Insulin resistance and low sympathetic nerve activity in the Tsumura Suzuki obese diabetic mouse: a new model of spontaneous type 2 diabetes mellitus and obesity

Takahashi, Akira; Tabuchi, Masahiro; Suzuki, Wataru; Iizuka, Satoshi; Nagata, Mitsuru; Ikeya, Yukinobu; Takeda, Susumu; Shimada, Tsutomu; Aburada, Masaki

doi:10.1016/j.metabol.2006.08.007

Cited by 41 publications

(36 citation statements)

References 33 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%

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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%

“…Blood glucose, total cholesterol (TC), triglyceride (TG) and insulin were measured using commercial assay kit according to our previous method. 14) Tumor necrosis factor-a (TNF-a) were measured using TNF-a ELISA kit (COSMO BIO CO., LTD., Tokyo).…”

Section: Test Drugmentioning

confidence: 99%

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Shimada

Kudo

Akase

et al. 2008

Biological & Pharmaceutical Bulletin

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“…10,11 Tsumura Suzuki obese diabetes (TSOD) mice are novel polygenic models of spontaneous type-2 diabetes mellitus that develop moderate degrees of obesity, especially apparent in animals more than 11 weeks of age. 12,13 Unlike MSG mice, male TSOD mice showed glycosuria, hyperglycemia, and hyperinsulinemia without any special treatments. 14 In addition, the pathological characteristics of these mice were also examined under severe circumstances because steatohepatitis and liver nodules were frequently observed in male TSOD mice during preliminary examination.…”

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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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“…5) The insulin-stimulated uptake of 2-[ 3 H] deoxyglucose and translocation of glucose transporter-4 protein were impaired in skeletal muscle and adipose tissues in TSOD mice. 6,7) Thus, TSOD mice have both increased resistance to insulin and decreased insulin secretion in response to glucose. Genome-wide screening in TSOD mouse for loci linked to body weight and glucose homeostasis indicated that obesity and hyperglycemia are closely associated with three quantitative trait loci; Nidd4 on chromosome 11 interacts with the glucose level, Nidd5 on chromosome 2 interacts with both the insulin level and body weight and Nidd6 on chromosome 1 interacts with body weight.…”

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Possible Involvement of Hypothalamic Nucleobindin-2 in Hyperphagic Feeding in Tsumura Suzuki Obese Diabetes Mice

Miyata

Yamada

Kawada

2012

Biological & Pharmaceutical Bulletin

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The aim of this study was to clarify the hypothalamic neuropeptides that are associated with hyperphagic feeding in Tsumura Suzuki Obese Diabetes (TSOD) mice, a model of type 2 diabetes with polygenic abnormalities. TSOD mice showed an increase in body weight and hyperleptinemia from 1 month of age and hyperphagic feeding, hyperglycemia, hyperlipidemia and hyperinsulinemia from 3 to 12 months of age compared with age-matched non-diabetic control Tsumura Suzuki Non Obesity (TSNO) mice. The mRNA level of nucleobindin-2 (NUCB2), the precursor of the anorexigenic neuropeptide nesfatin-1, was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice from 3 to 12 months of age. The protein level of NUCB2 was significantly decreased in the hypothalamus of TSOD mice compared with that in TSNO mice at 3 months of age. The mRNA levels of galanin, melanin-concentrating hormone, neuropeptide Y, and pro-opiomelanocortin were significantly changed in the hypothalamus in TSOD mice at several time points. Another model of type 2 diabetes, db/db mice, which is a mutant mouse that lacks a functional leptin receptor, showed hyperphagic feeding but no change in hypothalamic NUCB2 mRNA compared with non-diabetic control db/ mice. The results suggest that the disrupted control of hypothalamic NUCB2-mediated signaling may contribute to hyperphagic feeding in TSOD mice. In addition, the mechanism for the development of hyperphagic feeding in TSOD mice is different than that in db/db mice. Key words hyperphagic feeding; nucleobindin-2; hypothalamus; obesity; diabetesThe world-wide prevalence of obesity and type 2 diabetes mellitus (T2DM) is increasing, and genetic analyses in humans are difficult since these conditions are also associated with environmental factors. Therefore, model animals are highly useful in biomedical studies and may lead to new insights into human obesity and T2DM.1) Tsumura Suzuki Obese Diabetes (TSOD) mouse has been recently established as a model animal of obese T2DM by the selective breeding of ddY mice that show both obesity and urinary glucose.2) The adiposity and significantly higher body mass index in TSOD mice compared to those in non-diabetic control Tsumura Suzuki Non Obesity (TSNO) mice are detected as early as 4 weeks of age, and are maintained until at least 18 months of age.3,4) TSOD mice showed a high level of blood glucose after the intraperitoneal injection of glucose and a blunted glucosestimulated insulin secretion compared with TSNO mice.5) In addition, the hypoglycemic response to insulin treatment in TSOD mice was blunted compared to that in TSNO mice. 5)The insulin-stimulated uptake of 2-[ 3 H] deoxyglucose and translocation of glucose transporter-4 protein were impaired in skeletal muscle and adipose tissues in TSOD mice.6,7) Thus, TSOD mice have both increased resistance to insulin and decreased insulin secretion in response to glucose. Genome-wide screening in TSOD mouse for loci linked to body weight and glucose homeostasis indicated that obesity and hyperg...

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Insulin resistance and low sympathetic nerve activity in the Tsumura Suzuki obese diabetic mouse: a new model of spontaneous type 2 diabetes mellitus and obesity

Cited by 41 publications

References 33 publications

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

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

Possible Involvement of Hypothalamic Nucleobindin-2 in Hyperphagic Feeding in Tsumura Suzuki Obese Diabetes Mice

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