Dose dependent development of diabetes mellitus and non-alcoholic steatohepatitis in monosodium glutamate-induced obese mice
Introduction
The amount of obesity in humans is increasing every year due to lifestyle changes (Farrigan and Pang, 2002, Park et al., 2003). It is essential to have many animal models of human obesity to facilitate research on the various diseases associated with obesity. Spontaneous or genetically modified animal models of diabetes mellitus (Mordes and Rossini, 1981, Gao et al., 2004, Seckl et al., 2004, Mathews and Leiter, 2005) have been used widely. With respect to drug-induced experimental animal models of diabetes mellitus with obesity, gold thioglucose treatment (Marshall et al., 1955, Liebelt and Perry, 1957, Katsuki et al., 1962, Matsuo and Shino, 1972) and high-fat diets (Rebuffe et al., 1993, Pitombo et al., 2006) have been previously reported. We reported that a useful mouse model which was induced by monosodium glutamate (MSG) in neonate. MSG mice developed severe obesity and diabetes mellitus without any other treatment such as special diet after five-days of subcutaneous injection of MSG to newborn mice. They showed nearly spontaneous clinical course of life-style related diseases, therefore MSG mice were suit animal models of human complications following obesity.
We reported that ICR-MSG mice administered MSG (2 mg/g) for 5 consecutive days developed severe obesity, urinary glucose, hyperglycemia, hyperinsulinemia, and a decrease in both glucose tolerance and insulin sensitivity. In these animals, a severe hypertrophy of pancreatic islets due to the proliferation of B cells was observed, indicating that ICR-MSG mice could be used as the animal model of human type 2 diabetes mellitus (Nagata et al. 2006). In addition, we reported that these MSG-induced obese animals, when administered MSG (2 mg/g) for 5 days, were a useful model of non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) in humans (Nakanishi et al. 2008). This is because these ICR-MSG mice showed the development of marked centrilobular fatty change with fibrosis progressing to hepatic neoplasm in the liver. Matsuyama et al. (1972) induced obesity in mice with a single subcutaneously administered dose of MSG, which was a 4 mg/g higher dose than the dosing we used. Scomparin et al. (2006) increased the dosing frequency and induced severe obesity in Swiss mice by repeated subcutaneous administration of MSG at 4 mg/g. However, inclusive of the above cases, there has been no evidence examining the relationship between these diseases and the MSG dosage. Differences in the severity of the obesity and the complications, such as diabetes mellitus and liver disease, may be related to differences in the dosing period, the dose of MSG, and the mouse strain. In the present study, we examined the most appropriate MSG doses and the usefulness of the system as a model of diabetes mellitus and NAFLD/NASH in ICR-MSG mice.
Section snippets
Animals
Twelve pregnant Crj:CD-1(ICR) mice (twelfth day of pregnancy) were purchased from Charles River Laboratories Japan Inc., and 165 neonates born to 11 of those mice were used. In our previous study, a 5-day course of subcutaneous MSG injections at a 2 mg/g dose to Crj:CD-1(ICR) mice induced severe obesity (Nagata et al. 2006). In another study, the subcutaneous administration of MSG at 3 to 6 mg/g for 6 days resulted in the death of 70.6% of the CFLP mice studied (Bunyan et al. 1976). In light of
Growth curve
The growth curves are shown in Fig. 1. In the female 4 mg/g × 1 group, body weight increased rapidly after 5 weeks of age as compared with the control group, showing a significant difference after 6 weeks of age (p < 0.001). In the female 4 mg/g × 5 group, body weight was significantly lower until 3–4 weeks of age compared with the control group (p < 0.01–0.001). However, thereafter it rapidly increased, as with the female 4 mg/g × 1 group. The female 2 mg/g × 5 group showed a body weight profile over time that
Discussion
We previously reported that MSG administered at 2 mg/g subcutaneously for 5 consecutive days to Crj:CD-1(ICR) mice induced severe obesity, diabetes mellitus (Nagata et al. 2006), and liver lesions resembling NAFLD/NASH (Nakanishi et al. 2008). In this study, we investigated the induction of more severe obesity, diabetes mellitus and NAFLD/NASH by increasing the dose of MSG.
Body weight increased most markedly in the 4 mg/g × 1 group in both the male and female mice. In the 4 mg/g × 5 groups, the
Conclusions
It was demonstrated that a single 4 mg/g dose of MSG was the most suitable as the obese model and induced not only severe obesity and diabetes mellitus, but also liver changes resembling human NAFLD/NASH. A small amount of MSG in the newborn develops obesity and the other complications without hyperphagia after a long term.
Acknowledgments
We thank Mr. Syuichi Tayama for technical assistance. This work was supported in part by the ‘High-Tech Research Center’ project for private universities with a matching fund subsidy from MEXT (Ministry of Education Culture, Sports, Science and Technology, 2004-2008) of Japan.
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