Diabetic Complications in a New Animal Model (TSOD mouse) of Spontaneous NIDDM with Obesity

Iizuka, Seiichi; Suzuki, Wataru; Tabuchi, Masahiro; Nagata, Mitsuru; Imamura, Saburo; Kobayashi, Yujiro; Kanitani, Masanao; Yanagisawa, Toshihiko; Kase, Yoshio; Takeda, Susumu; Aburada, Masaki; Takahashi, Kazuaki W.

doi:10.1538/expanim.54.71

Cited by 63 publications

(44 citation statements)

References 30 publications

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“…The TSNO mice were established as a non-disease model that did not develop obesity and diabetes. From the above results, we speculated that TSOD mice would develop obesity and various metabolic disorders, as has been shown to occur in studies in other animal models which we have previously reported on [12][13][14]18) and would be suitable for use in the evaluation of the drug effects on obesity and metabolic disorders. At the age of 4 weeks, body weight, and the amounts of visceral and subcutaneous fat were comparable between TSOD mice and TSNO mice, suggesting that obesity and metabolic disorders had not yet developed at this age.…”

Section: Tionmentioning

confidence: 63%

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Shimada

Kudo

Akase

et al. 2008

Biological & Pharmaceutical Bulletin

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Visceral fat accumulation induces insulin resistance, abnormal glucose metabolism, abnormal lipid metabolism and hypertension. Furthermore, even when these individual diseases are present in only a mild form, if more than one of these diseases is present, this may induce development of arteriosclerosis or ischemic cardiovascular diseases.1,2) For these reasons, it is important that some form of medical therapy including exercise and diet therapy be devised to prevent the development of obesity and various metabolic disorders.Bofutsushosan, a traditional Japanese herbal medicine comprising 18 crude drugs (Table 1), has been an effective treatment for obesity, constipation and hypertension. Bofutsushosan was shown to reduce body weight and improve impaired glucose tolerance in a clinical trial.3) In addition, several pharmacological studies have reported on its ability to counter obesity, [4][5][6][7][8] fatty liver, 9,10) and arteriosclerotic diseases. 11)In the present study, we investigated the preventive effects of Bofutsushosan on various disease states (diabetes, hyperlipidemia, hypertension and diabetic peripheral neuropathy) that accompany metabolic disorders, focusing on visceral fat accumulation using a model animal, TSOD (Tsumura, Suzuki, Obese, Diabetes) mice, which are known to develop disease states similar to human metabolic disorders including glucose intolerance, hyperlipidemia, hypertension, hyperinsulinemia and peripheral neuropathy. [12][13][14] MATERIALS AND METHODS Experimental AnimalsWe used male TSOD mice aged 3 weeks. As a control animal, male TSNO (Tsumura, Suzuki, Non-Obesity) mice 12) aged 3 weeks were used as these animals do not develop obesity and various metabolic disorders. All mice were obtained from the Institute for Animal Reproduction (Ibaragi Prefecture). The animals were housed in an animal room under the following conditions: room temperature of 23Ϯ2°C, relative humidity of 55Ϯ10% and 12 h of light per day. In the 1-week acclimation period, the animals were given ad libitum powder feed MF (Oriental Yeast Co., Ltd.) and water. Following this period, the powder feed was switched to the study feed containing the test drug, and the animals were kept for further 8 weeks. We certify that all ap- Clinical and Biomedical Sciences, Showa Pharmaceutical University; 3-3165 Higashi-tamagawagakuen, Machida, Tokyo 142-8501, Japan. Received January 23, 2008; accepted May 7, 2008; published online May 8, 2008 Visceral fat accumulation has been reported as the most important risk factor for the development of various metabolic disorders. In this study, the preventive effects of Bofutsushosan, a Japanese Kampo preparation, on obesity and various metabolic disorders were investigated focusing on visceral fat accumulation using Tsumura, Suzuki, Obese, Diabetes (TSOD) mice, which showed significant accumulation of visceral fat, and developed metabolic disorders including glucose intolerance, hyperlipidemia, hypertension and hyperinsulinemia. At 2 months after initiation of the study, the c...

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Section: Tionmentioning

confidence: 63%

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Shimada

Kudo

Akase

et al. 2008

Biological & Pharmaceutical Bulletin

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“…Thus far, it has been reported that blood TG levels in TSOD mice are greater than those in TSNO mice. 29,33 These data suggest that the hepatic dysfunction observed early in time is associated with the development of fatty liver disease in TSOD mice. In the visceral fat, enlargement of adipocytes, perivascular and pericapsular CD8-positive lymphoid aggregations, and CLSs with macrophage aggregation were observed after 4 months of age.…”

Section: Discussionmentioning

confidence: 75%

“…The major genetic determinants of blood glucose levels, insulin levels, and body weight were identified on chromosome 11, chromosome 2, and chromosome 1 and 2, respectively. In addition, Iizuka et al 29 reported that TSOD mice showed spontaneous non-insulin-dependent diabetes mellitus with severe motor neuropathy and hypertrophy of pancreatic islets owing to proliferation and swelling of b cells. On the other hand, morphological evidence found in the livers of male TSOD mice has not yet been investigated in detail.…”

Section: Discussionmentioning

confidence: 99%

Spontaneous onset of nonalcoholic steatohepatitis and hepatocellular carcinoma in a mouse model of metabolic syndrome

Nishida

Tsuneyama

Fujimoto

et al. 2013

Laboratory Investigation

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Metabolic syndrome is a worldwide healthcare issue and a dominant risk factor for the development of incurable diseases that affect the entire body. The hepatic manifestations of this syndrome include nonalcoholic fatty liver disease (NAFLD) and its progressive variant nonalcoholic steatohepatitis (NASH). The basic pathogenesis of NAFLD/NASH remains controversial because it is difficult to clarify the disease process of NASH on the basis of metabolic syndrome alone. To determine the pathogenesis and effective treatment, an excellent animal model of NASH is required. Tsumura Suzuki obese diabetes (TSOD) male mice spontaneously develop diabetes mellitus, obesity, glucosuria, hyperglycemia, and hyperinsulinemia without any special treatments such as gene manipulation. In this study, we examined the histopathological characteristics of visceral fat and liver of 56 male TSOD mice aged 4-17 months and 9 male Tsumura Suzuki non-obesity (control) mice aged 6-12 months. In the visceral fat, enlargement of adipocytes and perivascular and pericapsular CD8-positive lymphoid aggregation were observed in 4-month-old mice. Abnormal expression of tumor necrosis factor-a, interleukin-6, and lipid peroxidation endo products was observed in macrophages. In the liver, microvesicular steatosis, hepatocellular ballooning, and Mallory bodies were observed in 4-month-old mice, with severity worsening with increasing time. These pathological findings in the liver mimic those seen in patients with NASH. Interestingly, small liver nodules with high cellularity and absence of portal tracts were frequently observed after 12 months. Most of them showed nuclear and structural atypia, and mimicked human hepatocellular carcinoma. The degree of steatosis in the non-tumor portions of the liver improved when the liver nodules developed. These findings were not observed in control mice. Here, we report that TSOD male mice spontaneously developed NAFLD without any special treatment, and that these mice are a valuable model for assessing NASH and NASH carcinogenesis owing to metabolic syndrome.

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“…In histopathological analyses in kidney, glomerular lesions, such as GBM thickening and mesangial area enlargement, are observed after 18 weeks of age [40]. The sensory neuropathy is observed after 12 months of age, and the motor neuropathy is also shown after 14 months of age.…”

Section: Tsumura Suzuki Obese Diabetics (Tsod) Mousementioning

confidence: 98%