Abstract 312: Akt1-Mediated Muscle Growth Will Regress Adiposity and Insulin Resistance in Obese Mice
Obesity is the most common risk factor for cardiovascular diseases. Although it is known that increasing skeletal muscle activity can reduce obesity and improve obesity-related diseases, mouse models that can assess the molecular relationships between muscle growth and obesity are lacking. We have generated a skeletal muscle-specific, conditional transgenic (TG) mouse that can induce the growth of functional skeletal muscle by switching Akt1 signaling on or off and assessed the hypothesis that robust skeletal muscle growth can reverse obesity and insulin resistance in diet-induced obese mice. Activation of Akt1 signaling for 2 weeks led to an increase in muscle mass (238.0±6.9 vs. 170.6±4.9 mg, gastrocnemius muscle weight, p<0.01). Akt1-induced muscle hypertrophy led to higher peak grip force compared with control muscle (104.7±3.7 vs. 69.8±0.8 g, p<0.05). Under conditions of repressed Akt1 expression, mice were fed high fat/sucrose diet to induce obesity. Although there was no difference in daily food intake, activation of Akt1 signaling in skeletal muscle of obese mice dramatically reduced fat mass calculated by MRI measurements (3.9±0.7 vs. 8.4±0.7 cm3, p<0.01). TG mice showed increased oxygen consumption ratio measured by indirect colorimeter (2887±66 vs. 2615±62ml/kg/min, p<0.01), in spite of decrease in ambulatory activity levels (20788±2911 vs. 34557±3932 beam brakes/day, p<0.01). Glucose and insulin tolerance test revealed that diet-induced severe insulin resistance was clearly improved after Akt1 activation in skeletal muscle. When Akt1-induced muscle growth was blocked by treatment with rapamycin, the fat mass regression effect was not observed. In conclusion, Akt1-mediated skeletal muscle growth, independent of food consumption or physical activity, can regress adiposity and obesity related insulin resistance.