Reduced Muscle IκB Expression and Insulin Resistance in Obese Zucker Rats: Effect of Training
Abstract Number: 1004-P
Authors: APIRADEE SRIWIJITKAMOL, JOHN L. IVY, CHRISTINE CHRIST-ROBERTS, RALPH A. DEFRONZO, LAWRENCE J. MANDARINO, NICOLAS MUSI.
Institutions: San Antonio, TX; Austin, TX; Tempe, AZ.
Results: It has been hypothesized that activation of the IκB/NFκB pathway represents a mechanism which contributes to skeletal muscle insulin resistance. This pathway is activated by inflammatory stimuli, such as cytokines and lipids. We compared IκB/NFκB signaling in mixed gastrocnemius muscle from 5 obese and 5 lean sedentary Zucker rats, by measuring the abundance of the inhibitory protein IκB. Using a hindlimb perfusion system, insulin-stimulated muscle glucose uptake also was quantitated. IκBβ protein content was reduced by 48% (P=0.02) in the obese rats, indicating increased IκB/NFκB signaling. The reduction in IκBβ in the obese rats was associated with a 60% decrease in insulin-stimulated glucose uptake (P=0.003). Plasma free fatty acid (FFA) levels were 2-fold higher in the obese group (P<0.001), while plasma TNFα concentrations were not different between groups. Intramyocellular triglyceride (TG) content was 4.5-fold higher in the obese group (P=0.01) and correlated inversely with IκBβ protein (r=-0.7, P=0.02) and with insulin-stimulated glucose uptake (r=-0.75, P=0.01). The effect of seven weeks of treadmill exercise on muscle IκBβ content was then examined in 7 obese Zucker rats. Training increased IκBβ by 89% (P=0.04), and this increase was accompanied with a 120% increase in insulin-stimulated glucose uptake (P<0.001). However, training did not reduce elevated plasma FFA or myocellular TG content, and had no effect on TNFα plasma levels. Conclusions: 1) obese insulin-resistant rats have decreased IκB muscle content, an indicator of increased IκB/NFκB signaling; 2) increased IκB/NFκB pathway activity is strongly correlated with myocellular TG content, suggesting that abnormalities in lipid metabolism may be responsible for stimulating the IκB/NFκB pathway and impairing insulin action; and 3) training increases IκB content and improves insulin action, however, these effects are not due to a reduction in plasma FFA concentrations or myocellular TG content.