Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14

Babaya, Naru; Fujisawa, Tomomi; Nojima, K.; Itoi-Babaya, Michiko; Yamaji, Kazuya; Yamada, Kazunori; Kobayashi, Misato; Ueda, Hironori; Hiromine, Yoshihisa; Noso, Shinsuke; Ikegami, Hiroshi

doi:10.1007/s00125-010-1737-5

Cited by 19 publications

(45 citation statements)

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“…The food intake and body weight of the mice in both groups were determined twice weekly. The BMI value was calculated as body weight (grams) divided by the square of the anal-nasal length (centimeters) (15). The body composition was analyzed using EchoMRI-100 from Echo Medical Systems (Houston, TX).…”

Section: Animals and Animal Treatmentsmentioning

confidence: 99%

The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

Gao

Liu

2012

AAPS J

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Abstract. The effect of activation of liver X receptor by N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)ethyl]phenyl] benzenesulfonamide (T0901317) on high fat diet (HFD)-induced obesity and insulin resistance was examined in C57BL/6 mice. When on HFD continuously for 10 weeks, C57BL/6 mice became obese with an average body weight of 42 g, insulin resistant, and glucose intolerant. Twice weekly intraperitoneal injections of T0901317 at 50 mg/kg in animals on the same diet completely blocked obesity development, obesity-associated insulin resistance, and glucose intolerance. Quantitative real-time PCR analysis showed that T0901317-treated animals had significantly higher mRNA levels of genes involved in energy metabolism, including Ucp-1, Pgc1a, Pgc1b, Cpt1a, Cpt1b, Acadm, Acadl, Aox, and Ehhadh. Transcription activation of Cyp7a1, Srebp-1c, Fas, Scd-1, and Acc-1 genes was also seen in T0901317-treated animals. T0901317 treatment induced reversible aggregation of lipids in the liver. These results suggest that liver X receptor could be a potential target for prevention of obesity and obesity-associated insulin resistance.

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Section: Animals and Animal Treatmentsmentioning

confidence: 99%

The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

Gao

Liu

2012

AAPS J

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“…To obtain direct evidence that Nidd2n on Chr 14 confers susceptibility to diabetes, we constructed consomic C3H-Chr 14 NSY mice, in which the NSY-derived whole Chr 14 was introgressed onto the genetic background of control C3H mice [8], because the regions showing significant linkage with Nidd2n were broad (peak region near D14Mit5 ) [6]. C3H-Chr 14 NSY mice showed significantly higher blood glucose levels than those in C3H mice, indicating that Chr 14 harbors a locus for hyperglycemia.…”

Section: Introductionmentioning

confidence: 99%

Genetic dissection of susceptibility genes for diabetes and related phenotypes on mouse chromosome 14 by means of congenic strains

et al. 2014

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BackgroundA susceptibility locus, Nidd2n, for type 2 diabetes has been mapped to mouse chromosome 14 (Chr 14) and confirmed using the consomic strain (C3H-Chr 14NSY) of the Nagoya-Shibata-Yasuda (NSY) mouse, an animal model of spontaneous type 2 diabetes. The aim of this study was to localize and characterize Nidd2n.ResultsWe constructed two novel congenic strains homozygous for different segments of NSY-Chr 14 on the control C3H/HeNcrj (C3H) background: R1 (C3H.NSY-(D14Mit206-D14Mit5)) possesses the proximal and middle segment, and R2 (C3H.NSY-(D14Mit206-D14Mit186)) possesses the most proximal segment of NSY-Chr 14. Diabetes-related phenotypes were studied in comparison with those of consomic C3H-Chr 14NSY (R0) and parental NSY and C3H strains. Congenic R1 and R2 showed significantly higher post-challenge glucose than that in C3H mice. Fasting glucose, in contrast, was significantly lower in R1 and R2 than in C3H mice. Insulin sensitivity was significantly impaired in R1 and R2 compared to C3H mice. R2 showed significantly higher body weight and fat-pad weight than those in C3H and R1. Leptin level was significantly higher in R0, R1 and R2 than in C3H mice, with R2 showing the highest level, similar to that in NSY mice. Serum adiponectin level was significantly lower in R0, R1 and R2 than in C3H mice, while it was significantly higher in NSY than in C3H mice.ConclusionsThese data indicate that Chr 14 harbors multiple genes for diabetes-related phenotypes. The original Nidd2n, which is located in the middle region of Chr 14, was divided into two segments; Nidd2.1n in proximal Chr 14 and Nidd2.2n in distal Chr 14. Nidd2.1n contributes to post-challenge hyperglycemia, insulin resistance and adiposity. Nidd2.2n contributes to fasting as well as post-challenge hyperglycemia and insulin resistance. Adp1n, which contributes to decreased adiposity and increased insulin sensitivity, rather than a diabetogenic gene, was mapped in the middle segment.

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“…Similar gradual changes were shown in the selection index traits of NSY mouse [2] and SHR rat [9] during the selective breeding. As a consequence of selective breeding, several independent genetic loci containing genes regulating their metabolic impairments were identified by genetic linkage analyses in the established animal models [10][11][12]. Hence, the gradual changes in the metabolic phenotypes shown in the present study suggest that the genetic loci associated with the quantitative traits have been selectively enriched in SDG-P and SDG-R.…”

Section: Discussionmentioning

confidence: 58%

Transgenerational changes of metabolic phenotypes in two selectively bred mouse colonies for different susceptibilities to diet-induced glucose intolerance

et al. 2015

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Selective breeding is a powerful approach to investigate genotype-phenotype interactions in complex traits involving multiple genes. The polygenic background of selectively bred animal models can mimic the polygenic etiology of lifestyle-related diseases, such as type 2 diabetes and obesity. For instance, Goto-Kakizaki (GK) rat [1] and NagoyaShibata-Yasuda (NSY) mouse [2], both of which were selectively bred for hyperglycemia, are useful models to investigate the pathogenesis of type 2 diabetes. Levin et al. [3] performed repetitive selective breeding for diet-induced obesity-prone (DIO) and -resistant (DR) traits in Sprague-Dawley rats. Although body weight was the sole criterion for the selection, Transgenerational changes of metabolic phenotypes in two selectively bred mouse colonies for different susceptibilities to diet-induced glucose intolerance Mototsugu Nagao, Akira Asai, Hitoshi Sugihara and Shinichi Oikawa Department of Endocrinology, Diabetes and Metabolism, Graduate School of Medicine, Nippon Medical School, Japan Abstract. We recently established 2 mouse lines with different susceptibilities (prone and resistant) to high-fat diet (HFD)-induced glucose intolerance by selective breeding (designated selectively bred diet-induced glucose intolerance-prone [SDG-P] and -resistant [SDG-R], respectively). In the present study, we analyzed transgenerational changes in metabolic phenotypes in these 2 mouse colonies to explore how the distinct phenotypes have emerged through the repetitive selection. Using C57BL/6, C3H, and AKR as background strains, mice showing inferior and superior glucose tolerance after HFD feeding were selected and bred repetitively over 20 generations to produce SDG-P and SDG-R, respectively. In addition to the blood glucose levels, HFD intake and body weight were also measured over the selective breeding period. As the generations proceeded, SDG-P mice became more susceptible to HFD-induced glucose intolerance and body weight gain, whereas SDG-R mice had gradually reduced HFD intake. The differences in fasting and post-glucose challenge blood glucose levels, body weight, and HFD intake became more evident between the 2 colonies through the selective breeding, mainly due to the HFD-induced glucose metabolism impairment and body weight gain in SDG-P mice and the reduction of HFD intake in SDG-R mice. These transgenerational changes in the metabolic phenotypes suggest that the genetic loci associated with the quantitative traits have been selectively enriched in SDG-P and SDG-R.Key words: High-fat diet, Type 2 diabetes, Selective breeding, Feeding behavior DIO rats also exhibited diet-induced hyperglycemia compared with DR rats [3,4]. Similarly, other metabolic traits often accompany the selection criterion in selectively bred rodent models (e.g., hyperphagia in young-adult GK rats [5], cardiovascular diseases in spontaneously hypertensive (SHR) rats [6]). Such a cluster of metabolic impairments in selective breeding models resembles the pathophysiology of type 2 diabetes and obesity...

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Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14

Cited by 19 publications

References 50 publications

The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

The Liver X Receptor Agonist T0901317 Protects Mice from High Fat Diet-Induced Obesity and Insulin Resistance

Genetic dissection of susceptibility genes for diabetes and related phenotypes on mouse chromosome 14 by means of congenic strains

Transgenerational changes of metabolic phenotypes in two selectively bred mouse colonies for different susceptibilities to diet-induced glucose intolerance

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