Mfn1 Deficiency in the Liver Protects Against Diet-Induced Insulin Resistance and Enhances the Hypoglycemic Effect of Metformin

Mitochondrial function can be influenced by mitochondrial shape and connectivity with other cellular organelles through fusion and fission processes. Disturbances in mitochondrial architecture and mitochondrial fusion-related genes are observed in situations of type 2 diabetes and obesity, leading to a highly fissioned mitochondrial network. To directly test the effect of reduced mitochondrial fusion on hepatic metabolism, we generated mice with a liver-specific deletion of the Mfn1 gene (Mfn1LKO) and monitored their energy homeostasis, mitochondrial function, and susceptibility to diet-induced insulin resistance. Livers from Mfn1LKO mice displayed a highly fragmented mitochondrial network. This was coupled to an enhanced mitochondrial respiration capacity and a preference for the use of lipids as the main energy source. Although Mfn1LKO mice are similar to control mice fed a low-fat diet, they are protected against insulin resistance induced by a high-fat diet. Importantly, Mfn1 deficiency increased complex I abundance and sensitized animals to the hypoglycemic effect of metformin. Our results suggest that targeting Mfn1 could provide novel avenues to ameliorate glucose homeostasis in obese patients and improve the effectiveness of metformin.