Chronic Blockade of Nitric Oxide Synthesis Reduces Adiposity and Improves Insulin Resistance in High Fat-Induced Obese Mice

Abstract

Genetic deletion of inducible nitric oxide synthase (NOS) in mice has been shown to improve high-fat diet (HFD)-induced insulin resistance. However, a pathophysiological role of endogenous nitric oxide (NO) in obesity-related insulin resistance remains controversial. To address this issue, we examined the metabolic phenotypes in HFD-induced obese mice with chronic blockade of NO synthesis by a NOS inhibitor, N(G)-nitro-l-arginine methyl ester (L-NAME). Six-week-old male C57BL/6j mice were provided free access to either a standard diet (SD) or a HFD and tap water with or without L-NAME (100 mg/kg.d) for 12 wk. L-NAME treatment significantly attenuated body weight gain of mice fed either SD or HFD without affecting calorie intake. L-NAME treatment in HFD-fed mice improved glucose tolerance and insulin sensitivity. HFD feeding induced inducible NOS mRNA expression, but not the other two NOS isoforms, in white adipose tissue (WAT) and skeletal muscle. L-NAME treatment up-regulated uncoupling protein-1 in brown adipose tissue of HFD-fed mice but down-regulated monocyte chemoattractant protein-1 and CD68 mRNAs levels in WAT. HFD feeding up-regulated leptin mRNA levels but conversely down-regulated adiponectin mRNA levels in WAT, but these effects were unaffected by L-NAME treatment. Moreover, L-NAME treatment also increased peroxisome proliferator-uncoupling protein-3 mRNA levels in skeletal muscles of HFD-fed mice. Increased urinary excretion of norepinephrine after HFD feeding was augmented in L-NAME-treated mice. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and serine phosphorylation of Akt/Akt2 in soleus muscle was markedly impaired in HFD-fed mice but reversed by L-NAME treatment. In conclusion, chronic NOS blockade by L-NAME in mice ameliorates HFD-induced adiposity and glucose intolerance, accompanied by reduced adipose inflammation and improved insulin signaling in skeletal muscle, suggesting that endogenous NO plays a modulatory role in the development of obesity-related insulin resistance.

Uncoupling protein 1 expression and high-fat diets

“…Eleven studies show no effect, and 9 even report a decrease. The variance of reported effect sizes tends to be higher on the mRNA level and in some cases is divergent from protein levels even in the same samples (75).…”

Lack of Inducible Nitric Oxide Synthase Prevents Lipid-Induced Skeletal Muscle Insulin Resistance Without Attenuating Cytokine Level

“…Furthermore, high-fat-fed obese mice show an increased level of iNOS and the absence of the iNOS gene protects against high-fat diet-induced skeletal muscle insulin resistance (13). Blockade of iNOS by N G -nitro-L-arginine methyl ester (L-NAME) improves high-fat diet-induced obesity and glucose intolerance in experimental rodents (23). The present data also demonstrated that lack of the iNOS gene also prevented lipid infusion-induced insulin resistance in skeletal muscle.…”

Wpływ L-argininy i kwasu askorbinowego na zawartość tłuszczu trzewnego oraz stężenia metaloproteinaz 2 i 9 u szczurów karmionych dietą wysokotłuszczową

“…After 12 weeks of either a standard diet (SD) or a HF diet, alone or combined with L-NAME (100 mg/kg/d), it was found that L-NAME treatment significantly attenuated body-weight gain in both groups of mice without affecting calorie intake. Chronic NOS blockade by L-NAME in mice ameliorated HF diet induced adiposity and glucose intolerance; it also reduced adipose inflammation and improved insulin signalling in skeletal muscle [26].…”