Moderate SirT1 Overexpression Protects against High Fat Diet Induced Insulin Resistance and Mitochondrial Dysfunction

Background: High fat diet may cause a diabetic phenotype, which is associated with increased cardiac events and worse outcome in cardiac surgery. The key mechanism relate to insulin resistance and mitochondrial dysfunction. The protein deacetylase SirT1, a known longevity factor, improves insulin sensitivity but also affects mitochondrial biogenesis.

Objective: We assessed the influence of high fat diet on insulin signaling, cardiac and mitochondrial function in wild type and hemizygote transgenic SirT1 mice.

Methods: Wild type (wt) and hemizygote SirT1 transgenic mice at 8 weeks of age were exposed either to high fat diet (D12492) or standard chow (SD). After 8 weeks of HFD, cardiac function was assessed by echocardiography and respiratory capacity of isolated mitochondria was measured. Furthermore, glucose tolerance was investigated with a glucose tolerance test (GTT) and insulin signaling of several organs was assessed with Western blot. SirT1 protein expression was also assessed.

Results: After 8 weeks of high fat diet (HFD), mice displayed increased body mass and epididymal fat weight. This weight gain was significantly less pronounced in SirT1 mice. Echocardiography revealed normal cardiac morphology, systolic and diastolic function after HFD. Cardiac citrate synthase activity was unaffected. However, mitochondrial respiratory capacity with glutamate as substrate was slightly decreased with HFD in wt mice. This effect was not present in SirT1 mice with HFD (wt-SD 688 ± 62 versus wt-HFD 483 ± 116 versus SirT1-SD 535 ± 85 versus SirT1-HFD 771 ± 90 natomsO/min/mg). HFD led to impaired glucose tolerance in wt and SirT1 mice. However, SirT1 mice displayed improved glucose tolerance and lower maximal blood glucose levels during GTT than wt (AUC: 1228 ± 101 versus 1913 ± 95 versus 1158 ± 92 versus 1569 ± 104). Insulin response as assessed by insulin stimulated P-Akt/Akt ratio was unchanged in heart and skeletal muscle after HFD. However, SirT1 protein expression in heart and skeletal muscle was 2-fold increased in Sirt1 mice compared with wt mice and further increased with HFD.

Conclusion: A moderate overexpression of SirT1 improves insulin sensitivity and protects against high fat diet induced mitochondrial dysfunction.