Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats

Okuno, Shiro; Kondo, Mari; Yamasaki, Yoshio; Miyao, Hideo; Ono, Toshihide; Iwanaga, Tomoyuki; Omori, Keiichi; Okano, M.; Suzuki, Mikio; Momota, Hiroyuki; Hishigaki, Haretsugu; Hayashi, I.; Goto, Yoshihiro; Shinomiya, Hiroichi; Harada, Yosuke; Hirashima, Tsukasa; Kanemoto, Naohide; Asai, Tomio; Wakitani, Shigeyuki; Takagi, Toshihisa; Nakamura, Yusuke; Tanigami, Akira; Watanabe, Takeshi

doi:10.1046/j.1463-1326.2002.00217.x

Cited by 8 publications

(27 citation statements)

References 13 publications

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“…Our earlier initial data showed that the region between D1Rat76 and D1Rat459 harbours the Dmo1 causative gene; 9–11 this was then narrowed down to 1.7 cM between D1Rat461 and D1Rat459 , physically corresponding to, at most, 1.1 Mb 12 …”

Section: Resultsmentioning

confidence: 98%

“…For all studies described in the present paper, only male rats were used. All physiological parameters were measured as described previously 2–5,9–12 . The adiposity index was calculated as abdominal fat weight/bodyweight.…”

Section: Methodsmentioning

confidence: 99%

“…To dissect precisely the effect of Dmo1 , we have established congenic lines by introducing a Dmo1 allele from the non‐diabetic Brown‐Norway (BN) or Fischer 344 (F344) strains onto an OLETF background. Introduction of the normal Dmo1 allele produced a wide range of therapeutic effects, including reduced food intake, reduced obesity, decreased plasma triglyceride and total cholesterol levels and lowered plasma glucose levels 9–11 . It also led to decreased fat deposition in the liver and attenuated diabetic complications in the kidney 11 .…”

Section: Introductionmentioning

confidence: 99%

“…Introduction of the normal Dmo1 allele produced a wide range of therapeutic effects, including reduced food intake, reduced obesity, decreased plasma triglyceride and total cholesterol levels and lowered plasma glucose levels 9–11 . It also led to decreased fat deposition in the liver and attenuated diabetic complications in the kidney 11 . Although the therapeutic effects of the Dmo1 correction are wide ranging, in the present paper Dmo1 is proven to be involved primarily in feeding regulation, whereas other effects are likely to be secondary and a result of normalized food intake.…”

Section: Introductionmentioning

confidence: 99%

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MUTATED G‐PROTEIN‐COUPLED RECEPTOR GPR10 IS RESPONSIBLE FOR THE HYPERPHAGIA/DYSLIPIDAEMIA/OBESITY LOCUS OF Dmo1 IN THE OLETF RAT

Watanabe

Suzuki

Yamasaki

et al. 2005

Clin Exp Pharma Physio

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1. We have confirmed the Diabetes Mellitus OLETF type I (Dmo1) effect on hyperphagia, dyslipidaemia and obesity in the Otsuka Long-Evans Tokushima Fatty (OLETF) strain. The critical interval was narrowed down to 570 kb between D1Got258 to p162CA1 by segregation analyses using congenic lines. 2. Within the critical 570 kb region of the Dmo1 locus, we identified the G-protein-coupled receptor gene GPR10 as the causative gene mutated in the OLETF strain. The ATG translation initiation codon of GPR10 is changed into ATA in this strain and, so, is unavailable for the initiation of translation. 3. The GPR10 protein has a cognate ligand, namely prolactin-releasing peptide (PrRP). Centrally administered PrRP suppressed the food intake of congenic rats that have a Brown Norway derived Dmo1 region (i.e. with wild-type GPR10), but did not suppress that of the OLETF strain, indicating that GPR10 is without function and could explain hyperphagia in the OLETF strain. 4. Moreover, when restricted in food volume to the same level consumed by the congenic strain, OLETF rats showed few differences in the parameters of dyslipidaemia and obesity compared with congenic strains. 5. Taken together, these results demonstrate that the mutated GPR10 receptor is responsible for the hyperphagia leading to obesity and dyslipidaemia in the obese diabetic strain rat.

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Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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MUTATED G‐PROTEIN‐COUPLED RECEPTOR GPR10 IS RESPONSIBLE FOR THE HYPERPHAGIA/DYSLIPIDAEMIA/OBESITY LOCUS OF Dmo1 IN THE OLETF RAT

Watanabe

Suzuki

Yamasaki

et al. 2005

Clin Exp Pharma Physio

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“…We used interval mapping methods to elucidate the most likely Dmo1 interval in BC5:F1 animals, which show various genotypes across the approximate 30 cM interval between D1Rat76 and D1Rat460 . Because obesity, dyslipidaemia and hyperglycaemia correlate well in the original OLETF strain and in our congenic strains 1,6–8 and all logarithm of odds (LOD) peaks for Dmo1 phenotypes, including bodyweight ( P = 0.005), abdominal fat weight ( P = 9.65 × 10 −4 ), plasma cholesterol ( P = 1.56 × 10 −6 ), plasma triglyceride ( P = 1.96 × 10 −8 ) and plasma glucose levels after oral glucose challenges ( P = 5.9 × 10 −4 to 0.04), accumulate at the same position represented by D1Rat90 marker (all data are for the phenotypes at 30 weeks; TK Watanabe et al. , unpubl.…”

Section: Methodsmentioning

confidence: 88%

A < 1.7 cM interval is responsible for Dmo1 obesity phenotypes in OLETF rats

Watanabe¹,

Okuno²,

Yamasaki³

et al. 2004

Clin Exp Pharmacol Physiol

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1. Dmo1 (Diabetes Mellitus OLETF type I) is a major quantitative trait locus for dyslipidaemia, obesity and diabetes phenotypes of male Otsuka Long Evans Tokushima Fatty (OLETF) rats. 2. Our congenic lines, produced by transferring Dmo1 chromosomal segments from the non-diabetic Brown Norway (BN) rat into the OLETF strain, have confirmed the strong, wide-range therapeutic effects of Dmo1 on dyslipidaemia, obesity and diabetes in the fourth (BC4) and fifth (BC5) generations of congenic animals. Analysis of a relatively small number of BC5 rats (n = 71) suggested that the critical Dmo1 interval lies within a < 4.9 cM region between D1Rat461 and D1Rat459. 3. To confirm the assignment of the Dmo1 critical interval, we intercrossed BC5 animals to produce a larger study population (BC5:F1 males; n = 406). For the present study, we used bodyweight at 18 weeks of age as an index of obesity; this phenotype is representative of the closely associated dyslipidaemia and hyperglycaemia phenotypes. 4. Interval mapping assigned logarithm of odds (LOD) peaks at the D1Rat90 marker (LOD = 9.11). One LOD support interval lies within the < 1.7 cM region between D1Rat461 and D1Rat459. 5. This large intercross study confirms that Dmo1 is likely localized within the interval.

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Current literature in diabetes

2002

Diabetes Metabolism Res

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In order to keep subscribers up‐to‐date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of diabetes/metabolism. Each bibliography is divided into 17 sections: 1 Books, Reviews & Symposia; 2 General; 3 Genetics; 4 Epidemiology; 5 Immunology; 6 Prediction; 7 Prevention; 8 Intervention: a) General; b) Pharmacology; 9 Pathology: a) General; b) Cardiovascular; c) Neurological; d) Renal; 10 Endocrinology & Metabolism; 11 Nutrition; 12 Animal Studies; 13 Techniques. Within each section, articles are listed in alphabetical order with respect to author (9 Weeks journals ‐ Search completed at 25th September 2002)

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Substitution of Dmo1 with normal alleles results in decreased manifestation of diabetes in OLETF rats

Abstract: Improvements in metabolic parameters and histopathological scores show that correction of the Dmo1 genetic pathway in the diabetic and mildly obese OLETF rat strain produces wide-ranging therapeutic effects. Thus, this pathway might represent a new drug target also applicable to humans.

Cited by 8 publications

References 13 publications

MUTATED G‐PROTEIN‐COUPLED RECEPTOR GPR10 IS RESPONSIBLE FOR THE HYPERPHAGIA/DYSLIPIDAEMIA/OBESITY LOCUS OF Dmo1 IN THE OLETF RAT

MUTATED G‐PROTEIN‐COUPLED RECEPTOR GPR10 IS RESPONSIBLE FOR THE HYPERPHAGIA/DYSLIPIDAEMIA/OBESITY LOCUS OF Dmo1 IN THE OLETF RAT

A < 1.7 cM interval is responsible for Dmo1 obesity phenotypes in OLETF rats

Current literature in diabetes

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