One region on chromosome 17 is associated with plasma and pancreatic insulin content in an obese mouse model

Background and aim The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and related pathologies such as insulin resistance and fatty liver. The aim of this study was to identify genetic variants associated with plasma and pancreatic insulin content in two sub-strains of the BFMI (BFMI861-S1 and BFMI861-S2). These lines are genetically close related but differ in several metabolic phenotypes (e.g. blood glucose concentration, plasma insulin, and body weight).

Methods An advanced intercross line (AIL) was generated from the cross BFMI861-S1 x BFMI861-S2. In generation 10, plasma insulin and pancreatic insulin content were collected in 397 male mice at 25 weeks under a high fat, high carbohydrate diet. To perform QTL-analysis with the collected phenotypes, genotyping was performed using GigaMUGA SNP chip and KASP assay. Candidate gene prioritization was performed using whole genome sequencing data, gene expression, and proteomics data of the parental lines.

Results QTL mapping identified one QTL on chromosome 17 (7,725,897 – 26,054,796) associated with plasma and pancreatic insulin content. Candidate gene prioritization identified Acat2 as the most likely candidate gene in this region. This gene carries one deleterious missense variant in the N-terminal domain and shows downregulation at both mRNA and protein level in the gonadal adipose tissue of the BFMI861-S1 line.

Conclusion QTL mapping and candidate gene prioritization discovered a locus on chromosome 17 involved in the regulation of insulin metabolism. The results confirmed that our BFMI861-S1 line with its unique genetic background is a powerful population to detect metabolic QTL.

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Publication History

Article published online:
26 May 2022