title: Bhlhe40, a potential diabetic modifier gene on Dbm1 locus, negatively controls myocyte fatty acid oxidation.
abstract: We have previously identified significant quantitative trait loci (QTL) Dbm1 (diabetic modifier QTL 1) on chromosome 6, affecting plasma glucose and insulin concentrations and body weight on F(2) progeny of hypoinsulinemic diabetic Akita mice, with the heterozygous Ins2 gene Cys96Tyr mutation, and non-diabetic A/J mice. To discover diabetic modifier genes on Dbm1, we constructed congenic strain for Dbm1 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 Dbm1 was associated with lower plasma glucose concentrations in glucose tolerance test (GTT) in the hypoinsulinemic condition derived from the Ins2 mutation and lower plasma insulin concentrations and body weight in the normoinsulinemic condition without the Ins2 mutation than the homozygote for A/J allele, as we performed QTL analysis on F(2) 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 Bhlhe40 gene expression in muscle is decreased in congenic mice. According to the in vitro functional analyses, Bhlhe40 was shown to negatively control fatty acid oxidation in cultured myocyte. Based on these, we conclude that Bhlhe40 is a possible candidate diabetic modifier gene responsible for Dbm1 locus affecting diabetes and/or obesity through negatively controlling fatty acid oxidation in muscle.
authors.affiliation: Department of Metabolic Diseases, Pharmacology Research Labs., Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Takeshita
authors.forename: Takao
authors.initials: T
authors.lastname: Suzuki
authors.forename: Susumu
authors.initials: S
authors.lastname: Kitayama
authors.forename: Maki
authors.initials: M
authors.lastname: Moritani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Itakura
mesh_terms: D052436:Adipose Tissue, White; D000483:Alleles; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D001786:Blood Glucose; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D004822:Epididymis / Q000166:cytology; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D005951:Glucose Tolerance Test; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006720:Homozygote; D007328:Insulin / Q000097:blood / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D010084:Oxidation-Reduction; D040641:Quantitative Trait Loci / Q000235:genetics*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D005227:Fatty Acids; D018398:Homeodomain Proteins; D007328:Insulin; C491539:Bhlhe40 protein, mouse; C561967:Ins2 protein, mouse