Development of ghrelin transgenic mice for elucidation of clinical implication of ghrelin
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- Aotani Daisuke
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Ariyasu Hiroyuki
- The First Department of Medicine, Wakayama Medical University, Wakayama, Japan
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- Shimazu-Kuwahara Satoko
- Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Shimizu Yoshiyuki
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Nomura Hidenari
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Murofushi Yoshiteru
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Kaneko Kentaro
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Izumi Ryota
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Matsubara Masaki
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Kanda Hajime
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Noguchi Michio
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Tanaka Tomohiro
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Kusakabe Toru
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Miyazawa Takashi
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
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- Nakao Kazuwa
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan
Abstract
To elucidate the clinical implication of ghrelin, we have been trying to generate variable models of transgenic (Tg) mice overexpressing ghrelin. We generated Tg mice overexpressing des-acyl ghrelin in a wide variety of tissues under the control of β-actin promoter. While plasma des-acyl ghrelin level in the Tg mice was 44-fold greater than that of control mice, there was no differences in the plasma ghrelin level between des-acyl ghrelin Tg and the control mice. The des-acyl ghrelin Tg mice exhibited the lower body weight and the shorter body length due to modulation of GH-IGF-1 axis. We tried to generate Tg mice expressing a ghrelin analog, which possessed ghrelin-like activity (Trp3-ghrelin Tg mice). The plasma Trp3-ghrelin concentration in Trp3-ghrelin Tg mice was approximately 85-fold higher than plasma ghrelin (acylated ghrelin) concentration seen in the control mice. Because Trp3-ghrelin is approximately 24-fold less potent than ghrelin, the plasma Trp3-ghrelin concentration in Trp3-ghrelin Tg mice was calculated to have approximately 3.5-fold biological activity greater than that of ghrelin (acylated ghrelin) in the control mice. Trp3-ghrelin Tg mice did not show any phenotypes except for reduced insulin sensitivity in 1-year old. After the identification of ghrelin O-acyltransferase (GOAT), we generated doubly Tg mice overexpressing both mouse des-acyl ghrelin and mouse GOAT in the liver by cross-mating the two kinds of Tg mice. The plasma ghrelin concentration of doubly Tg mice was approximately 2-fold higher than that of the control mice. No apparent phenotypic changes in body weight and food intake were observed in doubly Tg mice. Further studies are ongoing in our laboratory to generate Tg mice with the increased plasma ghrelin level to a greater extent. The better understanding of physiological and pathophysiological significance of ghrelin from experiments using an excellent animal model may provide a new therapeutic approach for human diseases.
Journal
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- Endocrine Journal
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Endocrine Journal 64 (Suppl.), S31-S33, 2017
The Japan Endocrine Society
