NADPH oxidase mutation protects against skeletal muscle insulin resistance in high fat fed mice

Abstract

In the present study, we hypothesized that NADPH oxidase‐dependent increases in reactive oxygen species (ROS) associated with diet‐induced obesity impair skeletal muscle insulin action and mitochondrial function. Pathogen free B6(Cg)‐Ncf1m1J/J mice ( Jackson Laboratory), which harbor an inactivating mutation for the p47phox subunit of NADPH oxidase, and C57/BL6J (C57) control mice were maintained on either a high fat diet (HF; 45%) or low fat normal chow diet (LF, 10%) for 10 weeks. Final body weights were significantly greater for mice fed HF compared to LF diets in both C57 (29%) and B6(Cg)‐Ncf1m1J/J (30%) mice. Insulin‐stimulated glucose uptake in soleus muscle (ex vivo) was significantly lower in HF vs. LF fed C57 mice (−41%; p<0.05), but not in HF B6(Cg)‐Ncf1m1J/J mice (−6%; p>0.05), suggesting that NADPH oxidase activation is integral to HF diet‐induced muscle insulin resistance. Hindlimb muscle cytochrome oxidase (COX) activity increased with HF feeding in the B6(Cg)‐Ncf1m1J/J mice (38%; p<0.05), but not in HF fed C57 mice. There was no significant change in muscle citrate synthase activity with HF feeding in either the B6(Cg)‐Ncf1m1J/J or C57 mice. In summary, the adverse effects of HF feeding on skeletal muscle insulin sensitivity and mitochondrial COX activity were abrogated in mice with a p47phox subunit inactivating mutation.Supported by an Endocrine Society Research Award.