Abstract
BackgroundMice carrying the Ay allele at the agouti locus become obese and are heavier than their non-Ay littermates. However, this does not hold true for the genetic background of the DDD mouse strain. At 22 weeks of age, DDD.Cg-Ay females are heavier than DDD females, whereas DDD.Cg-Ay males are lighter than DDD males. This study aimed to determine the possible cause and identify the genes responsible for the lower body weight of DDD.Cg-Ay males.ResultsGrowth curves of DDD.Cg-Ay mice were analyzed and compared with those of B6.Cg-Ay mice from 5 to 25 weeks. In DDD.Cg-Ay males, body weight gain stopped between 16 and 17 weeks and the body weight gradually decreased; thus, the lower body weight was a consequence of body weight loss. Quantitative trait locus (QTL) mapping was performed in backcrossed (BC) males of DDD × (B6 × DDD.Cg-Ay) F1-Ay mice. For the body weight at 25 weeks, significant QTLs were identified on chromosomes 1 and 4. The DDD allele was associated with a lower body weight at both loci. In particular, the QTL on chromosome 4 interacted with the Ay allele. Furthermore, suggestive QTLs for plasma glucose and high molecular weight adiponectin levels were coincidentally mapped to chromosome 4. The DDD allele was associated with increased glucose and decreased adiponectin levels. When the body weight at 25 weeks and plasma glucose levels were considered as dependent and independent variables, respectively, BC Ay males were classified into two groups according to statistical analysis using the partition method. Mice of one group had significantly higher glucose and lower adiponectin levels than those of the other group and exhibited body weight loss as observed with DDD-Ay males.ConclusionsThe lower body weight of DDD.Cg-Ay male mice was a consequence of body weight loss. Diabetes mellitus has been suggested to be a possible contributory factor causing body weight loss. The QTL on distal chromosome 4 contained the major responsible genes. This QTL interacted with the Ay allele, implying the reason why body weight loss occurs in DDD.Cg-Ay but not in DDD males.
Highlights
Mice carrying the Ay allele at the agouti locus become obese and are heavier than their non-Ay littermates
We developed a third mouse strain congenic for the Ay allele in an inbred DDD/Sgn strain background, (i.e., DDD.Cg-Ay; hereafter DDD-Ay) [12]
All pairs were compared by Tukey–Kramer honestly significant difference (HSD) tests; the results of statistical comparisons are shown only for those related to DDD-Ay males
Summary
Mice carrying the Ay allele at the agouti locus become obese and are heavier than their non-Ay littermates. This does not hold true for the genetic background of the DDD mouse strain. The agouti gene is expressed only in the skin [2,3], and it regulates pigmentation by acting as an inverse agonist of the melanocortin 1 receptor [4,5]. In Ay mice, the Ay allele is associated with a large deletion, which causes agouti gene expression to be aberrantly controlled by the unrelated Raly gene promoter and results in its ectopic overexpression [3,6,7,8]. DDD-Ay females are significantly obese compared with B6-Ay and KK-Ay females [13]
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