Nitro‐aspirin improves high‐fat diet induced insulin resistance in mice by attenuation of iNOS induction in skeletal muscle tissue

Abstract

Nitric oxide (NO) plays a pivotal role in the regulation of glucose homeostasis. In insulin resistant humans and high-fat diet (HFD) fed mice, the inducible form of NO synthase (iNOS) is upregulated in skeletal muscle, where it contributes to insulin resistance, as evidenced by protection against HFD-induced insulin resistance in iNOS knockout mice. Conversely, there is evidence that slow releasing NO donors improve insulin sensitivity in HFD-fed mice, but the mechanism is unknown. We hypothesized that it may do so by attenuating iNOS induction in skeletal muscle. We, therefore, studied the effects of nitro-aspirin (100 mg/kg/day during wk 8) on glucose uptake in vivo (hyperinsulinemic clamp) in C57BL6 mice fed with HFD for 8 wks. In additional mice, we studied the effects of nitro-aspirin on iNOS protein and RNA expression (RT-PCR) in skeletal muscle. As expected, glucose infusion rate during the steady state of the clamp was significantly lower in HFD- than normal chow fed mice (68.1±14.9 vs. 93.3±15.7 mg/kg per min, P<0.01). Nitro-aspirin partially restored insulin sensitivity in HFD fed mice (80.8±9.9 mg/kg per min, P=0.03 vs. vehicle), whereas aspirin had no effect. Most, importantly, nitro aspirin, but not aspirin, abolished (P<0.02) the HFD-induced increase in iNOS protein expression, and attenuated (P<0.04) the increase in RNA expression in skeletal muscle. These findings provide the very first evidence that a slow releasing NO-donor prevents iNOS induction and inflammation in skeletal muscle tissue and improves glucose homeostasis in insulin-resistant HFD-fed mice.