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Ghrelin in Health and Disease pp 131–147Cite as

GOAT and the Regulation of Energy and Glucose Homeostasis

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Part of the book series: Contemporary Endocrinology ((COE,volume 10))

Abstract

Ghrelin is the only known circulating hormone that potently stimulates food intake and adipogenesis in rodents and humans. Through a unique posttranslational modification, the premature ghrelin peptide is acyl-modified with a medium-chain fatty acid at the serine-3 position by ghrelin-O-acyl transferase (GOAT) to form acyl ghrelin. This step is necessary to activate ghrelin’s only known receptor, the growth hormone secretagogue receptor 1a, also known as the ghrelin receptor. GOAT activity is highly influenced by the availability of dietary lipids; dietary lipids serve as a direct GOAT substrate for ghrelin acylation. Further, GOAT gene expression and circulating acyl ghrelin levels are decreased after long-term starvation when dietary lipids are absent. These findings suggest that the ghrelin-GOAT system plays an important role in linking nutrient availability with endogenous regulation of energy homeostasis, especially adipogenesis. Recent data further suggest that GOAT is a significant factor in the regulation of glucose homeostasis as specific pharmacological GOAT inhibition improves glucose tolerance and insulin secretion. During caloric restriction, the ghrelin-GOAT system may play an important role for the maintenance of physiological range glucose levels by stimulating the secretion of growth hormone.

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References

  1. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature. 2000;407: 908–13.

    Article  CAS  PubMed  Google Scholar 

  2. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402:656–60.

    Article  CAS  PubMed  Google Scholar 

  3. Cowley MA, Smith RG, Diano S, et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron. 2003;37:649–61.

    Article  CAS  PubMed  Google Scholar 

  4. Dickson SL, Leng G, Robinson IC. Systemic administration of growth hormone-releasing peptide activates hypothalamic arcuate neurons. Neuroscience. 1993;53:303–6.

    Article  CAS  PubMed  Google Scholar 

  5. Gropp E, Shanabrough M, Borok E, et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat Neurosci. 2005;8:1289–91.

    Article  CAS  PubMed  Google Scholar 

  6. Luquet S, Perez FA, Hnasko TS, Palmiter RD. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science. 2005;310:683–5.

    Article  CAS  PubMed  Google Scholar 

  7. Cummings DE, Purnell JQ, Frayo RS, Schmidova K, Wisse BE, Weigle DS. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes. 2001;50: 1714–9.

    Article  CAS  PubMed  Google Scholar 

  8. Liu J, Prudom CE, Nass R, et al. Novel ghrelin assays provide evidence for independent regulation of ghrelin acylation and secretion in healthy young men. J Clin Endocrinol Metab. 2008;93: 1980–7.

    Article  CAS  PubMed  Google Scholar 

  9. Callahan HS, Cummings DE, Pepe MS, Breen PA, Matthys CC, Weigle DS. Postprandial suppression of plasma ghrelin level is proportional to ingested caloric load but does not predict intermeal interval in humans. J Clin Endocrinol Metab. 2004;89:1319–24.

    Article  CAS  PubMed  Google Scholar 

  10. Cummings DE. Ghrelin and the short- and long-term regulation of appetite and body weight. Physiol Behav. 2006;89:71–84.

    Article  CAS  PubMed  Google Scholar 

  11. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273:974–7.

    Article  CAS  PubMed  Google Scholar 

  12. Matsumoto M, Hosoda H, Kitajima Y, et al. Structure–activity relationship of ghrelin: pharmacological study of ghrelin peptides. Biochem Biophys Res Commun. 2001;287:142–6.

    Article  CAS  PubMed  Google Scholar 

  13. Toshinai K, Yamaguchi H, Sun Y, et al. Des-acyl ghrelin induces food intake by a mechanism independent of the growth hormone secretagogue receptor. Endocrinology. 2006;147: 2306–14.

    Article  CAS  PubMed  Google Scholar 

  14. Thompson NM, Gill DA, Davies R, et al. Ghrelin and des-octanoyl ghrelin promote adipogenesis directly in vivo by a mechanism independent of the type 1a growth hormone secretagogue receptor. Endocrinology. 2004;145:234–42.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang W, Chai B, Li JY, Wang H, Mulholland MW. Effect of des-acyl ghrelin on adiposity and glucose metabolism. Endocrinology. 2008;149:4710–6.

    Article  CAS  PubMed  Google Scholar 

  16. Gutierrez JA, Solenberg PJ, Perkins DR, et al. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci U S A. 2008;105:6320–5.

    Article  CAS  PubMed  Google Scholar 

  17. Yang J, Brown MS, Liang G, Grishin NV, Goldstein JL. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell. 2008;132:387–96.

    Article  CAS  PubMed  Google Scholar 

  18. Hofmann K. A superfamily of membrane-bound O-acyltransferases with implications for wnt signaling. Trends Biochem Sci. 2000;25:111–2.

    Article  CAS  PubMed  Google Scholar 

  19. Gahete MD, Cordoba-Chacon J, Salvatori R, Castano JP, Kineman RD, Luque RM. Metabolic regulation of ghrelin O-acyl transferase (GOAT) expression in the mouse hypothalamus, pituitary, and stomach. Mol Cell Endocrinol. 2010;317:154–60.

    Article  CAS  PubMed  Google Scholar 

  20. Sakata I, Yang J, Lee CE, et al. Colocalization of ghrelin O-acyltransferase and ghrelin in gastric mucosal cells. Am J Physiol Endocrinol Metab. 2009;297:E134–41.

    Article  CAS  PubMed  Google Scholar 

  21. Ohgusu H, Shirouzu K, Nakamura Y, et al. Ghrelin O-acyltransferase (GOAT) has a preference for n-hexanoyl-CoA over n-octanoyl-CoA as an acyl donor. Biochem Biophys Res Commun. 2009;386:153–8.

    Article  CAS  PubMed  Google Scholar 

  22. Yang J, Zhao TJ, Goldstein JL, Brown MS. Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. Proc Natl Acad Sci U S A. 2008;105:10750–5.

    Article  CAS  PubMed  Google Scholar 

  23. Takahashi T, Ida T, Sato T, et al. Production of n-octanoyl-modified ghrelin in cultured cells requires prohormone processing protease and ghrelin O-acyltransferase, as well as n-octanoic acid. J Biochem. 2009;146:675–82.

    Article  CAS  PubMed  Google Scholar 

  24. Kirchner H, Gutierrez JA, Solenberg PJ, et al. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med. 2009;15:741–5.

    Article  CAS  PubMed  Google Scholar 

  25. Nishi Y, Hiejima H, Hosoda H, et al. Ingested medium-chain fatty acids are directly utilized for the acyl modification of ghrelin. Endocrinology. 2005;146:2255–64.

    Article  CAS  PubMed  Google Scholar 

  26. Stengel A, Goebel M, Wang L, Tache Y, Sachs G, Lambrecht NW. Differential distribution of ghrelin-O-acyltransferase (GOAT) immunoreactive cells in the mouse and rat gastric oxyntic mucosa. Biochem Biophys Res Commun. 2010;392:67–71.

    Article  CAS  PubMed  Google Scholar 

  27. Gonzalez CR, Vazquez MJ, Lopez M, Dieguez C. Influence of chronic undernutrition and leptin on GOAT mRNA levels in rat stomach mucosa. J Mol Endocrinol. 2008;41:415–21.

    Article  CAS  PubMed  Google Scholar 

  28. Reimer RA, Maurer AD, Lau DC, Auer RN. Long-term dietary restriction influences plasma ghrelin and GOAT mRNA level in rats. Physiol Behav. 2010;99:605–10.

    Article  CAS  PubMed  Google Scholar 

  29. Kineman RD, Gahete MD, Luque RM. Identification of a mouse ghrelin gene transcript that contains intron 2 and is regulated in the pituitary and hypothalamus in response to metabolic stress. J Mol Endocrinol. 2007;38:511–21.

    Article  CAS  PubMed  Google Scholar 

  30. Nogueiras R, Tovar S, Mitchell SE, et al. Regulation of growth hormone secretagogue receptor gene expression in the arcuate nuclei of the rat by leptin and ghrelin. Diabetes. 2004; 53:2552–8.

    Article  CAS  PubMed  Google Scholar 

  31. Date Y, Kojima M, Hosoda H, et al. Ghrelin, a novel growth hormone-releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology. 2000;141:4255–61.

    Article  CAS  PubMed  Google Scholar 

  32. Zhao TJ, Liang G, Li RL, et al. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci U S A. 2010; 107:7467–72.

    Article  CAS  PubMed  Google Scholar 

  33. Wortley KE, del Rincon JP, Murray JD, et al. Absence of ghrelin protects against early-onset obesity. J Clin Invest. 2005;115:3573–8.

    Article  CAS  PubMed  Google Scholar 

  34. Zigman JM, Nakano Y, Coppari R, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115:3564–72.

    Article  CAS  PubMed  Google Scholar 

  35. Lopez M, Lage R, Saha AK, et al. Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin. Cell Metab. 2008;7:389–99.

    Article  CAS  PubMed  Google Scholar 

  36. Rudolph J, Esler WP, O’Connor S, et al. Quinazolinone derivatives as orally available ghrelin receptor antagonists for the treatment of diabetes and obesity. J Med Chem. 2007;50: 5202–16.

    Article  CAS  PubMed  Google Scholar 

  37. Xin Z, Serby MD, Zhao H, et al. Discovery and pharmacological evaluation of growth hormone secretagogue receptor antagonists. J Med Chem. 2006;49:4459–69.

    Article  CAS  PubMed  Google Scholar 

  38. Barnett BP, Hwang Y, Taylor MS, et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science. 2010;330:1689–92.

    Article  CAS  PubMed  Google Scholar 

  39. Kojima M, Kangawa K. Ghrelin: structure and function. Physiol Rev. 2005;85:495–522.

    Article  CAS  PubMed  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Internal Medicine and Endocrinology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH, USA

    Henriette Kirchner M.S., Ph.D.

  2. Department of Internal Medicine, University of Cincinnati, 2180 E. Galbraith Road, Room A-123, Cincinnati, OH, 45237, USA

    Matthias Tschöp M.D.

  3. Department of Medicine, University of Cincinnati, Cincinnati, OH, 45237, USA

    Jenny Tong M.D., M.P.H.

Authors
  1. Henriette Kirchner M.S., Ph.D.
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  2. Matthias Tschöp M.D.
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  3. Jenny Tong M.D., M.P.H.
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Corresponding author

Correspondence to Matthias Tschöp M.D. .

Editor information

Editors and Affiliations

  1. , Department of Metabolism and Aging, The Scripps Research Institute Florida, Scripps Way 3B3 130, Jupiter, 33458, Florida, USA

    Roy G. Smith

  2. , Department of Medicine, University of Virginia, Ray C Hunt Drive 450, Charlottesville, 22908, Virginia, USA

    Michael O. Thorner

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Kirchner, H., Tschöp, M., Tong, J. (2012). GOAT and the Regulation of Energy and Glucose Homeostasis. In: Smith, R., Thorner, M. (eds) Ghrelin in Health and Disease. Contemporary Endocrinology, vol 10. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-61779-903-7_7

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  • DOI: https://doi.org/10.1007/978-1-61779-903-7_7

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  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-61779-902-0

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