ID: 81: NANOFORMULATED COPPER/ZINC SUPEROXIDE DISMUTASE CAUSES MUSCLE METABOLIC ALTERATIONS AND IMPROVES SYSTEMIC INSULIN SENSITIVITY IN MICE

Oxidative stress mediates mitochondrial dysfunction and impairment of glucose metabolism in muscle thereby leading to systemic insulin resistance. In vivo studies have demonstrated that copper/zinc superoxide dismutase (Cu/ZnSOD)-deficient mice show oxidative damage in various organs including skeletal muscle. The objective of this study is to determine the role of nanoformulated Cu/ZnSOD (nanoSOD) in improving insulin sensitivity through effects inherent to muscle. Wild type mice were fed a standard chow diet for 10 weeks. A cohort of these mice received nanoSOD intraperitoneally at 1000 U/kg body weight once in two days for a period of 15 days. We noted that the fasting blood glucose level was significantly reduced in nanoSOD treated mice compared to control (P<0.05). Moreover, insulin tolerance test (ITT) revealed that nanoSOD treated mice showed improved glucose handling in response to insulin (0.75 U/kg body weight) compared to control mice. However, the response of these mice to acute glucose challenge as analyzed by glucose tolerance test was not different between groups. We next analyzed the muscle mRNA samples for genes involved in fatty acid metabolism. Interestingly, we noted that the expression of FASN and SREBP1, genes promoting fatty acid synthesis was significantly reduced in nanoSOD treated mice suggesting that de novo lipogenesis which can promote insulin resistance is reduced upon nanoSOD treatment. Further, the mRNA expression of PCX which promotes both gluconeogenesis and lipogenesis was significantly reduced (P<0.01) in nanoSOD treated mice compared to controls. Regarding genes regulating fatty acid metabolism, we noted that the expression of ACOX1, CPT1a, and CPT2, genes involved in mitochondrial fatty acid β-oxidation was reduced in nanoSOD treated mice. Interestingly, these metabolic changes were associated with reduced mRNA levels of inflammatory markers including TNFα, MMP12, and VCAM-1 in visceral adipose tissue in nanoSOD treated mice. However, in the liver, the mRNA level of genes involved in de novo lipogenesis and mitochondrial fatty acid β-oxidation was not altered upon nanoSOD treatment Taken together; our data demonstrate that nanoSOD improves systemic glucose handling which was associated with a reduction in de novo lipogenesis and fatty acid oxidation in muscle. Because fatty acid oversupply is a key mediator of muscle insulin resistance primarily via accumulation of fatty acid metabolites, our data suggest that changes in muscle fatty acid metabolism may play a role in mediating the effects of nanoSOD in improving systemic glucose handing and insulin resistance. .