Comparitive genomics of multiple backcross mouse populations identifies Sgcg as a novel potential obesity-modifier gene

To nominate novel disease genes for obesity and type 2 diabetes (T2D) we recently generated two mouse backcross populations of obese and T2D- susceptible New Zealand Obese (NZO/HI) mice with the two lean mouse strains 129P2/OlaHsd and C3HeB/FeJ. Comparative linkage analysis of our two female backcross populations identified seven novel body fat-associated quantitative trait loci (QTL). Only the locus Nbw14 (NZO body weight on chromosome 14) showed linkage to obesity-related traits in both backcross populations, indicating that the causal gene variant is likely specific for the NZO strain as NZO allele carriers in both crosses displayed elevated body weight and fat mass. To nominate candidate genes for Nbw14, we used a combined approach of gene expression and haplotype analysis to filter for NZO-specific gene variants in gonadal white adipose tissue (gWAT), which appeared to be the most likely target tissue. Only two genes, Arl11 and Sgcg, fulfilled our criteria. In addition, expression QTL analysis revealed cis-signals for both genes within in the Nbw14 locus. Retroviral overexpression of Sgcg in 3T3-L1 adipocytes resulted in increased glucose uptake. In humans, mRNA levels of Sgcg correlated with BMI and body weight exclusively in diabetic subjects, suggesting that Sgcg represents a novel marker for metabolically unhealthy obesity in humans. In conclusion, our comparative-cross analysis could substantially improve the mapping resolution of the obesity locus Nbw14. Future studies will shine light on the mechanism by which Sgcg protects from the development of obesity. We used microarrays to enable the detection of candidate genes in the critical region in a combined approach of haplotype- and gene expression analysis to search for obesity related gene variants in the white adipose tissue.