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Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle

Abstract

Inducible nitric oxide synthase (iNOS) is induced by inflammatory cytokines in skeletal muscle and fat. It has been proposed that chronic iNOS induction may cause muscle insulin resistance. Here we show that iNOS expression is increased in muscle and fat of genetic and dietary models of obesity. Moreover, mice in which the gene encoding iNOS was disrupted (Nos2−/− mice) are protected from high-fat–induced insulin resistance. Whereas both wild-type and Nos2−/− mice developed obesity on the high-fat diet, obese Nos2−/− mice exhibited improved glucose tolerance, normal insulin sensitivity in vivo and normal insulin-stimulated glucose uptake in muscles. iNOS induction in obese wild-type mice was associated with impairments in phosphatidylinositol 3-kinase and Akt activation by insulin in muscle. These defects were fully prevented in obese Nos2−/− mice. These findings provide genetic evidence that iNOS is involved in the development of muscle insulin resistance in diet-induced obesity.

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Figure 1: iNOS expression in insulin target tissues of high-fat–fed and ob/ob obese mice and obese ZDF rats.
Figure 2: Insulin sensitivity, glucose tolerance and muscle glucose uptake of WT and Nos2−/− mice fed chow or high-fat diets.
Figure 3: Muscle-insulin sensitivity for glucose uptake of WT and Nos2−/− mice fed chow or high-fat diets.
Figure 4: Effects of high-fat feeding on insulin signaling components in skeletal muscle of WT and Nos2−/− mice.
Figure 5: Effects of high-fat feeding on insulin-induced PI 3-kinase activity and Akt phosphorylation in adipose tissue and liver of WT and Nos2−/− mice.

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Acknowledgements

We thank B. Marcotte and J. Lalonde for technical assistance; F. Tremblay for help with the determination of PI 3-kinase activity; R. Labrecque for help with the maintenance and care of the transgenic mice lines; C. Nathan for advice; and Y. Deshaies and C.H. Côté for critical reading of the manuscript. This work was supported by grants from the Canadian Institutes for Health Research (to A.M.).

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Correspondence to André Marette.

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Perreault, M., Marette, A. Targeted disruption of inducible nitric oxide synthase protects against obesity-linked insulin resistance in muscle. Nat Med 7, 1138–1143 (2001). https://doi.org/10.1038/nm1001-1138

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