Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation
iNOS, an important mediator of inflammation, has emerged as an important metabolic regulator. There are conflicting observations on the incidence of insulin resistance (IR) due to hyperglycemia/dyslipidemia in iNOS<sup>−/−</sup> mice. There are reports that high fat diet (HFD) fed mice e...
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MDPI AG
2020-08-01
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| Series: | Antioxidants |
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| Online Access: | https://www.mdpi.com/2076-3921/9/8/736 |
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| author | Hobby Aggarwal Priya Pathak Pragati Singh Jiaur R. Gayen Kumaravelu Jagavelu Madhu Dikshit |
| author_facet | Hobby Aggarwal Priya Pathak Pragati Singh Jiaur R. Gayen Kumaravelu Jagavelu Madhu Dikshit |
| author_sort | Hobby Aggarwal |
| collection | DOAJ |
| description | iNOS, an important mediator of inflammation, has emerged as an important metabolic regulator. There are conflicting observations on the incidence of insulin resistance (IR) due to hyperglycemia/dyslipidemia in iNOS<sup>−/−</sup> mice. There are reports that high fat diet (HFD) fed mice exhibited no change, protection, or enhanced susceptibility to IR. Similar observations were also reported for low fat diet (LFD) fed KO mice. In the present study chow fed iNOS<sup>−/−</sup> mice were examined for the incidence of IR, and metabolic perturbations, and also for the effect of sodium nitrite supplementation (50 mg/L). In IR-iNOS<sup>−/−</sup> mice, we observed significantly higher body weight, BMI, adiposity, blood glucose, HOMA-IR, serum/tissue lipids, glucose intolerance, enhanced gluconeogenesis, and disrupted insulin signaling. Expression of genes involved in hepatic and adipose tissue lipid uptake, synthesis, oxidation, and gluconeogenesis was upregulated with concomitant downregulation of genes for hepatic lipid excretion. Nitrite supplementation restored NO levels, significantly improved systemic IR, glucose tolerance, and also reduced lipid accumulation by rescuing hepatic insulin sensitivity, glucose, and lipid homeostasis. Obesity, gluconeogenesis, and adipose tissue insulin signaling were only partially reversed in nitrite supplemented iNOS<sup>−/−</sup> mice. Our results thus demonstrate that nitrite supplementation to iNOS<sup>−/−</sup> mice improves insulin sensitivity and metabolic homeostasis, thus further highlighting the metabolic role of iNOS. |
| first_indexed | 2024-03-10T17:35:25Z |
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| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T17:35:25Z |
| publishDate | 2020-08-01 |
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| series | Antioxidants |
| spelling | doaj.art-5116bd689a524ba69ff97faf403d5a3b2023-11-20T09:51:22ZengMDPI AGAntioxidants2076-39212020-08-019873610.3390/antiox9080736Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite SupplementationHobby Aggarwal0Priya Pathak1Pragati Singh2Jiaur R. Gayen3Kumaravelu Jagavelu4Madhu Dikshit5Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaPharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaPharmaceutics & Pharmacokinetics Division, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaPharmacology Division, CSIR-Central Drug Research Institute, Lucknow 226031, IndiaiNOS, an important mediator of inflammation, has emerged as an important metabolic regulator. There are conflicting observations on the incidence of insulin resistance (IR) due to hyperglycemia/dyslipidemia in iNOS<sup>−/−</sup> mice. There are reports that high fat diet (HFD) fed mice exhibited no change, protection, or enhanced susceptibility to IR. Similar observations were also reported for low fat diet (LFD) fed KO mice. In the present study chow fed iNOS<sup>−/−</sup> mice were examined for the incidence of IR, and metabolic perturbations, and also for the effect of sodium nitrite supplementation (50 mg/L). In IR-iNOS<sup>−/−</sup> mice, we observed significantly higher body weight, BMI, adiposity, blood glucose, HOMA-IR, serum/tissue lipids, glucose intolerance, enhanced gluconeogenesis, and disrupted insulin signaling. Expression of genes involved in hepatic and adipose tissue lipid uptake, synthesis, oxidation, and gluconeogenesis was upregulated with concomitant downregulation of genes for hepatic lipid excretion. Nitrite supplementation restored NO levels, significantly improved systemic IR, glucose tolerance, and also reduced lipid accumulation by rescuing hepatic insulin sensitivity, glucose, and lipid homeostasis. Obesity, gluconeogenesis, and adipose tissue insulin signaling were only partially reversed in nitrite supplemented iNOS<sup>−/−</sup> mice. Our results thus demonstrate that nitrite supplementation to iNOS<sup>−/−</sup> mice improves insulin sensitivity and metabolic homeostasis, thus further highlighting the metabolic role of iNOS.https://www.mdpi.com/2076-3921/9/8/736iNOS<sup>−/−</sup>nitritenitric oxideinsulin resistancedyslipidemialiver |
| spellingShingle | Hobby Aggarwal Priya Pathak Pragati Singh Jiaur R. Gayen Kumaravelu Jagavelu Madhu Dikshit Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation Antioxidants iNOS<sup>−/−</sup> nitrite nitric oxide insulin resistance dyslipidemia liver |
| title | Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation |
| title_full | Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation |
| title_fullStr | Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation |
| title_full_unstemmed | Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation |
| title_short | Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation |
| title_sort | systemic insulin resistance and metabolic perturbations in chow fed inducible nitric oxide synthase knockout male mice partial reversal by nitrite supplementation |
| topic | iNOS<sup>−/−</sup> nitrite nitric oxide insulin resistance dyslipidemia liver |
| url | https://www.mdpi.com/2076-3921/9/8/736 |
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