Identification of Epistatic Interaction Involved in Obesity Using the KK/Ta Mouse as a Type 2 Diabetes Model

doi:10.2337/diabetes.52.8.2175

Identification of Epistatic Interaction Involved in Obesity Using the KK/Ta Mouse as a Type 2 Diabetes Model

Is Zn-α₂ Glycoprotein-1 a Candidate Gene for Obesity?

From the Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan

Address correspondence and reprint requests to Yasuhiko Tomino, Professor, Division of Nephrology, Department of Internal Medicine, Juntendo University School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail: yasu{at}med.juntendo.ac.jp

Abstract

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-α₂ 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 × (BALB/c × 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.