Genetic analysis of obese diabetes in the TSOD mouse.

Hirayama, Isao; Yi, Zhaohong; Izumi, Sumiko; Arai, Ichiro; Suzuki, Wataru; Nagamachi, Yukio; Kuwano, Hiroyuki; Takeuchi, Toshiyuki; Izumi, Tetsuro

doi:10.2337/diabetes.48.5.1183

Cited by 130 publications

(91 citation statements)

References 8 publications

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“…Because plasma insulin concentrations were not altered, the Akita-derived alleles at Dbm4 appeared to confer insulin resistance that led to fasting hyperglycemia and hyperglycemia in response to glucose administration. Similar QTL analysis results were reported for TSOD mice, a T2D model established from the outbred ddY strain (Hirayama et al 1999). TSOD mice showed a suggestive linkage between plasma glucose concentrations and D15Mit63, relatively close to our LOD score peak at D15Mit233, with a recombination distance of about 0.3 cM.…”

Section: Discussionsupporting

confidence: 65%

“…Thus, in the region near D11Mit254, the Akita-derived alleles apparently induced insulin resistance in nondiabetic mice. A similar LOD score plot with respect to plasma glucose concentration was reported for the TSOD diabetic mouse (Hirayama et al 1999). This TSOD mouse locus (D11Mit128), named Nidd4, is separated from D11Mit254 by about only 1.0 Mb, which suggests the presence of a potential genetic modifier of T2D around Dbm2.…”

Section: Discussionmentioning

confidence: 67%

“…Quantitative trait loci (QTL) analysis has been applied to several rodent models of T2D to identify chromosomal loci for genetic modifiers. QTL analysis of obese animal models of T2D such as the OLETF rat (Kim et al 1998), the KKA y mouse (Suto et al 1998a, b), the NZO mouse (Reifsnyder et al 2000; Taylor et al 2001), and the TSOD mouse (Hirayama et al 1999), as well as nonobese animal T2D models such as the GK rat (Galli et al 1996; Gauguier et al 1996) and the SDT rat (Masuyama et al 2003), have identified QTLs that influence factors such as plasma glucose and insulin concentrations, body weight (BW), and fat weight. While a number of genes have been implicated in monogenic etiologies for T2D from animal models of diabetes, including ob, db, Tub, A y , and Agrp, none of these genes appears to explain the genetic background of most T2D cases in humans.…”

Section: Introductionmentioning

confidence: 99%

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Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice

et al. 2006

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Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

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Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice

et al. 2006

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“…14 Miura et al 12 reported that the insulinstimulated translocation of glucose transporter (GLUT)-4 from low-density microsomal membranes to plasma membranes was reduced in both the skeletal muscle and adipose tissue of TSOD mice and that the reduced insulin sensitivity was presumably owing to this impaired GLUT-4 translocation in both the skeletal muscle and adipocytes. Using a genome-wide screen for loci linked to glucose homeostasis and body weight in TSOD mice, Hirayama et al 28 mapped three quantitative trait loci involved in diabetes mellitus. 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.…”

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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“…16,17) In our experiments, the TSOD mice showed significant accumulation of visceral fat, and developed metabolic disorders including glucose intolerance, hyperlipidemia, hypertension, hyperinsulinemia and peripheral neuropathy. This was in sharp contrast to the TSNO control group.…”

Section: Tionmentioning

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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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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Genetic analysis of obese diabetes in the TSOD mouse.

Cited by 130 publications

References 8 publications

Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice

Diabetic modifier QTLs identified in F2 intercrosses between Akita and A/J mice

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

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

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