Aims: Mitochondrial uncoupling increases energy expenditure and has therapeutic potential for the treatment of metabolic disorders. We previously demonstrated that the mitochondrial uncoupler BAM15 reverses obesity and improves insulin sensitivity in mouse models of diet-induced obesity. This study aimed to determine the effect of BAM15 on glucose homeostasis in a more severe model of obesity and insulin resistance in leptin receptor-deficient (db/db) male mice.
Methods: Four groups of mice were maintained for 4 weeks on various diets; these included db/+ mice fed ad libitum chow (lean controls), db/db mice fed ad libitum chow (chow ad lib control), db/db mice pair-fed chow to match lean controls (chow pair-fed, positive control), and db/db mice with ad libitum access to chow diet containing 0.2% (w/w) BAM15 (BAM15-treated). Liver gene expression was analysed by RT-qPCR of frozen tissue.
Results: BAM15 treatment significantly lowered body mass with efficacy similar to pair-feeding. BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels comparable to lean controls, while the calorie restricted pair-fed group only showed partial improvement compared to chow ad lib controls. These improvements were associated with decreased liver mRNA expression of glucose-6-phosphatase in both the BAM15-treated and chow pair-fed mice compared to chow ad lib controls. Pair-feeding resulted in the best effect on lowering liver triglyceride levels amongst the db/db groups. There were no changes in fasting plasma insulin or liver cholesterol among any db/db groups.
Conclusions: These results indicate a strong effect of the mitochondrial uncoupler BAM15 on normalizing glucose homeostasis. This effect likely occurs through a mechanism that is independent of adiposity and liver triglyceride levels and at least in part associated with a decrease in gluconeogenesis. These results support further investigation into the therapeutic potential of BAM15 and related molecules as pharmacotherapies for diabetes.