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.