High-fat diet-induced impairment of skeletal muscle insulin sensitivity is not prevented by SIRT1 overexpression.
Skeletal muscle sirtuin 1 (SIRT1) expression is reduced under insulin-resistant conditions, such as those resulting from high-fat diet (HFD) feeding and obesity. Herein, we investigated whether constitutive activation of SIRT1 in skeletal muscle prevents HFD-induced muscle insulin resistance. To address this, mice with muscle-specific overexpression of SIRT1 (mOX) and wild-type (WT) littermates were fed a control diet (10% calories from fat) or HFD (60% of calories from fat) for 12 wk. Magnetic resonance imaging and indirect calorimetry were used to measure body composition and energy expenditure, respectively. Whole body glucose metabolism was assessed by oral glucose tolerance test, and insulin-stimulated glucose uptake was measured at a physiological insulin concentration in isolated soleus and extensor digitorum longus muscles. Although SIRT1 was significantly overexpressed in muscle of mOX vs. WT mice, body weight and percent body fat were similarly increased by HFD for both genotypes, and energy expenditure was unaffected by diet or genotype. Importantly, impairments in glucose tolerance and insulin-mediated activation of glucose uptake in skeletal muscle that occurred with HFD feeding were not prevented in mOX mice. In contrast, mOX mice showed enhanced postischemic cardiac functional recovery compared with WT mice, confirming the physiological functionality of the SIRT1 transgene in this mouse model. Together, these results demonstrate that activation of SIRT1 in skeletal muscle alone does not prevent HFD-induced glucose intolerance, weight gain, or insulin resistance.
['White|Amanda T|AT|', 'Philp|Andrew|A|', 'Fridolfsson|Heidi N|HN|', 'Schilling|Jan M|JM|', 'Murphy|Anne N|AN|', 'Hamilton|D Lee|DL|', 'McCurdy|Carrie E|CE|', 'Patel|Hemal H|HH|', 'Schenk|Simon|S|']
D050154:Adiposity D000818:Animals D001823:Body Composition D059305:Diet, High-Fat D004734:Energy Metabolism D018149:Glucose Intolerance D006321:Heart D007333:Insulin Resistance D008297:Male D008810:Mice, Inbred C57BL D008822:Mice, Transgenic D008931:Mitochondria, Muscle D018482:Muscle, Skeletal D015428:Myocardial Reperfusion Injury D009765:Obesity D010101:Oxygen Consumption D011897:Random Allocation D056564:Sirtuin 1 D015854:Up-Regulation D015430:Weight Gain
skeletal muscle SIRT1 high-fat diet insulin resistance