Chromosome 2 locus Nidd5 has a potent effect on adiposity in the TSOD mouse

Mizutani, Shin; Gomi, Hiroshi; Hirayama, Isao; Izumi, Tetsuro

doi:10.1007/s00335-005-0161-5

Cited by 29 publications

(40 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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: 68%

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Shimada

Kudo

Akase

et al. 2008

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

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...

show abstract

Section: Tionmentioning

confidence: 68%

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Shimada

Kudo

Akase

et al. 2008

Biological & Pharmaceutical Bulletin

View full text Add to dashboard Cite

show abstract

“…A previous study mapped an overlapping QTL Mob that confers increased adiposity in F2 (C57BL6/J × CAST/Ei) mice inheriting chromosomal regions from B6 and lower adiposity in mice inheriting the CAST chromosomal region ( 39 , 40 ). Conversely, BALB/c alleles of Nidd5 on chromosome 2 have been shown to decrease obesity in Tsumura Suzuki obese diabetic (TSOD) mice ( 41 ). Underlying mechanisms were not described; however, analysis of lipolysis in those models would indicate whether a common locus was involved in obesity resistance.…”

Section: Discussionmentioning

confidence: 99%

Genetic control of ATGL-mediated lipolysis modulates adipose triglyceride stores in leptin-deficient mice

Marcelin

Liu

et al. 2012

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org and genetic factors ( 4 ). Because of the increasing prevalence of obesity worldwide, identifi cation of tissues and molecules to target should be a high priority to expand the list of potential therapeutic modalities ( 5 ).The adipose tissue-derived hormone leptin and its downstream signaling pathways play a central role in obesity, as leptin or leptin receptor defi ciency provokes morbid obesity ( 6-9 ). In addition, leptin resistance has been implicated in obesity ontogenesis ( 10 ). Most leptin receptor-mediated pathways are active mainly within the central nervous system ( 11 ), principally localized within the hypothalamus, to decrease food intake, increase energy expenditure, inhibit lipogenesis, and maintain normal glucose homeostasis ( 12 ). Consistent with these pleiotropic functions of leptin, studies on the regulation of body composition has centered upon leptin and the mechanisms mediated by its receptor. Alternatively, identifying pathways that regulate fat mass independently of leptin would be of interest in the design of therapies aimed to combat obesity.We and others have reported that mouse inbred strains carry specifi c sets of genetic variants promoting signifi cant variation in the expression of the leptin-defi cient phenotype ( 13,14 ). Thus, regulatory pathways independent of leptin can control body composition and metabolism, and mapping of quantitative trait loci (QTL) using leptindefi cient inbred mice is an ideal method of identifying such pathways. In this setting, leptin-defi cient mice on a BALB/c genetic background have reduced adiposity when compared with ob / ob mice of the prototypic C57BL/6J strain ( 15 ). However, the functional and genetic bases for these variant phenotypes were not thoroughly characterized. Here, we performed a comprehensive analysis of the physiological mechanism(s) that limit body fat content in Abstract Dissecting the genetics of complex traits such as obesity allows the identifi cation of causal genes for disease. Here, we show that the BALB/c mouse strain carries genetic variants that confer resistance to obesity induced by leptindefi ciency or a high-fat diet (HFD). We set out to identify the physiological and genetic bases underlying this phenotype. When compared with C57BL6/J ob/ob mice (B6), BALB/c ob/ob mice exhibited decreased food intake, increased thermogenic capacity, and improved fat catabolism, each of which can potentially modify obesity. Interestingly, analysis of F1 ob/ob (progeny of B6 ob/+ × BALB/c ob+ ) mice revealed that obesity resistance in BALB/c ob/ob mice principally relied upon improved fat mobilization. This was mechanistically explained by increased adipose triglyceride lipase (ATGL) content in adipocytes, along with increased lipolysis and fatty acid oxidation. We conducted a genomewide scan and defi ned a quantitative trait locus (QTL) on chromosome 2. BALB/c alleles on chromosome 2 not only associated with the obesity resistance phenotype but also supported increased ATG...

show abstract

“…The effects of a sole QTL have been verified using congenic mice (Mizutani et al, 2006;Stoehr et al, 2004), but the responsible gene has not been identified for a long time. Recently, the novel diabetic modifier gene Sorcs1 was identified from QTL on chromosome 19 using sub-congenic as well as congenic mice derived from C57BL/6 and BTBR strains (Clee et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

<i>Bhlhe40</i>, a potential diabetic modifier gene on <i>Dbm1</i> locus, negatively controls myocyte fatty acid oxidation

et al. 2012

View full text Add to dashboard Cite

We have previously identified significant quantitative trait loci (QTL) Dbm1 (diabetic modifier QTL 1) on chromosome 6, affecting plasma glucose and insulin concentrations and body weight on F 2 progeny of hypoinsulinemic diabetic Akita mice, with the heterozygous Ins2 gene Cys96Tyr mutation, and non-diabetic A/J mice. To discover diabetic modifier genes on Dbm1, we constructed congenic strain for Dbm1 using the Akita allele as donor in A/J allele genetic background, and compared diabetes-related phenotypes to control mice. The homozygote for Akita allele of Dbm1 was associated with lower plasma glucose concentrations in glucose tolerance test (GTT) in the hypoinsulinemic condition derived from the Ins2 mutation and lower plasma insulin concentrations and body weight in the normoinsulinemic condition without the Ins2 mutation than the homozygote for A/J allele, as we performed QTL analysis on F 2 intercross mice. The Akita allele also decreased the epididymal white adipose tissue (EWAT) weight. According to the analysis of sub-congenic strains, we narrowed down the responsible diabetic modifier region to 9 Mb. As fourteen candidate genes exist in this region, we analyzed genomic variants of these genes and gene expression in the muscle, liver, and EWAT and identified that Bhlhe40 gene expression in muscle is decreased in congenic mice. According to the in vitro functional analyses, Bhlhe40 was shown to negatively control fatty acid oxidation in cultured myocyte. Based on these, we conclude that Bhlhe40 is a possible candidate diabetic modifier gene responsible for Dbm1 locus affecting diabetes and/or obesity through negatively controlling fatty acid oxidation in muscle.

show abstract

Chromosome 2 locus Nidd5 has a potent effect on adiposity in the TSOD mouse

Cited by 29 publications

References 35 publications

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Preventive Effects of Bofutsushosan on Obesity and Various Metabolic Disorders

Genetic control of ATGL-mediated lipolysis modulates adipose triglyceride stores in leptin-deficient mice

<i>Bhlhe40</i>, a potential diabetic modifier gene on <i>Dbm1</i> locus, negatively controls myocyte fatty acid oxidation

Contact Info

Product

Resources

About