Usefulness of Obese Animal Models in Antiobesity Drug Development

Obese animal models have played key roles to elucidate the etiology of obesity and develop antiobesity drugs. In the first half of the chapter, we introduce the characteristics of obese animal models. In the second half of the chapter, we show the results of pharmacological studies using obese animal models for new antiobesity drugs

The Diagnosis and Treatment of Early-Stage Colorectal Cancer

The introduction of colorectal endoscopic submucosal dissection (ESD) has expanded the applications for endoscopic treatment; as a result, lesions with low metastatic potential can be treated endoscopically regardless of the lesion size. The most attractive feature of ESD is the achievement of en bloc resection with a lower local recurrence rate in comparison to that of endoscopic piecemeal mucosal resection. However, in case of gastric cancers, ESD is not as widely applied to the treatment of colorectal neoplasms because of its technical difficulty, longer procedural time, and increased perforation risk. In the movement toward diversified endoscopic treatment strategies for superficial colorectal neoplasms, endoscopists who begin to perform ESD need to recognize the indications of ESD, as well as the technical issues and associated complications of this procedure

Single Diabetic QTL Derived from OLETF Rat Is a Sufficient Agent for Severe Diabetic Phenotype in Combination with Leptin-Signaling Deficiency

Obesity has been considered one of the leading causative agents for diseases such as type 2 diabetes, stroke, and heart attack. Due to their complex etiology, establishing auseful animal model is increasingly crucial for better molecular understanding of how obesity influences on disease development. OLETF rat is a spontaneous model of type 2 diabetes. We mapped 14 hyperglycemia QTLs in the genome of the OLETF rat and subsequently generated a panel of congenic strains each possessing OB-R mutation in F344 genetic background. Here we show that one of the loci, Nidd2/of, is highly responsive to obesity. When leptin receptor mutation is introgressed into the Nidd2/of congenic strain, the rat showed hyperglycemia equivalent to that of the parental OLETF rat. This suggests that the Nidd2/of locus has a strong genetic interaction with leptin signaling pathway. Furthermore, when another hyperglycemia QTL Nidd1/of is additionally combined, the strain developed overt diabetes. A single QTL dissected out in spontaneous model normally exerts only mild effect on the quantitative trait, which makes it difficult to clone the gene. Our new model may help not only to identify the causative gene but also to investigate how obesity interacts with a QTL to regulate diabetic traits

The sphingosine-1-phosphate receptor modulator, FTY720, prevents the incidence of diabetes in Spontaneously Diabetic Torii rats

The sphingosine-1-phosphate (S1P) receptor modulator regulates lymphocyte trafficking, resulting in its depletion from circulation, which ultimately causes immunosuppression. In this study, we investigated the preventive effect of fingolimod (FTY720) in the non-obese type 2 diabetic model, Spontaneously Diabetic Torii (SDT) rats. The S1P receptor modulator, FTY720 (0.3 mg/kg p.o.), was administered for 12 weeks to SDT rats from 5 to 17 weeks of age. Based on our findings, FTY720 could suppress the incidence of diabetes in SDT rats. Further, glucose intolerance was improved in FTY720-treated SDT rats at 14 weeks of age. Based on the haematological and histological analyses performed at 17 to 18 weeks of age, a decrease in lymphocytes and monocytes in the peripheral blood and a decrease in lymphocyte and atrophy in spleen occurred in the FTY720-treated SDT rats. Furthermore, the pancreatic changes, such as inflammation, atrophy, and fibrosis in islets observed in SDT rats were improved by FTY720 treatment. These findings suggest that the immunomodulatory effects of FTY720 reduced the pancreatic lesion in SDT rats, thereby demonstrating its preventive effect against diabetes. The development of diabetes in SDT rats is related to disorders of the immune system. However, the S1P receptor modulator may be useful for treating type 2 diabetes

Analysis of haemodynamics and angiogenic response to ischaemia in the obese type 2 diabetic model Spontaneously Diabetic Torii <i>Lepr^fa</i> (SDT fatty) rats

Peripheral artery disease (PAD) is defined as peripheral blood flow impairment, especially in the legs, caused by atherosclerotic stenosis. The disease decreases quality of life because of intermittent claudication or necrosis of the leg. The hindlimb ischaemia model, in which ischaemia is induced by femoral artery ligation, is often utilized as a PAD model. In the hindlimb ischaemia model, nonmetabolic syndrome animals are mainly used. In this study, we investigated the usefulness of Spontaneously Diabetic Torii Leprfa (SDT fatty) rats, a new model for obese type 2 diabetes, as a new PAD animal model. We found that hindlimb blood flow in SDT fatty rats was significantly lower than that in Sprague–Dawley (SD) rats under nonischaemic conditions. Furthermore, SDT fatty rats showed a significantly higher plasma nitrogen oxide level, shorter prothrombin time, and shorter activated partial thromboplastin time than SD rats. In addition, we found that the change in blood flow 7 days after induction of hindlimb ischaemia and the number of Von Willebrand factor‐positive vessels in gastrocnemius muscles were significantly lower in SDT fatty rats than in SD rats. These results suggest that excess production of reactive oxygen species and coagulation activation could be involved in lower blood flow in non‐ischaemic rats and that decreased angiogenesis could be involved in the poor recovery of blood flow in SDT fatty rats with hindlimb ischaemia. Taken together, our results suggest that SDT fatty rats might be useful as a new model for PAD with metabolic syndrome

Replicated association of the single nucleotide polymorphism in EDG1 with marbling in three general populations of Japanese Black beef cattle

<p>Abstract</p> <p>Background</p> <p>Marbling, defined by the amount and the distribution of intramuscular fat and measured as beef marbling score (BMS), is an economically important trait of beef cattle in Japan. We recently reported that a single nucleotide polymorphism (SNP), namely, <it>c.-312A>G</it>, in the <it>endothelial differentiation</it>, <it>sphingolipid G-protein-coupled receptor</it>, <it>1 </it>(<it>EDG1</it>) gene was associated with the BMS level in the Japanese Black beef cattle population of Oita prefecture, with the <it>G </it>allele being associated with a high level of the BMS. Thus, the <it>c.-312A>G </it>SNP seems to be a candidate marker for marker-assisted selection. In this study, we investigated whether this association could be replicated in 3 other independent Japanese Black cattle populations and analyzed the effect of the SNP genotypes on the carcass traits other than the BMS.</p> <p>Findings</p> <p>Statistically significant differences in the BMS level were detected among the genotypes of the <it>c.-312A>G </it>SNP in the Japanese black beef cattle populations of Miyazaki (<it>P </it>= 0.0377) and Nagasaki (<it>P </it>= 0.0012) prefectures, and marginal difference was detected in the Kagoshima prefecture population (<it>P </it>= 0.0786). The <it>G </it>allele in the SNP was associated with an increase in the BMS level.</p> <p>The <it>G </it>allele also seemed to have a favorable influence, if any, on the carcass weight, rib eye area and rib thickness of the cattle populations.</p> <p>Conclusions</p> <p>These findings suggest that the association of the <it>c.-312A>G </it>SNP with the BMS level in the Japanese Black beef cattle population was replicated in other beef cattle populations, and revealed favorable effects of the <it>G </it>allele on the beef productivity in the general Japanese Black beef cattle population. Thus, we concluded that the <it>c.-312A>G </it>SNP is useful for effective marker-assisted selection to increase the BMS level in Japanese Black beef cattle.</p

Genetic Dissection of Complex Genetic Factor Involved in NIDDM of OLETF Rat

The Otsuka Long-Evans Tokushima Fatty (OLETF) rat is an animal model for obese-type, noninsulin-dependent diabetes mellitus (NIDDM) in humans. NIDDM in this rat model was shown to be regulated by multiple genes. We have identified 14 quantitative trait loci (QTLs) responsible for NIDDM (Nidd1-14/of) on chromosomes 1, 5, 7, 8, 9, 11, 12, 14, 16, and 17 by a whole genome search in 160 F2 progenies obtained by mating the OLETF and the F344 rats. Among these loci, two QTLs, Nidd1 and 2/of, were declared significant loci at a genome-wide level. Nidd3, 8, 9, and 13/of exhibited heterosis: heterozygotes showing significantly higher glucose levels than OLETF or F344 homozygotes. We also found evidence for interaction (epistasis) between Nidd1/of and Nidd2/of, between Nidd1/of and Nidd10/of, between Nidd2/of and Nidd8/of, and between Nidd2/of and Nidd14/of. Furthermore, Nidd6 and 11/of showed linkage with body weight, and Nidd1, 2, 8, 9, 10, and 12/of had an interaction with body weight. These indicated that NIDDM in the OLETF would have a higher degree of genetic complexity. We suggest several interesting candidate genes located in rat genomic regions for Nidd1-14/of or the syntenic regions in human genome

Permanent magnet bearings for horizontal- and vertical-shaft machines: A comparative study

Two types of magnetic bearing systems employing permanent magnets to be used for vertical-shaft and horizontal-shaft machines, respectively, have been designed and fabricated in our laboratory. In this article we report a comparative evaluation of (i) the permanent magnet configuration and its effect on radial disturbance attenuation, (ii) magnetic losses and their effect on energy storage, and (iii) the off-state position of the rotor magnet in two types of bearing systems. Experimental results are presented. © 1999 American Institute of Physics

Proteomic analysis of a diabetic congenic rat identified age-dependent alteration of an acidic protein

Proteomic analysis was performed in an attempt to identify a gene responsible for the expression of type 2 diabetes using a congenic rat, F.O-Nidd2/of, which possesses a single hyperglycemic QTL locus derived from the diabetic OLETF (Otsuka Long-Evans Tokushima Fatty) rat. Since the genetic difference between the congenic and its host strain, the F344 rat, is limited to the introgressed segment of 38 cM or ca. 2% of the rat whole genome, any discordant protein spots on two dimensional polyacrylamid gel electrophoresis (2D PAGE) will be considered strong candidate genes of this locus. Here we analyzed ca. one thousand protein spots in three different tissue types, liver, muscle and pancreas at 10, 20 and 30 weeks of age, we found that an acidic protein of 55 kD in muscle tissue shifts towards acidic end in an age dependent fashion in the congenic strain. However, the shift was not observed in the control rat, which is intriguing because the timing of the shift corresponds to the age at which hyperglycemia begins in the congenic. Future biochemical analysis should aid in elucidating the molecular mechanisms of glucose metabolism