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Molecular Pharmacology

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Research ArticleArticle

An Acyl-Ghrelin-Specific Neutralizing Antibody Inhibits the Acute Ghrelin-Mediated Orexigenic Effects in Mice

Shu-Chen Lu, Jing Xu, Narumol Chinookoswong, Shuying Liu, Shirley Steavenson, Colin Gegg, David Brankow, Richard Lindberg, Murielle Véniant and Wei Gu
Molecular Pharmacology April 2009, 75 (4) 901-907; DOI: https://doi.org/10.1124/mol.108.052852
Shu-Chen Lu
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Jing Xu
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Narumol Chinookoswong
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Shuying Liu
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Shirley Steavenson
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Colin Gegg
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David Brankow
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Richard Lindberg
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Murielle Véniant
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Wei Gu
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Abstract

Ghrelin is a 28-amino acid peptide secreted mainly by the stomach. Acyl-ghrelin, which binds to and activates the growth hormone secretagogue receptor type 1a (GHS-R1a), is considered to be the active form for its orexigenic effects. It has been demonstrated that peripheral administration of ghrelin stimulates food intake and adiposity in rodents and humans. Accordingly, different approaches to antagonize ghrelin/GHS-R1a signaling have been pursued for the treatment of obesity. In the present study, we generated and characterized high-affinity anti-acyl ghrelin-specific monoclonal antibodies (mAbs). In vitro, the lead mAb (33A) displayed specific binding to acyl-ghrelin, with an estimated Kd value < 100 pM. In recombinant receptor cell-based assays, 33A dose-dependently inhibited the ghrelin-mediated calcium signal, with an IC50 of ∼3.5 nM. In vivo, ghrelin dose-dependently stimulated food intake in mice, and this effect was fully blocked by a single injection of 33A. In a 4-week chronic study, 33A was shown to effectively bind to endogenous acyl-ghrelin; however, long-term administration of 33A did not affect food intake or body weight gain in a mouse model of diet-induced obesity. Our results indicate that peripheral neutralization of ghrelin can suppress appetite stimulated by a transient surge in ghrelin levels. The lack of long-term effects on body weight control by 33A suggests that compensatory mechanisms may contribute to the regulation of energy balance.

Footnotes

  • ABBREVIATIONS: Ghr, ghrelin; GHS-R1a, growth hormone secretagogue receptor type 1a; NPY, neuropeptide Y; AgRP, Agouti-related protein; HFD, high fat diet; DIO, diet-induced obese; mAb, monoclonal antibody; ELISA, enzyme-linked immunosorbent assay; aa, amino acids; Dap, diaminopropionic acid; KO, knockout.

    • Received October 17, 2008.
    • Accepted January 7, 2009.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 75 (4)
Molecular Pharmacology
Vol. 75, Issue 4
1 Apr 2009
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Research ArticleArticle

An Acyl-Ghrelin-Specific Neutralizing Antibody Inhibits the Acute Ghrelin-Mediated Orexigenic Effects in Mice

Shu-Chen Lu, Jing Xu, Narumol Chinookoswong, Shuying Liu, Shirley Steavenson, Colin Gegg, David Brankow, Richard Lindberg, Murielle Véniant and Wei Gu
Molecular Pharmacology April 1, 2009, 75 (4) 901-907; DOI: https://doi.org/10.1124/mol.108.052852

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Research ArticleArticle

An Acyl-Ghrelin-Specific Neutralizing Antibody Inhibits the Acute Ghrelin-Mediated Orexigenic Effects in Mice

Shu-Chen Lu, Jing Xu, Narumol Chinookoswong, Shuying Liu, Shirley Steavenson, Colin Gegg, David Brankow, Richard Lindberg, Murielle Véniant and Wei Gu
Molecular Pharmacology April 1, 2009, 75 (4) 901-907; DOI: https://doi.org/10.1124/mol.108.052852
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