, and Regulation of Growth Hormone Secretagogue Receptor
    • VI. Normal Physiology, Expression, and Regulation of Ghrelin O-acyltransferase
    • VII. Pathophysiology of Ghrelin Gene Products in Feeding and Body Weight Regulation
    • VIII. Normal Physiology and Pathophysiology of Ghrelin Gene Products in Feeding-Associated Gastrointestinal Motility
    • IX. Access of Ghrelin Gene Products to the Central Nervous System: Direct and Indirect Neuroendocrine Pathways
    • X. Direct Effects of Ghrelin Gene Products on Other Tissues
    • XI. Disturbance of Energy Homeostasis in Various Conditions: Roles of Ghrelin Gene Products in Obesity and Anorexia-Cachexia
    • XII. Therapeutic Approaches to Affecting the Ghrelin System: Endogenous Ghrelin Gene Products, Growth Hormone Secretagogue Receptor 1a, and Ghrelin O-acyltransferase
    • XIII. Conclusions
    • Acknowledgments.
    • Footnotes
    • References
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