Abstract 213: Differential Effects of Nanoformulated Copper/zinc Superoxide Dismutase in Regulating Fasting Blood Glucose Levels in Mice Fed a Low versus High Fat Diet

Abstract

We previously reported that nanoformulated copper/zinc superoxide dismutase (nanoSOD) ameliorates adipose tissue inflammation without altering systemic glucose homeostasis in a mouse model of diet-induced obesity. A recent report showed that mice lacking SOD1 exhibit insulin resistance only upon low fat (chow) but not high fat (HF)-diet feeding suggesting that the effect of nanoSOD in modulating systemic glucose levels may depend on the diet type. The objective of this study is to determine the effectiveness of nanoSOD in altering muscle gene expression and/or systemic glucose handling in mice fed a low versus high fat (HF) diet. Six-eight wk old wild type C57BL/6 mice were fed a low fat chow diet (CD) or a HF fat (45%) for 10 wk. The mice were injected with nanoSOD (1000 units/kg body wt.) once in two days for fifteen days. The fasting blood glucose level was significantly reduced in CD+NanoSOD-treated mice compared to CD control ( P <0.05) . Insulin tolerance test revealed that nanoSOD-treated mice showed improved glucose handling in response to insulin in CD but not in HF diet-fed mice. The muscle mRNA expression of LPL , a gene involved in fatty acid uptake, was significantly increased ( P <0.05) and ACOX-1 , a fatty acid oxidation gene, showed a trend towards an increase ( P <0.052) upon nanoSOD treatment in HF-diet fed mice. On the other hand, genes involved in fatty acid metabolism including ACOX1, CPT1a , and CPT2 were significantly down-regulated in CD+nanoSOD treated mice. Moreover, the expression of FASN ( P <0.05) and SREBP1 ( P <0.01), genes promoting fatty acid synthesis was significantly reduced in CD+nanoSOD treated mice. Further, the mRNA expression of PCX which promotes both gluconeogenesis and lipogenesis was significantly reduced ( P <0.01) in CD+nanoSOD treated mice. Taken together, our data show that nanoSOD exerts differential effects on the muscle expression of genes involved in fatty acid metabolism in low fat versus HF diet-fed conditions. Because fatty acid oversupply is a key mediator of muscle insulin resistance, a switch in nutrient supply favoring fatty acid oxidation during HF diet-feeding may have a role in mediating the differential influence of nanoSOD in modulating systemic glucose homeostasis in low versus HF diet-fed conditions.