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

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-␣ 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 ؋ (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. Diabetes 52:2175-2181, 2003

Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE): a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy

“…In addition, both DIGE proteomic analysis and western blotting indicated that ZAG production was significantly higher in the vitreous fluid from PDR patients compared with that from non-diabetic patients. We do not why ZAG levels are increased in the vitreous of diabetic patients with PDR, but it should be noted that hyperglycaemia has been involved in ZAG production [23], and gene expression of ZAG has been found to be upregulated in mice with diabetic nephropathy [24]. In addition, ZAG hinders cell proliferation and reduces Cdc2 expression (a rate-limiting step in cell cycle) [25] and may therefore be a reactive limiting factor for PDR progression.…”

“…Although its biological functions are incompletely understood, it seems to be a novel adipokine that may be involved in the local regulation of adipose tissue function [20][21][22][23]. ZAG has been recently identified by proteomic analysis in vitreous fluid from PDR patients [8,9].…”

Zinc-α2-glycoprotein: an adipokine modulator of body fat mass?

“…59 A single-nucleotide polymorphism in exon 2 of the ZAG gene was identified in KK/Ta mice and this polymorphism, a missense mutation at codon 24, may contribute to a type 2 diabetes-related phenotype involving obesity. 59 Further genetic evidence was provided by the demonstration that ZAG-knockout mice were susceptible to weight gain, particularly after a high-fat diet.…”

“…59 A single-nucleotide polymorphism in exon 2 of the ZAG gene was identified in KK/Ta mice and this polymorphism, a missense mutation at codon 24, may contribute to a type 2 diabetes-related phenotype involving obesity. 59 Further genetic evidence was provided by the demonstration that ZAG-knockout mice were susceptible to weight gain, particularly after a high-fat diet. 60 This phenotype appears to be the result of reduced lipolytic responses to several stimuli, including isoprenaline, CL316243 (a b3-agonist), foskolin and isobutylmethylxanthine, in adipocytes.…”

“…59 Our recent study has further examined whether ZAG modulates adiponectin production in human SGBS adipocytes. We have demonstrated that recombinant ZAG, at physiologically relevant concentrations, increases adiponectin release from differentiated human adipocytes.…”