Identification of epistatic interaction involved in obesity using the KK/Ta mouse as a Type 2 diabetes model: is Zn-alpha2 glycoprotein-1 a candidate gene for obesity?
The KK/Ta strain serves as a suitable polygenic mouse model for the common form of type 2 diabetes associated with obesity in humans. Recently, we reported the susceptibility loci contributing to type 2 diabetes and related phenotypes in KK/Ta mice. In this study, we focused on expression in the kidneys and liver of KK/Ta and BALB/c mice using differential display (DD) PCR. Zn-alpha(2) glycoprotein-1 (Azgp1) mRNA levels were increased in the kidneys and liver in KK/Ta mice, and sequence analysis revealed a missense mutation. We analyzed the relationship between this polymorphism and various phenotypes in 208 KK/Ta x (BALB/c x KK/Ta) F1 backcross mice. Statistical analysis revealed that Azgp1 and D17Mit218 exhibit a suggestive linkage to body weight (8 weeks) (logarithm of odds 2.3 and 2.9, respectively). Moderate gene-gene interactions were observed at these loci. Adiponectin mRNA levels in 3T3-L1 cells transfected with the expression pcDNA 3.1 vector containing Azgp1 coding sequence of KK/Ta mice were significantly higher than those of BALB/c mice. These results suggest that Azgp1 is a possible candidate gene for regulation of body weight, elucidation of polygenic inheritance, and age-dependent changes in the genetic control of obesity.
Gohda
Tomohito
T
Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan.
Makita
Yuichiro
Y
Shike
Toshihide
T
Tanimoto
Mitsuo
M
Funabiki
Kazuhiko
K
Horikoshi
Satoshi
S
Tomino
Yasuhiko
Y
D052242:Adiponectin; D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight; D033481:Chromosomes, Mammalian; D003920:Diabetes Mellitus / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D015870:Gene Expression; D036341:Intercellular Signaling Peptides and Proteins; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009765:Obesity; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D029589:Seminal Plasma Proteins / Q000235:genetics*; D014280:Triglycerides / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000090203:Zn-Alpha-2-Glycoprotein
D052242:Adiponectin; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012333:RNA, Messenger; D029589:Seminal Plasma Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D000090203:Zn-Alpha-2-Glycoprotein