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Nitro‐aspirin improves high‐fat diet induced insulin resistance in mice by attenuation of iNOS induction in skeletal muscle tissue
Author(s) -
Jayet PierreYves,
Dessen Pierre,
Thalmann Sebastien,
Schwab Marcos,
Vollenweider Peter,
Sartori Claudio,
Scherrer Urs
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1173
Subject(s) - medicine , endocrinology , insulin resistance , skeletal muscle , aspirin , nitric oxide synthase , nitric oxide , insulin , downregulation and upregulation , homeostasis , chemistry , glucose homeostasis , inflammation , biology , biochemistry , gene
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.