Systems genetics of susceptibility to obesity-induced diabetes in mice

disease (15). Although the role of genetic factors in the development of obesity-associated diabetes has long been appreciated, the genes responsible for differences in diabetes susceptibility remain largely uncharacterized. In the present study, we examined obese (db/db) F2 mice from a cross between B6 and DBA to identify loci that contribute to diabetic progression, insulin resistance, and lipid accumulation in the liver. We characterized two cohorts of mice: one at 5 wk of age prior to anticipated islet depletion and another cohort at 12 wk when BKS db/db begin to show decreased insulin production but prior to the onset of significant diabetic complications. For the loci contributing to diabetes-related traits that were identified, we examined candidate genes for cis-acting variations in gene expression. Additionally, we modeled liver gene coexpression networks to help identify mechanisms contributing to metabolic dysfunction in obesity-induced diabetes. METHODS Animals. We carried out an F2 intercross between the inbred strains DBA/2 and C57BL/6. These parental mice were obtained from The Jackson Laboratory (Bar Harbor, ME). The male C57BL/6 parents carried heterozygous deficiency in the leptin receptor (db /) and F1 progeny were selected for the presence of the mutant allele. Among F2 progeny, only those with homozygous deficiency in leptin receptor (db/db) were selected for further phenotype and genotype