RATIONALE: Excess consumption of sugar- and fat-rich foods has heightened the prevalence of cardiometabolic disease, which remains a driver of cardiovascular disease- and type II diabetes-related mortality globally. Skeletal muscle insulin resistance is an early feature of cardiometabolic disease and is a precursor to diabetes. Insulin resistance risk varies with self-reported race, whereby African-Americans have a greater risk of diabetes development relative to their White counterparts. Self-reported race is strongly associated with mitochondrial DNA (mtDNA) haplogroups, and previous reports have noted marked differences in bioenergetic and metabolic parameters in cells belonging to distinct mtDNA haplogroups, but the mechanism of these associations remains unknown. Additionally, distinguishing nuclear DNA (nDNA) and mtDNA contributions to cardiometabolic disease remains challenging in humans. The Mitochondrial-Nuclear eXchange (MNX) mouse model enables in vivo preclinical investigation of the role of mtDNA in cardiometabolic disease development, and has been implemented in studies of insulin resistance, fatty liver disease, and obesity in previous reports. METHODS: Six-week-old male C57 RESULTS: Comparative analyses between nDNA-matched wild-type and MNX strains demonstrated significantly increased body fat percentage in mice possessing C57 CONCLUSIONS: These results reveal novel nDNA-mtDNA interactions that drive significant changes in metabolite levels. Alterations to key metabolites involved in mitochondrial bioenergetic dysfunction and electron transport chain activity are implicated in elevated beta-oxidation during high-fat diet feeding
abnormally elevated rates of beta-oxidation may be a key driver of insulin resistance. The results reported here support the hypothesis that mtDNA influences cardiometabolic disease-susceptibility by modulating mitochondrial function and metabolic pathways.