Single-allele correction of the Dmo1 locus in congenic animals substantially attenuates obesity, dyslipidaemia and diabetes phenotypes of the OLETF rat.
1. Whole-genome scans have identified Dmo1 as a major quantitative trait locus for dyslipidaemia and obesity in the Otsuka Long Evans Tokushima Fatty (OLETF) rat. 2. We have produced congenic rats for the Dmo1 locus through successive back-cross breeding with diabetic OLETF rats. Marker-assisted speed congenic protocols were applied to efficiently transfer chromosomal segments from non-diabetic Brown Norway (BN) rats into the OLETF background. 3. In the fourth generation of congenic animals, we observed a substantial therapeutic effect of the Dmo1 locus on lipid metabolism, obesity control and plasma glucose homeostasis. 4. We have concluded that Dmo1 primarily affects lipid homeostasis, obesity control and/or glucose homeostasis at fasting and is secondarily involved in glucose homeostasis after loading. 5. The results of the present study show that single-allele correction of a genetic defect of the Dmo1 locus can generate a substantial therapeutic effect, despite the complex polygenic nature of type II diabetic syndromes.
Watanabe
T K
TK
Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan. watanabe@otsuka.gr.jp
Okuno
S
S
Ono
T
T
Yamasaki
Y
Y
Oga
K
K
Mizoguchi-Miyakita
A
A
Miyao
H
H
Suzuki
M
M
Momota
H
H
Goto
Y
Y
Shinomiya
H
H
Hishigaki
H
H
Hayashi
I
I
Asai
T
T
Wakitani
S
S
Takagi
T
T
Nakamura
Y
Y
Tanigami
A
A
D000483:Alleles; D000818:Animals; D020296:Animals, Congenic; D001786:Blood Glucose / Q000235:genetics*; D001835:Body Weight / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006949:Hyperlipidemias / Q000235:genetics*; D007328:Insulin / Q000097:blood; D008297:Male; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D051381:Rats; D020318:Rats, Long-Evans
D001786:Blood Glucose; D007328:Insulin