Searching for Genomic Region of High-Fat Diet-Induced Type 2 Diabetes in Mouse Chromosome 2 by Analysis of Congenic Strains

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.

Spontaneous restoration of functional β‐cell mass in obese SM/J mice

“…Like in humans, diabetic risk in obese mice depends on genetic background (Kahle et al., 2013; Kobayashi, Ohno, Ihara, Murai, & Kumazawa, 2014; Meulen et al., 2017; Sims et al., 2013). Variation in β‐cell heterogeneity likely underlies variability in islet stress response, and thus needs to be accounted for when comparing nondiabetic‐obese and diabetic‐obese populations.…”

A Systems Approach Implicates a Brain Mitochondrial Oxidative Homeostasis Co-expression Network in Genetic Vulnerability to Alcohol Withdrawal

“…For the second Alcw1/Alcdp1 model, we report the creation of the first reciprocal congenic (R2) on a D2 background. Due to the near-elimination of confounding genetic background effects, congenic models are extremely powerful tools for elucidating the gene or genes underlying QTL phenotypic effects (Shirley et al, 2004; Kozell et al, 2008, 2009; Doyle et al, 2014; Kato et al, 2014; Kobayashi et al, 2014). QTLs affecting a variety of phenotypes and behaviors in addition to Alcw1/Alcdp1 have been localized to distal mouse chromosome 1 (Mozhui et al, 2008), making this an attractive target for investigation.…”

Expression profile analysis of long non-coding RNAs involved in the metformin-inhibited gluconeogenesis of primary mouse hepatocytes

“…In the present study, the expression level of Gpr155 displayed a similar pattern of change to that of lncRNA ENSMUST00000138573. Kobayashi et al ( 33 ) revealed that Gpr155 was one of four candidate genes for type 2 diabetes by performing exome sequencing analysis. It has been shown that lncRNAs act as transcriptional cofactors to modulate the transcription of adjacent protein coding genes ( 34 ), which suggests that lncRNA NR_027710 and lncRNA ENSMUST00000138573 may affect the expression of PGC-1α and Gpr155 through an unknown mechanism.…”