Inhibition of the IKK pathway restores PI3-K activity in high-fat fed rodent skeletal muscles

High-fat feeding impairs insulin-stimulated rates of glucose transport, which appears to be a direct result of insulin being unable to fully activate phosphoinositide (PI)-3 kinase. Activation of the IKK pathway has been reported to contribute to inducing skeletal muscle insulin resistance, and we have recently observed that components of the IKK pathway are activated in high fat-fed rodent skeletal muscle. It is not known if the inhibition of the IKK pathway will rescue insulin-stimulated PI3-K activity in high fat-fed rodent skeletal muscle. Sprague-Dawley rats were fed either a control diet or high fat diet for 4 weeks and then allocated (n=8/group) to normal diet, control (CON), high fat diet, control (HF-CON), high fat diet, IKK inhibited (HF-IKK), high fat diet, JNK inhibited (HF-JNK) or high fat diet, NF-κB inhibited (HF-NF-κB) groups. Inhibitors were provided for 5 days by subcutaneous injection after which all animals underwent hind limb perfusions. Insulin-stimulated rates of 3-MG transport and PI3-K activity were significantly increased in the red quadriceps of HF-IKK and HF-NF-κB compared to HF-CON, IKKβ serine phosphorylation was decreased in HF-IKK and HF-NF-κB, and IRS-1 serine phosphorylation was significantly lower in HF-JNK, HF-NF-κB and HF-IKK compared to HF-CON. Suppressing the activation of the IKK pathway in the skeletal muscle of high fat-fed rats resulted in the rescue of insulin stimulated PI3-K activity. This suggests that the IKK pathway plays a significant role in the inhibition of insulin-stimulated PI3-K activity in the skeletal muscle of the high fat-fed rat.