Glucose and Weight Control in Mice with a Designed Ghrelin O-Acyltransferase Inhibitor

被引：201

作者：

Barnett, Brad P. ^{[1
,2
,3
]}

Hwang, Yousang ^{[1
]}

Taylor, Martin S. ^{[1
,2
,3
]}

Kirchner, Henriette ^{[4
,10
]}

Pfluger, Paul T. ^{[4
]}

Bernard, Vincent ^{[2
,3
]}

Lin, Yu-yi ^{[2
,3
,9
]}

Bowers, Erin M. ^{[1
]}

Mukherjee, Chandrani ^{[1
]}

Song, Woo-Jin ^{[5
,6
,7
]}

Longo, Patti A. ^{[8
]}

Leahy, Daniel J. ^{[8
]}

Hussain, Mehboob A. ^{[5
,6
,7
]}

Tschoep, Matthias H. ^{[4
,10
]}

Boeke, Jef D. ^{[2
,3
]}

Cole, Philip A. ^{[1
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA

[2] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

[3] Johns Hopkins Univ, Sch Med, High Throughput Biol Ctr, Baltimore, MD 21205 USA

[4] Univ Cincinnati, Dept Internal Med, Metab Dis Inst, Obes Res Ctr, Cincinnati, OH 45237 USA

[5] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Metab, Baltimore, MD 21205 USA

[6] Johns Hopkins Univ, Sch Med, Dept Med, Div Metab, Baltimore, MD 21205 USA

[7] Johns Hopkins Univ, Sch Med, Dept Biol Chem, Div Metab, Baltimore, MD 21205 USA

[8] Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA

[9] Natl Taiwan Univ, Inst Biochem & Mol Biol, Coll Med, Taipei 100, Taiwan

[10] German Inst Human Nutr, Dept Pharmacol, D-14558 Nuthetal, Germany

来源：

SCIENCE | 2010年 / 330卷 / 6011期

关键词：

DES-ACYL GHRELIN; INSULIN-SECRETION; OBESITY; GOAT; HORMONE; ADIPOSITY; PHENOTYPE; RELEASE; PEPTIDE; HUMANS;

D O I：

10.1126/science.1196154

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Ghrelin is a gastric peptide hormone that stimulates weight gain in vertebrates. The biological activities of ghrelin require octanoylation of the peptide on Ser(3), an unusual posttranslational modification that is catalyzed by the enzyme ghrelin O-acyltransferase (GOAT). Here, we describe the design, synthesis, and characterization of GO-CoA-Tat, a peptide-based bisubstrate analog that antagonizes GOAT. GO-CoA-Tat potently inhibits GOAT in vitro, in cultured cells, and in mice. Intraperitoneal administration of GO-CoA-Tat improves glucose tolerance and reduces weight gain in wild-type mice but not in ghrelin-deficient mice, supporting the concept that its beneficial metabolic effects are due specifically to GOAT inhibition. In addition to serving as a research tool for mapping ghrelin actions, GO-CoA-Tat may help pave the way for clinical targeting of GOAT in metabolic diseases.

引用

页码：1689 / 1692

页数：4

共 28 条

[1] UCP2 mediates ghrelin's action on NPY/AgRP neurons by lowering free radicals [J].

Andrews, Zane B. ;

Liu, Zhong-Wu ;

Walllingford, Nicholas ;

Erion, Derek M. ;

Borok, Erzsebet ;

Friedman, Jeffery M. ;

Tschop, Matthias H. ;

Shanabrough, Marya ;

Cline, Gary ;

Shulman, Gerald I. ;

Coppola, Anna ;

Gao, Xiao-Bing ;

Horvath, Tamas L. ;

Diano, Sabrina .

NATURE, 2008, 454 (7206) :846-851

[2] Transgenic mice overexpressing des-acyl ghrelin show small phenotype [J].

Ariyasu, H ;

Takaya, K ;

Iwakura, H ;

Hosoda, H ;

Akamizu, T ;

Arai, Y ;

Kangawa, K ;

Nakao, K .

ENDOCRINOLOGY, 2005, 146 (01) :355-364

[3] Non-acylated ghrelin counteracts the metabolic but not the neuroendocrine response to acylated ghrelin in humans [J].

Broglio, F ;

Gottero, C ;

Prodam, F ;

Gauna, C ;

Muccioli, G ;

Papotti, M ;

Abribat, T ;

Van der Lely, AJ ;

Ghigo, E .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2004, 89 (06) :3062-3065

[4] Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis [J].

Dezaki, Katsuya ;

Sone, Hedeyuki ;

Yada, Toshihiko .

PHARMACOLOGY & THERAPEUTICS, 2008, 118 (02) :239-249

[5] Ghrelin uses Gαi2 and activates voltage-dependent K+ channels to attenuate glucose-induced Ca2+ signaling and insulin release in islet β-cells -: Novel signal transduction of ghrelin [J].

Dezaki, Katsuya ;

Kakei, Masafumi ;

Yada, Toshihiko .

DIABETES, 2007, 56 (09) :2319-2327

[6] Ghrelin stimulates, whereas des-octanoyl ghrelin inhibits, glucose output by primary hepatocytes [J].

Gauna, C ;

Delhanty, PJD ;

Hofland, LJ ;

Janssen, JAMJL ;

Broglio, F ;

Ross, RJM ;

Ghigo, E ;

van der Lely, AJ .

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, 2005, 90 (02) :1055-1060

[7] Unraveling the role of the ghrelin gene peptides in the endocrine pancreas [J].

Granata, Riccarda ;

Baragli, Alessandra ;

Settanni, Fabio ;

Scarlatti, Francesca ;

Ghigo, Ezio .

JOURNAL OF MOLECULAR ENDOCRINOLOGY, 2010, 45 (03) :107-118

[8] Introducing GOAT: a target for obesity and anti-diabetic drugs? [J].

Gualillo, Oreste ;

Lago, Francisca ;

Dieguez, Carlos .

TRENDS IN PHARMACOLOGICAL SCIENCES, 2008, 29 (08) :398-401

[9] Ghrelin octanoylation mediated by an orphan lipid transferase [J].

Gutierrez, Jesus A. ;

Solenberg, Patricia J. ;

Perkins, Douglas R. ;

Willency, Jill A. ;

Knierman, Michael D. ;

Jin, Zhaoyan ;

Witcher, Derrick R. ;

Luo, Shuang ;

Onyia, Jude E. ;

Hale, John E. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (17) :6320-6325

[10] A superfamily of membrane-bound O-acyltransferases with implications for Wnt signaling [J].

Hofmann, K .

TRENDS IN BIOCHEMICAL SCIENCES, 2000, 25 (03) :111-112

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