Mitochondrial oxidative phosphorylation (OXPHOS) plays an important role in the pathophysiology of obesity and type 2 diabetes. The OXPHOS system is composed of five enzymes (Complexes I-V) that are referred to as the electron transport chain. Complex I dysfunction is the most common OXPHOS disorder in humans. Utilizing the unpublished analysis of data from Hybrid Mouse Diversity Panel (HMDP) generated by our lab, we identified one polygenic mouse model (BXD44/RwwJ) with a robust reduction in total Complex I abundance across multiple tissues including the brain. The BXD recombinant inbred lines are derived from intercrosses between the C57BL/6J and DBA/2J founder strains.
To examine the effect of Complex I insufficiency on body weight regulation, we generated a cohort of male BXD44 mice, and utilised the founder stains C57BL/6J and DBA/2J mice as controls. From 12 weeks of age, BXD44 mice were significantly heavier than C57BL/6J and DBA/2J control mice. This significant increase in body weight was attributed to an increase in fat mass, with a decrease in lean mass. In addition, BXD44 mice also developed dramatic glucose intolerance and insulin resistance, compared to C57BL/6J and DBA/2J control mice.
The leptin-melanocortin axis in the hypothalamus plays a vital role in the regulation of energy homeostasis and glucose metabolism. Interestingly, it also plays an important role in regulating hypothalamic mitochondrial OXPHOS. It has been reported that the mitochondrial OXPHOS pathway was the most significant leptin-regulated pathway in the PVN.
Therefore, we hypothesized that Complex I insufficiency in the hypothalamus of BXD44 mice disrupts the leptin-melanocortin pathway, and therefore leads to obesity and glucose intolerance. We will perform experiments to determine whether BXD44 mice have an impaired leptin signalling pathway in the hypothalamus. The findings of this project will likely make significant contributions to our knowledge of polygenic risk for obesity and diabetes.