Searching for genomic region of high-fat diet-induced type 2 diabetes in mouse chromosome 2 by analysis of congenic strains

PLoS One. 2014 May 1;9(5):e96271. doi: 10.1371/journal.pone.0096271. eCollection 2014.

Abstract

SMXA-5 mice are a high-fat diet-induced type 2 diabetes animal model established from non-diabetic SM/J and A/J mice. By using F2 intercross mice between SMXA-5 and SM/J mice under feeding with a high-fat diet, we previously mapped a major diabetogenic QTL (T2dm2sa) on chromosome 2. We then produced the congenic strain (SM.A-T2dm2sa (R0), 20.8-163.0 Mb) and demonstrated that the A/J allele of T2dm2sa impaired glucose tolerance and increased body weight and body mass index in the congenic strain compared to SM/J mice. We also showed that the combination of T2dm2sa and other diabetogenic loci was needed to develop the high-fat diet-induced type 2 diabetes. In this study, to narrow the potential genomic region containing the gene(s) responsible for T2dm2sa, we constructed R1 and R2 congenic strains. Both R1 (69.6-163.0 Mb) and R2 (20.8-128.2 Mb) congenic mice exhibited increases in body weight and abdominal fat weight and impaired glucose tolerance compared to SM/J mice. The R1 and R2 congenic analyses strongly suggested that the responsible genes existed in the overlapping genomic interval (69.6-128.2 Mb) between R1 and R2. In addition, studies using the newly established R1A congenic strain showed that the narrowed genomic region (69.6-75.4 Mb) affected not only obesity but also glucose tolerance. To search for candidate genes within the R1A genomic region, we performed exome sequencing analysis between SM/J and A/J mice and extracted 4 genes (Itga6, Zak, Gpr155, and Mtx2) with non-synonymous coding SNPs. These four genes might be candidate genes for type 2 diabetes caused by gene-gene interactions. This study indicated that one of the genes responsible for high-fat diet-induced diabetes exists in the 5.8 Mb genomic interval on mouse chromosome 2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Fat / metabolism
  • Animals
  • Blood Glucose / metabolism
  • Chromosomes, Mammalian / genetics*
  • Diabetes Mellitus, Type 2 / chemically induced
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Diet, High-Fat
  • Epistasis, Genetic
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Integrin alpha6 / genetics*
  • MAP Kinase Kinase Kinases / genetics*
  • Membrane Proteins / genetics*
  • Mice
  • Mice, Congenic
  • Mitochondrial Proteins / genetics*
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Receptors, G-Protein-Coupled / genetics*
  • Sequence Analysis, DNA
  • Weight Gain

Substances

  • Blood Glucose
  • Gpr155 protein, mouse
  • Integrin alpha6
  • Membrane Proteins
  • Mitochondrial Proteins
  • Mtx2 protein, mouse
  • Receptors, G-Protein-Coupled
  • MAP Kinase Kinase Kinases
  • ZAK protein, mouse

Associated data

  • SRA/DRA002145

Grants and funding

This research was supported by JSPS KAKENHI Grant Number 24380068. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.