Systemic Insulin Resistance and Metabolic Perturbations in Chow Fed Inducible Nitric Oxide Synthase Knockout Male Mice: Partial Reversal by Nitrite Supplementation

Abstract

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−/− 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−/− 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−/− 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−/− mice. Our results thus demonstrate that nitrite supplementation to iNOS−/− mice improves insulin sensitivity and metabolic homeostasis, thus further highlighting the metabolic role of iNOS.

IL‐17 signaling induces iNOS+ microglia activation in retinal vascular diseases

“…Indeed, M1 microglia are considered to be pro-inflammatory and express iNOS, leading to potential damage via reactive nitrogen species (Kalkman & Feuerbach, 2016). Knockdown of iNOS gene could prevent the leukostasis and breakdown of BRB in the retina of diabetic mice and rats, further indicating the association between iNOSexpressing microglia and the vascular damage in DR (Aggarwal et al, 2020). In addition, IL-6 could act as the effector of activated microglia (Li et al, 2021).…”

Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria And Metabolites Remediate Insulin Resistance In INOS Knockout Mice

“…The body length was also measured from nose tip to the tail's base of each mouse. Body mass index (BMI) was calculated using the formula body weight (g) divided by the square of nose to anus length (cm) as previously described [27] at the end of 4 weeks of antibiotic treatment. The weekly food consumption was measured by housing 2-3 mice per cage and adding the pre-weighed food pellets to each cage and measuring the food left over on a sensitive weighing balance twice weekly.…”

“…Liver tissue (50 mg) was processed as described previously [27] for the estimation of hepatic total cholesterol, triglycerides and free fatty acids (FFA) using Randox kit. Brie y, for TC estimation, samples were homogenized on ice in 1ml hexane:isopropanol mixture (3:2 ratio) followed by centrifugation, supernatant collection and drying in Centrivap concentrator (Labconco, USA).…”

Role of nitric oxide in orthodontic tooth movement (Review)

“…Furthermore, osteopontin has been shown to suppress the osteoblast response to ultrasound by inhibiting the expression of nNOS and iNOS through FAK downregulation (194). This inconsistency may be explained in view of the possibility of an alternative way of NO production induction by other NOS isoforms and through a non-enzymatic NO production manner (including reduction of nitrite and denitrosylation of some proteins), in case a specific NOS isoform is absent (195)(196)(197). The aforementioned ultrasound results can only prove the role of nNOS or iNOS in ultrasound-induced promotion on osteoblasts; however, those results do not contradict the involvement of eNOS.…”