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. 2012 Sep 1;113(5):758-65.
doi: 10.1152/japplphysiol.01018.2011. Epub 2012 Jul 12.

Obesity, insulin resistance, and skeletal muscle nitric oxide synthase

Raymond M Kraus  1 , Joseph A Houmard, William E Kraus, Charles J Tanner, Joseph R Pierce, Myung Dong Choi, Robert C Hickner
Affiliations

Obesity, insulin resistance, and skeletal muscle nitric oxide synthase

Raymond M Kraus et al. J Appl Physiol (1985). .

Abstract

The molecular mechanisms responsible for impaired insulin action have yet to be fully identified. Rodent models demonstrate a strong relationship between insulin resistance and an elevation in skeletal muscle inducible nitric oxide synthase (iNOS) expression; the purpose of this investigation was to explore this potential relationship in humans. Sedentary men and women were recruited to participate (means ± SE: nonobese, body mass index = 25.5 ± 0.3 kg/m(2), n = 13; obese, body mass index = 36.6 ± 0.4 kg/m(2), n = 14). Insulin sensitivity was measured using an intravenous glucose tolerance test with the subsequent modeling of an insulin sensitivity index (S(I)). Skeletal muscle was obtained from the vastus lateralis, and iNOS, endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) content were determined by Western blot. S(I) was significantly lower in the obese compared with the nonobese group (~43%; P < 0.05), yet skeletal muscle iNOS protein expression was not different between nonobese and obese groups. Skeletal muscle eNOS protein was significantly higher in the nonobese than the obese group, and skeletal muscle nNOS protein tended to be higher (P = 0.054) in the obese compared with the nonobese group. Alternative analysis based on S(I) (high and low tertile) indicated that the most insulin-resistant group did not have significantly more skeletal muscle iNOS protein than the most insulin-sensitive group. In conclusion, human insulin resistance does not appear to be associated with an elevation in skeletal muscle iNOS protein in middle-aged individuals under fasting conditions.

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Figures

Fig. 1.
Fig. 1.
Insulin sensitivity index (SI) of nonobese (n = 13) and obese (n = 14) sedentary men and women (40–65 yr) determined from intravenous glucose tolerance tests with subsequent analyses by the Bergman minimal model. *Significant difference between nonobese and obese groups (P < 0.05).
Fig. 2.
Fig. 2.
Total skeletal muscle inducible NO synthase (iNOS) protein content determined by Western blot analyses from the vastus lateralis muscle of nonobese (n = 13) and obese (n = 14) sedentary subjects. Representative iNOS Western blot including the iNOS-positive control [(+)iNOS], stimulated mouse macrophage (A), representative Ponceau S stained blot for total protein quantification (B), and comparison between nonobese and obese total skeletal muscle iNOS protein content (C). No statistically significant difference was observed.
Fig. 3.
Fig. 3.
The relationship between SI and total skeletal muscle iNOS protein content in nonobese (n = 13) and obese (n = 14) sedentary subjects (A) and the relationship between SI and total skeletal muscle iNOS protein content in exclusively the obese subjects (B). Although no statistically significant relationship was observed for the entire cohort, isolated analysis of the obese subjects found a significant correlation (P < 0.05).
Fig. 4.
Fig. 4.
Comparison of total skeletal muscle iNOS protein content between groups generated according to each subject's SI, high vs. low tertile (n = 9/group). No statistically significant difference was observed.
Fig. 5.
Fig. 5.
Skeletal muscle endothelial NO synthase (eNOS) protein content determined by Western blot analyses from the vastus lateralis muscle of nonobese (n = 13) and obese (n = 14) sedentary subjects. Representative eNOS Western blot (A), representative Ponceau S stained blot for total protein quantification (B), and comparison between nonobese and obese skeletal muscle eNOS protein content (C). *Significant difference between nonobese and obese (P < 0.05).
Fig. 6.
Fig. 6.
Comparison of skeletal muscle eNOS protein content between groups generated according to each subject's SI, high vs. low tertile (n = 9/group). No statistically significant difference was observed.
Fig. 7.
Fig. 7.
Skeletal muscle neuronal NO synthase (nNOS) protein content determined by Western blot analyses from the vastus lateralis muscle of nonobese (n = 13) and obese (n = 14) sedentary subjects. Representative nNOS Western blot (A), and comparison between nonobese and obese skeletal muscle nNOS protein content (B). The representative nNOS Western blot has an accompanying representative Ponceau S stained blot, which is shown in Fig. 5B. The representative eNOS and nNOS blots share the same Ponceau S blot because commercial stripper was utilized so that membranes could be reprobed. No statistically significant difference was observed.
Fig. 8.
Fig. 8.
Comparison of skeletal muscle nNOS protein content between groups generated according to each subject's SI, high vs. low tertile (n = 9/group). No statistically significant difference was observed.
Fig. 9.
Fig. 9.
Linear regression between SI and skeletal muscle nNOS protein content among nonobese (n = 13) and obese (n = 14) sedentary subjects. There was a significant positive association between SI and skeletal muscle nNOS protein content.
Fig. 10.
Fig. 10.
Skeletal muscle 3-nitrotyrosine protein content determined by Western blot analyses from the vastus lateralis muscle of nonobese (n = 13) and obese (n = 14) sedentary subjects. Representative 3-nitrotyrosine Western blot. No statistically significant difference was observed.
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