The Role Of SIRT1 In Obesity And Insulin Resistance

PART I:Three single nucleotide variants of SIRT1 gene are associated with overweight in a Chinese populationObjective:The prevalence of obesity and metabolic syndrome has fueled research on genetic loci of candidate genes. We herein aimed to explore whether common allelic variations in the SIRT1 gene were associated with overweight in a Chinese cohort.Methods:Four haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen for linkage disequilibrium, prevalence≥2.0%, minor allele frequency≥0.05, and coverage of the SIRT1 variability. They were genotyped in 820 Chinese individuals by PCR amplification and the ligase detection reaction.Results:The rs1050929AA and rs10823116 GG alleles had significantly higher occurrence rates in the overweight group whereas the rs7894483TT alleles had a significantly lower rate. The association of carriers of rs10509291AT with modestly higher risk of overweight was consistent with a dominant model for the A allele. Carriers of two haplotypes, ATAA (rs7894483/rs10823116) and ATAG showed a significantly higher risk (OR:17.11 and 5.12) of overweight compared with carriers of AAAG (P<0.01). In agreement with a reduced risk of overweight in carriers of rs10509291TT genotype, carriers of TTATAA or TTATGG [rs10509291/rs7894483/rs10823116] had a lower risk of overweight than carriers of ATAA(OR:13.88 vs 17.11) and ATGG (OR:1.14 vs 5.12), respectively.Conclusions:The findings of this study suggest that the rs10509291, rs7894483, and rs10823116 SNP alleles interact and have a significant association with excess weight gain in the Chinese population.PARTⅡ:Resveratrol-activated SIRT1 Improves insulin resisitance in Catch-up Growth RatsObjective:Caloric restriction (CR) followed by re-feeding, a phenomenon known as catch-up growth (CUG), affects mitochondrial function and results in systemic insulin resistance (IR). We intended to observe the effect of CUG on SIRTl expression and activity, and to increase SIRT1 activity, we interfered the rats with resveratrol, thus relieving the negative effects of mitochondrial dysfunction.Methods:Rats (8 weeks of age) were divided into three groups:normal chow (NC), CUG, and catch-up growth with RES intervention (CUGE). Fat distribution, skeletal muscle and systemic IR were measured in each group after 4 and 8 weeks. Mitochondrial biogenesis and function, oxidative stress levels, and antioxidant enzyme activity in skeletal muscle were assessed. Results:CUG induced IR resulted in significant reductions in both average glucose infusion rate60-120 (GIR60-120) at euglycemia and skeletal muscle glucose uptake. Mitochondrial citrate synthase (CS) activity was lower and activity of complexesⅠ-Ⅳin the intermyofibrillar (IMF) and subsarcolemmal (SS) mitochondria were reduced by 20-40%, with the decrease being more pronounced in the SS fraction. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels were significantly higher in IMF and SS mitochondria while antioxidant enzyme activity was decreased. However, oral administration of RES increased SIRT1 activity, reduced abdominal fat accumulation, improved mitochondrial number and insulin sensitivity. RES treatment decreased levels of lipid peroxides and ROS, and restored antioxidant enzyme activity.Conclusions:We investigated the potential of RES in CUG to prevent IR by increasing activity of the mitochondrial respiratory chain and antioxidant enzymes in skeletal muscle. This study demonstrates that SIRT1 protects insulin sensitivity by improving the activity of skeletal muscle mitochondrial complexes and the antioxidant defense status in CUG rats. Thus, SIRT1 has therapeutic potential for preventing CUG-related metabolic disorders.