Bhlhe40, a potential diabetic modifier gene on Dbm1 locus, negatively controls myocyte fatty acid oxidation

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Author(s)

Abstract

We have previously identified significant quantitative trait loci (QTL) <i>Dbm1</i> (diabetic modifier QTL 1) on chromosome 6, affecting plasma glucose and insulin concentrations and body weight on F<sub>2</sub> progeny of hypoinsulinemic diabetic Akita mice, with the heterozygous <i>Ins2</i> gene Cys96Tyr mutation, and non-diabetic A/J mice. To discover diabetic modifier genes on <i>Dbm1</i>, we constructed congenic strain for <i>Dbm1</i> using the Akita allele as donor in A/J allele genetic background, and compared diabetes-related phenotypes to control mice. The homozygote for Akita allele of <i>Dbm1</i> was associated with lower plasma glucose concentrations in glucose tolerance test (GTT) in the hypoinsulinemic condition derived from the <i>Ins2</i> mutation and lower plasma insulin concentrations and body weight in the normoinsulinemic condition without the <i>Ins2</i> mutation than the homozygote for A/J allele, as we performed QTL analysis on F<sub>2</sub> intercross mice. The Akita allele also decreased the epididymal white adipose tissue (EWAT) weight. According to the analysis of sub-congenic strains, we narrowed down the responsible diabetic modifier region to 9 Mb. As fourteen candidate genes exist in this region, we analyzed genomic variants of these genes and gene expression in the muscle, liver, and EWAT and identified that <i>Bhlhe40</i> gene expression in muscle is decreased in congenic mice. According to the <i>in vitro</i> functional analyses, <i>Bhlhe40</i> was shown to negatively control fatty acid oxidation in cultured myocyte. Based on these, we conclude that <i>Bhlhe40</i> is a possible candidate diabetic modifier gene responsible for <i>Dbm1</i> locus affecting diabetes and/or obesity through negatively controlling fatty acid oxidation in muscle.

Journal

  • Genes & Genetic Systems

    Genes & Genetic Systems 87(4), 253-264, 2012-08-25

    The Genetics Society of Japan

References:  37

Codes

  • NII Article ID (NAID)
    10031126618
  • NII NACSIS-CAT ID (NCID)
    AA11077421
  • Text Lang
    ENG
  • Article Type
    ART
  • ISSN
    13417568
  • NDL Article ID
    024078309
  • NDL Call No.
    Z53-W539
  • Data Source
    CJP  NDL  J-STAGE 
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