Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice

To determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, we generated transgenic mice expressing the mitochondrial uncoupling prote in (Ucp) in skeletal muscle. Skeletal muscle oxygen consumption was 98% hig her in Ucp-L mice (with low expression) and 246% higher in Ucp-H mice (with high expression) than in wild-type mice. Ucp mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels o f glucose and triglycerides and better glucose tolerance than did control m ice. Ucp-L mice were resistant to obesity induced by two different high-fat diets. Ucp-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol, and an increased metabolic rate at rest a nd with exercise. They were also more responsive to insulin, and had enhanc ed glucose transport in skeletal muscle in the setting of increased muscle triglyceride content. These data suggest that manipulating respiratory unco upling in muscle is a viable treatment for obesity and its metabolic sequel ae.