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Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice

Gene Therapy volumeĀ 22,Ā pages 750ā€“757 (2015)Cite this article

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Abstract

Ghrelin is a stomach-derived peptide hormone that stimulates appetite and promotes adiposity through binding to the growth hormone secretagogue receptor (GHS-R1a). Administration of ghrelin in rodents increases weight gain due to stimulating food intake and reducing fat utilization. Therefore, reducing circulating ghrelin levels holds the potential to reduce weight gain. We developed a GHS-R1a-fusion constructs of a decoy protein containing the ligand-binding domains of the ghrelin receptor. Intramuscular injection of the GHSR/Fc plasmid decreased circulating levels of acylated-ghrelin. When challenged with the high fat diet, treated mice displayed reduced weight gain compared with controls, which was associated with reduced fat accumulation in the peritoneum but not lean mass. Quantitative PCR with reverse transcription showed increased PPARĪ³ and hormone sensitive lipase transcripts levels in adipose tissue of treated animals, illustrating a preference for increased fat utilization. Intra-peritoneal glucose tolerance and insulin tolerance tests showed improved glucose clearance and insulin sensitivity in GHSR/Fc treated animals. We suggest that in vivo expression of the GHSR-based fusion protein prevents diet-induced weight gain, altering adipose gene expression and improving glucose tolerance. These findings, while confirming the role of ghrelin in peripheral energy metabolism, suggest that a strategy involving neutralization of the circulation ghrelin by intramuscular injection of the GHSR1/Fc fusion construct may find clinical application in the treatment of obesity.

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Acknowledgements

We thank Dr Kui Chen for his contribution in the plasmid construction and assistance with the animal work. Dr Younes Aniniā€™s laboratory was supported by grants from the Canadian Institutes of Health Research (MOP-82795), Canada foundation for innovation, The Dalhousie Medical research Foundation and the IWK Research Foundation. Jeff Gagnon was supported by studentships from the Natural Sciences and Engineering Research Council, the Canadian Heart and Stroke foundation and the IWK Research Foundation. Dr Qinghua Wangā€™s laboratory was supported by grants from the Canadian Institute for Health Research (CIHR), Juvenile Diabetes Research Foundation (JDRF) and Canadian Diabetes Association (CDA). Qinghua Wang was supported by CIHR New Investigator Program.

Author information

Author notes

  1. J GagnonĀ &Ā L Zhu

    Present address: 5Current address: Department of Chemistry and Biology, College of Science, National University of Defense Technology, Changsha, Hunan, People's Republic of China.,

  2. L Zhu: These authors contributed equally to study.

  3. Y Anini and Q Wang: Authors led the study equally.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Dalhousie University, Halifax, NS, Canada

    J GagnonĀ &Ā Y Anini

  2. Department of Physiology and Biophysics, Dalhousie University, Halifax, NS, Canada

    J GagnonĀ &Ā Y Anini

  3. Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada

    L ZhuĀ &Ā Q Wang

  4. Departments of Physiology and Medicine, University of Toronto, Toronto, ON, Canada

    L ZhuĀ &Ā Q Wang

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  1. J Gagnon
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Correspondence to Y Anini.

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Gagnon, J., Zhu, L., Anini, Y. et al. Neutralizing circulating ghrelin by expressing a growth hormone secretagogue receptor-based protein protects against high-fat diet-induced obesity in mice. Gene Ther 22, 750ā€“757 (2015). https://doi.org/10.1038/gt.2015.38

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