Pharmacological inhibition of dynamin‐related protein 1 attenuates skeletal muscle insulin resistance in obesity

Dynamin‐related protein‐1 (Drp1) is a key regulator in mitochondrial fission. Excessive Drp1‐mediated mitochondrial fission in skeletal muscle under the obese condition is associated with impaired insulin action. However, it remains unknown whether pharmacological inhibition of Drp1, using the Drp1‐specific inhibitor Mitochondrial Division Inhibitor 1 (Mdivi‐1), is effective in alleviating skeletal muscle insulin resistance and improving whole‐body metabolic health under the obese and insulin‐resistant condition. We subjected C57BL/6J mice to a high‐fat diet (HFD) or low‐fat diet (LFD) for 5‐weeks. HFD‐fed mice received Mdivi‐1 or saline injections for the last week of the diet intervention. Additionally, myotubes derived from obese insulin‐resistant humans were treated with Mdivi‐1 or saline for 12 h. We measured glucose area under the curve (AUC) from a glucose tolerance test (GTT), skeletal muscle insulin action, mitochondrial dynamics, respiration, and H(2)O(2) content. We found that Mdivi‐1 attenuated impairments in skeletal muscle insulin signaling and blood glucose AUC from a GTT induced by HFD feeding (p < 0.05). H(2)O(2) content was elevated in skeletal muscle from the HFD group (vs. LFD, p < 0.05), but was reduced with Mdivi‐1 treatment, which may partially explain the improvement in skeletal muscle insulin action. Similarly, Mdivi‐1 enhanced the mitochondrial network structure, reduced reactive oxygen species, and improved insulin action in myotubes from obese humans (vs. saline, p < 0.05). In conclusion, inhibiting Drp1 with short‐term Mdivi‐1 administration attenuates the impairment in skeletal muscle insulin signaling and improves whole‐body glucose tolerance in the setting of obesity‐induced insulin resistance. Targeting Drp1 may be a viable approach to treat obesity‐induced insulin resistance.