logo

SCIENCE CHINA Life Sciences, Volume 59 , Issue 3 : 281-291(2016) https://doi.org/10.1007/s11427-015-4973-6

Ghrelin O-acyltransferase (GOAT) and energy metabolism

More info
  • ReceivedAug 17, 2015
  • AcceptedOct 9, 2015
  • PublishedJan 4, 2016

Abstract


Funded by

National Natural Science Foundation of China(81330010,81390354)

American Diabetes Association grant(1-13-BS-225)


Acknowledgment

Acknowledgements This work was supported by the National Natural Science Foundation of China (81330010, 81390354) and American Diabetes Association grant (1-13-BS-225).


Interest statement

Compliance and ethics The author(s) declare that they have no conflict of interest.


References

[1] Alen F., Crespo I., Ramírez-López M.T., Jagerovic N., Goya P., de Fonseca F.R., de Heras R.G., Orio L., Luque R.M.. Ghrelin-induced orexigenic effect in rats depends on the metabolic status and is counteracted by peripheral CB1 receptor antagonism. PLoS ONE, 2013, 8: e60918 CrossRef PubMed ADS Google Scholar

[2] An W., Li Y., Xu G., Zhao J., Xiang X., Ding L., Li J., Guan Y., Wang X., Tang C., et al. Modulation of ghrelin O-acyltransferase expression in pancreatic islets. Cell Physiol Biochem, 2010, 26: 707-716 CrossRef PubMed Google Scholar

[3] Asakawa A., Inui A., Kaga T., Yuzuriha H., Nagata T., Ueno N., Makino S., Fujimiya M., Niijima A., Fujino M.A., et al. Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin. Gastroenterology, 2001, 120: 337-345 CrossRef PubMed Google Scholar

[4] Barnett B.P., Hwang Y., Taylor M.S., Kirchner H., Pfluger P.T., Bernard V., Lin Y., Bowers E.M., Mukherjee C., Song W.J., et al. Glucose and weight control in mice with a designed ghrelin O-acyltransferase inhibitor. Science, 2010, 330: 1689-1692 CrossRef PubMed ADS Google Scholar

[5] Bowers, C.Y., Reynolds, G.A., and Momany, F.A. (1984). New advances on the regulation of growth hormone (GH) secretion. Internat. J. Neurol 18, 188–205. Google Scholar

[6] Cai H., Cong W., Daimon C.M., Wang R., Tschöp M.H., Sévigny J., Martin B., Maudsley S., Meyerhof W.. Altered lipid and salt taste responsivity in ghrelin and GOAT null mice. PLoS ONE, 2013, 8: e76553 CrossRef PubMed ADS Google Scholar

[7] Chen M.H., Li Y.J., Kawakami T., Xu S.M., Chuang P.T.. Palmitoylation is required for the production of a soluble multimeric Hedgehog protein complex and long-range signaling in vertebrates. Genes Dev, 2004, 18: 641-659 CrossRef PubMed Google Scholar

[8] Cummings D.E., Purnell J.Q., Frayo R.S., Schmidova K., Wisse B.E., Weigle D.S.. A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes, 2001, 50: 1714-1719 CrossRef PubMed Google Scholar

[9] Davies J.S., Kotokorpi P., Eccles S.R., Barnes S.K., Tokarczuk P.F., Allen S.K., Whitworth H.S., Guschina I.A., Evans B.A.J., Mode A., et al. Ghrelin induces abdominal obesity via GHS-R-dependent lipid retention. Mol Endocrinol, 2009, 23: 914-924 CrossRef PubMed Google Scholar

[10] Davis J.F., Perello M., Choi D.L., Magrisso I.J., Kirchner H., Pfluger P.T., Tschoep M., Zigman J.M., Benoit S.C.. GOAT induced ghrelin acylation regulates hedonic feeding. Hormones Behav, 2012, 62: 598-604 CrossRef PubMed Google Scholar

[11] De Winter B.Y., De Man J.G., Seerden T.C., Depoortere I., Herman A.G., Peeters T.L., Pelckmans P.A.. Effect of ghrelin and growth hormone-releasing peptide 6 on septic ileus in mice. Neurogastroenterol Motil, 2004, 16: 439-446 CrossRef PubMed Google Scholar

[12] Esler W.P., Rudolph J., Claus T.H., Tang W., Barucci N., Brown S.E., Bullock W., Daly M., Decarr L., Li Y., et al. Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss. Endocrinology, 2007, 148: 5175-5185 CrossRef PubMed Google Scholar

[13] Finger B.C., Dinan T.G., Cryan J.F.. Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task. Psychopharmacology, 2012, 220: 173-181 CrossRef PubMed Google Scholar

[14] Fujino K., Inui A., Asakawa A., Kihara N., Fujimura M., Fujimiya M.. Ghrelin induces fasted motor activity of the gastrointestinal tract in conscious fed rats. J Physiol, 2003, 550: 227-240 CrossRef Google Scholar

[15] Fukuda H., Mizuta Y., Isomoto H., Takeshima F., Ohnita K., Ohba K., Omagari K., Taniyama K., Kohno S.. Ghrelin enhances gastric motility through direct stimulation of intrinsic neural pathways and capsaicin-sensitive afferent neurones in rats. Scandinavian J Gastroenterology, 2004, 39: 1209-1214 CrossRef PubMed Google Scholar

[16] Gahete M.D., Córdoba-Chacón J., Salvatori R., Castaño J.P., Kineman R.D., Luque R.M.. Metabolic regulation of ghrelin O-acyl transferase (GOAT) expression in the mouse hypothalamus, pituitary, and stomach. Mol Cellular Endocrinol, 2010, 317: 154-160 CrossRef PubMed Google Scholar

[17] Garner A.L., Janda K.D.. A small molecule antagonist of ghrelin O-acyltransferase (GOAT). Chem Commun, 2011, 47: 7512-7514 CrossRef PubMed Google Scholar

[18] Goebel-Stengel M., Hofmann T., Elbelt U., Teuffel P., Ahnis A., Kobelt P., Lambrecht N.W.G., Klapp B.F., Stengel A.. The ghrelin activating enzyme ghrelin-O-acyltransferase (GOAT) is present in human plasma and expressed dependent on body mass index. Peptides, 2013, 43: 13-19 CrossRef PubMed Google Scholar

[19] González C.R., Vázquez M.J., López M., Diéguez C.. Influence of chronic undernutrition and leptin on GOAT mRNA levels in rat stomach mucosa. J Mol Endocrinol, 2008, 41: 415-421 CrossRef PubMed Google Scholar

[20] Gutierrez J.A., Solenberg P.J., Perkins D.R., Willency J.A., Knierman M.D., Jin Z., Witcher D.R., Luo S., Onyia J.E., Hale J.E.. Ghrelin octanoylation mediated by an orphan lipid transferase. Proc Natl Acad Sci USA, 2008, 105: 6320-6325 CrossRef PubMed ADS Google Scholar

[21] Heppner, K.M., Muller, T.D., Kirchner, H., Perez-Tilve, D., Pfluger, P.T., Tschop, M.H., and Hofmann, S.M. (2013). The role of ghrelin- octanoyl-acyl-transferase in thermoregulation. J Endocrinol Invest 36, 180–184. Google Scholar

[22] Hofmann K.. A superfamily of membrane-bound O -acyltransferases with implications for Wnt signaling. Trends Biochem Sci, 2000, 25: 111-112 CrossRef Google Scholar

[23] Howard A.D., Feighner S.D., Cully D.F., Arena J.P., Liberator P.A., Rosenblum C.I., Hamelin M., Hreniuk D.L., Palyha O.C., Anderson J., et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science, 1996, 273: 974-977 CrossRef PubMed ADS Google Scholar

[24] Jászberényi M., Bujdosó E., Bagosi Z., Telegdy G.. Mediation of the behavioral, endocrine and thermoregulatory actions of ghrelin. Hormones Behav, 2006, 50: 266-273 CrossRef PubMed Google Scholar

[25] Kang K., Schmahl J., Lee J.M., Garcia K., Patil K., Chen A., Keene M., Murphy A., Sleeman M.W.. Mouse ghrelin- O-acyltransferase (GOAT) plays a critical role in bile acid reabsorption. FASEB J, 2012, 26: 259-271 CrossRef PubMed Google Scholar

[26] Khalil E.M., De Angelis J., Ishii M., Cole P.A.. Mechanism-based inhibition of the melatonin rhythm enzyme: pharmacologic exploitation of active site functional plasticity. Proc Natl Acad Sci USA, 1999, 96: 12418-12423 CrossRef PubMed ADS Google Scholar

[27] Kirchner H., Gutierrez J.A., Solenberg P.J., Pfluger P.T., Czyzyk T.A., Willency J.A., Schürmann A., Joost H.G., Jandacek R.J., Hale J.E., et al. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med, 2009, 15: 741-745 CrossRef PubMed Google Scholar

[28] Kirchner H., Heppner K.M., Holland J., Kabra D., Tschöp M.H., Pfluger P.T., Maedler K.. Ablation of ghrelin O-acyltransferase does not improve glucose intolerance or body adiposity in mice on a leptin-deficient ob/ob background. PLoS ONE, 2013, 8: e61822 CrossRef PubMed ADS Google Scholar

[29] 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: 656-660 CrossRef PubMed ADS Google Scholar

[30] Landgren S., Simms J.A., Hyytiä P., Engel J.A., Bartlett S.E., Jerlhag E.. Ghrelin receptor (GHS-R1A) antagonism suppresses both operant alcohol self-administration and high alcohol consumption in rats. Addiction Biol, 2012, 17: 86-94 CrossRef PubMed Google Scholar

[31] Lau O.D., Kundu T.K., Soccio R.E., Ait-Si-Ali S., Khalil E.M., Vassilev A., Wolffe A.P., Nakatani Y., Roeder R.G., Cole P.A.. HATs off. Mol Cell, 2000, 5: 589-595 CrossRef Google Scholar

[32] Lawrence C.B., Snape A.C., Baudoin F.M.H., Luckman S.M.. Acute central ghrelin and GH secretagogues induce feeding and activate brain appetite centers. Endocrinology, 2002, 143: 155-162 CrossRef PubMed Google Scholar

[33] Lee H.M., Wang G., Englander E.W., Kojima M., Greeley Jr. G.H.. Ghrelin, a new gastrointestinal endocrine peptide that stimulates insulin secretion: enteric distribution, ontogeny, influence of endocrine, and dietary manipulations. Endocrinology, 2002, 143: 185-190 CrossRef PubMed Google Scholar

[34] Levin F., Edholm T., Schmidt P.T., Grybäck P., Jacobsson H., Degerblad M., Höybye C., Holst J.J., Rehfeld J.F., Hellström P.M., et al. Ghrelin stimulates gastric emptying and hunger in normal-weight humans. J Clin Endocrinol Metab, 2006, 91: 3296-3302 CrossRef PubMed Google Scholar

[35] Li Z., Xu G., Qin Y., Zhang C., Tang H., Yin Y., Xiang X., Li Y., Zhao J., Mulholland M., et al. Ghrelin promotes hepatic lipogenesis by activation of mTOR-PPAR signaling pathway. Proc Natl Acad Sci USA, 2014, 111: 13163-13168 CrossRef PubMed ADS Google Scholar

[36] Lim C.T., Kola B., Korbonits M.. The ghrelin/GOAT/GHS-R system and energy metabolism. Rev Endocr Metab Disord, 2011, 12: 173-186 CrossRef PubMed Google Scholar

[37] Lin L., Saha P.K., Ma X., Henshaw I.O., Shao L., Chang B.H.J., Buras E.D., Tong Q., Chan L., McGuinness O.P., et al. Ablation of ghrelin receptor reduces adiposity and improves insulin sensitivity during aging by regulating fat metabolism in white and brown adipose tissues. Aging Cell, 2011, 10: 996-1010 CrossRef PubMed Google Scholar

[38] Longo K.A., Charoenthongtrakul S., Giuliana D.J., Govek E.K., McDonagh T., Qi Y., DiStefano P.S., Geddes B.J.. Improved insulin sensitivity and metabolic flexibility in ghrelin receptor knockout mice. Regulatory Peptides, 2008, 150: 55-61 CrossRef PubMed Google Scholar

[39] Mela D.J., Sacchetti D.A.. Sensory preferences for fats: relationships with diet and body composition. Am J Clin Nutrition, 1991, 53: 908-915 CrossRef PubMed Google Scholar

[40] Molfino A., Gioia G., Muscaritoli M.. The hunger hormone ghrelin in cachexia. Expert Opin Biol Ther, 2013, 13: 465-468 CrossRef PubMed Google Scholar

[41] Nakazato M., Murakami N., Date Y., Kojima M., Matsuo H., Kangawa K., Matsukura S.. A role for ghrelin in the central regulation of feeding. Nature, 2001, 409: 194-198 CrossRef PubMed Google Scholar

[42] Ohgusu H., Shirouzu K., Nakamura Y., Nakashima Y., Ida T., Sato T., Kojima M.. 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: 153-158 CrossRef PubMed Google Scholar

[43] Ohgusu, H., Takahashi, T., and Kojima, M. (2012). Enzymatic characterization of GOAT, ghrelin O-acyltransferase. Methods Enzymol 514, 147–163. Google Scholar

[44] Patterson M., Bloom S.R., Gardiner J.V.. Ghrelin and appetite control in humans—potential application in the treatment of obesity. Peptides, 2011, 32: 2290-2294 CrossRef PubMed Google Scholar

[45] Perello M., Sakata I., Birnbaum S., Chuang J.C., Osborne-Lawrence S., Rovinsky S.A., Woloszyn J., Yanagisawa M., Lutter M., Zigman J.M.. Ghrelin increases the rewarding value of high-fat diet in an orexin-dependent manner. Biol Psychiatry, 2010, 67: 880-886 CrossRef PubMed Google Scholar

[46] Petrova E., Rios-Esteves J., Ouerfelli O., Glickman J.F., Resh M.D.. Inhibitors of hedgehog acyltransferase block sonic hedgehog signaling. Nat Chem Biol, 2013, 9: 247-249 CrossRef PubMed Google Scholar

[47] Qi Y., Longo K.A., Giuliana D.J., Gagne S., McDonagh T., Govek E., Nolan A., Zou C., Morgan K., Hixon J., et al. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps. BMC Physiol, 2011, 11: 1 CrossRef PubMed Google Scholar

[48] Reimer R.A., Maurer A.D., Lau D.C.W., Auer R.N.. Long-term dietary restriction influences plasma ghrelin and GOAT mRNA level in rats. Physiol Behav, 2010, 99: 605-610 CrossRef PubMed Google Scholar

[49] Shiiya T., Nakazato M., Mizuta M., Date Y., Mondal M.S., Tanaka M., Nozoe S.I., Hosoda H., Kangawa K., Matsukura S.. Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion. J Clin Endocrinol Metab, 2002, 87: 240-244 CrossRef PubMed Google Scholar

[50] Shimbara T., Mondal M.S., Kawagoe T., Toshinai K., Koda S., Yamaguchi H., Date Y., Nakazato M.. Central administration of ghrelin preferentially enhances fat ingestion. NeuroSci Lett, 2004, 369: 75-79 CrossRef PubMed Google Scholar

[51] Shin Y.K., Martin B., Kim W., White C.M., Ji S., Sun Y., Smith R.G., Sévigny J., Tschöp M.H., Maudsley S., et al. Ghrelin is produced in taste cells and ghrelin receptor null mice show reduced taste responsivity to salty (NaCl) and sour (citric acid) tastants. PLoS ONE, 2010, 5: e12729 CrossRef PubMed ADS Google Scholar

[52] Skibicka K.P., Hansson C., Egecioglu E., Dickson S.L.. Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression. Addiction Biol, 2012, 17: 95-107 CrossRef PubMed Google Scholar

[53] Smith R.G., Sun Y., Betancourt L., Asnicar M.. Growth hormone secretagogues: prospects and potential pitfalls. Best Practice Res Clin Endocrinol Metab, 2004, 18: 333-347 CrossRef PubMed Google Scholar

[54] Srinivas S.R., Gopal E., Zhuang L., Itagaki S., Martin P.M., Fei Y.J., Ganapathy V., Prasad P.D.. Cloning and functional identification of slc5a12 as a sodium-coupled low-affinity transporter for monocarboxylates (SMCT2). Biochem J, 2005, 392: 655-664 CrossRef PubMed Google Scholar

[55] Stengel A., Goebel M., Wang L., Taché Y., Sachs G., Lambrecht N.W.G.. 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 CrossRef PubMed Google Scholar

[56] Stevanovic D., Trajkovic V., Müller-Lühlhoff S., Brandt E., Abplanalp W., Bumke-Vogt C., Liehl B., Wiedmer P., Janjetovic K., Starcevic V., et al. Ghrelin-induced food intake and adiposity depend on central mTORC1/S6K1 signaling. Mol Cellular Endocrinol, 2013, 381: 280-290 CrossRef PubMed Google Scholar

[57] Sun Y., Asnicar M., Saha P.K., Chan L., Smith R.G.. Ablation of ghrelin improves the diabetic but not obese phenotype of ob/ob mice. Cell Metab, 2006, 3: 379-386 CrossRef PubMed Google Scholar

[58] Szentirmai E., Kapás L., Sun Y., Smith R.G., Krueger J.M.. The preproghrelin gene is required for the normal integration of thermoregulation and sleep in mice. Proc Natl Acad Sci USA, 2009, 106: 14069-14074 CrossRef PubMed ADS Google Scholar

[59] Tack J., Depoortere I., Bisschops R., Delporte C., Coulie B., Meulemans A., Janssens J., Peeters T.. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut, 2006, 55: 327-333 CrossRef PubMed Google Scholar

[60] Takada R., Satomi Y., Kurata T., Ueno N., Norioka S., Kondoh H., Takao T., Takada S.. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev Cell, 2006, 11: 791-801 CrossRef PubMed Google Scholar

[61] Taylor M.S., Ruch T.R., Hsiao P.Y., Hwang Y., Zhang P., Dai L., Huang C.R.L., Berndsen C.E., Kim M.S., Pandey A., et al. Architectural organization of the metabolic regulatory enzyme ghrelin O-acyltransferase. J Biol Chem, 2013, 288: 32211-32228 CrossRef PubMed Google Scholar

[62] Teramae H., Yoshikawa T., Inoue R., Ushida K., Takebe K., Nio-Kobayashi J., Iwanaga T.. The cellular expression of SMCT2 and its comparison with other transporters for monocarboxylates in the mouse digestive tract. Biomed Res, 2010, 31: 239-249 CrossRef Google Scholar

[63] Teubner B.J.W., Garretson J.T., Hwang Y., Cole P.A., Bartness T.J.. Inhibition of ghrelin O-acyltransferase attenuates food deprivation-induced increases in ingestive behavior. Hormones Behav, 2013, 63: 667-673 CrossRef PubMed Google Scholar

[64] Theander-Carrillo C., Wiedmer P., Cettour-Rose P., Nogueiras R., Perez-Tilve D., Pfluger P., Castaneda T.R., Muzzin P., Schürmann A., Szanto I., et al. Ghrelin action in the brain controls adipocyte metabolism. J Clin Investigation, 2006, 116: 1983-1993 CrossRef PubMed Google Scholar

[65] Trudel L., Tomasetto C., Rio M.C., Bouin M., Plourde V., Eberling P., Poitras P.. Ghrelin/motilin-related peptide is a potent prokinetic to reverse gastric postoperative ileus in rat. Am J Physiol-Gastrointestinal Liver Physiol, 2002, 282: G948-G952 CrossRef PubMed Google Scholar

[66] Tschöp M., Smiley D.L., Heiman M.L.. Ghrelin induces adiposity in rodents. Nature, 2000, 407: 908-913 CrossRef PubMed Google Scholar

[67] Tsubone T., Masaki T., Katsuragi I., Tanaka K., Kakuma T., Yoshimatsu H.. Ghrelin regulates adiposity in white adipose tissue and UCP1 mRNA expression in brown adipose tissue in mice. Regulatory Peptides, 2005, 130: 97-103 CrossRef PubMed Google Scholar

[68] Vaughan A.M., Oram J.F.. ABCG1 redistributes cell cholesterol to domains removable by high density lipoprotein but not by lipid-depleted apolipoproteins. J Biol Chem, 2005, 280: 30150-30157 CrossRef PubMed Google Scholar

[69] Wiedmer P., Strasser F., Horvath T.L., Blum D., Dimarchi R., Lutz T., Schürmann A., Joost H.G., Tschöp M.H., Tong J.. Ghrelin-induced hypothermia: a physiological basis but no clinical risk. Physiol Behav, 2011, 105: 43-51 CrossRef PubMed Google Scholar

[70] Xu G., Li Y., An W., Li S., Guan Y., Wang N., Tang C., Wang X., Zhu Y., Li X., et al. Gastric mammalian target of rapamycin signaling regulates ghrelin production and food intake. Endocrinology, 2009, 150: 3637-3644 CrossRef PubMed Google Scholar

[71] Xu G., Wang Z., Li Y., Li Z., Tang H., Zhao J., Xiang X., Ding L., Ma L., Yuan F., et al. Ghrelin contributes to derangements of glucose metabolism induced by rapamycin in mice. Diabetologia, 2012, 55: 1813-1823 CrossRef PubMed Google Scholar

[72] Yang J., Brown M.S., Liang G., Grishin N.V., Goldstein J.L.. Identification of the acyltransferase that octanoylates ghrelin, an appetite-stimulating peptide hormone. Cell, 2008a, 132: 387-396 CrossRef PubMed Google Scholar

[73] Yang J., Zhao T.J., Goldstein J.L., Brown M.S.. Inhibition of ghrelin O-acyltransferase (GOAT) by octanoylated pentapeptides. Proc Natl Acad Sci USA, 2008b, 105: 10750-10755 CrossRef PubMed ADS Google Scholar

[74] Zhao T.J., Liang G., Li R.L., Xie X., Sleeman M.W., Murphy A.J., Valenzuela D.M., Yancopoulos G.D., Goldstein J.L., Brown M.S.. Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice. Proc Natl Acad Sci USA, 2010, 107: 7467-7472 CrossRef PubMed ADS Google Scholar

[75] Zhu X., Cao Y., Voogd K., Voodg K., Steiner D.F.. On the processing of proghrelin to ghrelin. J Biol Chem, 2006, 281: 38867-38870 CrossRef PubMed Google Scholar

[76] Zigman J.M., Nakano Y., Coppari R., Balthasar N., Marcus J.N., Lee C.E., Jones J.E., Deysher A.E., Waxman A.R., White R.D., et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Investigation, 2005, 115: 3564-3572 CrossRef PubMed Google Scholar

  • Figure 1

    Roles of GOAT/acyl-ghrelin system in energy metabolism. Octanoylation of ghrelin (sequence as: GSSFLSPEHQKAQQRKESKKPPAKLQPR) by ghrelin O-acyltransferase (GOAT) on its third amino acid (serine-3) is necessary for the hormone’s biological functions, Octanoylated ghrelin regulates food intake by inducing hyperphagia and increasing gastrointestinal motility, modulates glucose metabolism by altering insulin secretion and sensitivity, as well as stimulates adiposity by increasing lipid storage and/or decreasing lipid expenditure.

qqqq

Contact and support