After 58 generations of selection, different Berlin Fat Mouse Inbred (BFMI) lines were generated through repeated brother–sister mating. Originally, the Berlin Fat Mouse population was selected for juvenile obesity. The goal of the current study was to identify genetic factors contributing to obesity and glucose homeostasis in the Berlin Fat Mouse. Therefore, studies on different populations are needed to identify additional causal genes to better understand their direct and interaction effects contributing to the metabolic syndrome. Nevertheless, genome-wide association studies on body mass index and other traits of the metabolic syndrome identified loci, that combined, account for only 1–7% of the variance in the examined population. Heritability estimates for each trait of the metabolic syndrome are high with some estimates exceeding 50%.
The metabolic syndrome is defined as a metabolic abnormality that leads to high body weight, ectopic fat storage, insulin resistance, high blood pressure, and chronic low-grade inflammation. In addition, we provided evidence for direct and indirect genetic effects on blood glucose concentration in the insulin-resistant mouse line BFMI861-S1. QTL mapping together with a detailed prioritization approach allowed us to identify candidate genes associated with traits of the metabolic syndrome. Two additional QTL were detected for gonadal adipose tissue weight on Chr 15 (67.9–74.6 Mb) and for body weight on Chr 16 (3.9–21.4 Mb). Prioritized positional candidate genes for the identified QTL were Notch2 and Fmo5 (Chr 3) and Plg and Acat2 (Chr 17). Direct effects on adipose tissue weight, liver weight, and blood glucose concentration were suggested for Chr 17-QTL. Causal modeling suggested for Chr 3-QTL direct effects on adipose tissue weight, but indirect effects on blood glucose concentration. Overlapping QTL for gonadal adipose tissue weight and blood glucose concentration were detected on chromosome (Chr) 3 (95.8–100.1 Mb), and for gonadal adipose tissue weight, liver weight, and blood glucose concentration on Chr 17 (9.5–26.1 Mb).
For the prioritization of positional candidate genes whole genome sequencing and gene expression data of the parental lines were used.
Additional 197 males were genotyped for 7 top SNPs in QTL regions. QTL-analysis was performed after selective genotyping of 200 mice using the GigaMUGA Genotyping Array. In generation 10, 397 males of an advanced intercross line (AIL) BFMI861-S1 × BFMI861-S2 were challenged with a high-fat, high-carbohydrate diet and phenotyped over 25 weeks. BFMI861-S1 is insulin resistant and stores ectopic fat in the liver, whereas BFMI861-S2 is insulin sensitive. This study aimed to identify genetic variants associated with impaired glucose metabolism using the obese lines BFMI861-S1 and BFMI861-S2, which are genetically closely related, but differ in several traits. The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and the metabolic syndrome.
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