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

• Published in: Endocrinology (Philadelphia) 2007-10, Vol.148 (10), p.4548-4556
• Main Authors: Tsuchiya, Kyoichiro, Sakai, Haruna, Suzuki, Noriko, Iwashima, Fumiko, Yoshimoto, Takanobu, Shichiri, Masayoshi, Hirata, Yukio
• Format: Article
• Language: English
• Subjects: Adiponectin; Adipose tissue; Adipose tissue (brown); Adipose Tissue - enzymology; Adipose Tissue - metabolism; Adiposity - drug effects; AKT protein; AKT2 protein; Animals; Arginine; Biological and medical sciences; Blood Pressure - drug effects; Body fat; Body weight; Body weight gain; Catecholamines - urine; Diet; Dietary Fats - administration & dosage; Drinking water; Drug Administration Schedule; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Gene expression; Gene Expression - drug effects; Glucose; Glucose tolerance; Glucose Tolerance Test; High fat diet; Inflammation - genetics; Insulin; Insulin - metabolism; Insulin Resistance; Isoenzymes - metabolism; Isoforms; Leptin; Male; Medical sciences; Metabolic diseases; Metabolism - genetics; Mice; Mice, Inbred C57BL; Monocyte chemoattractant protein; Monocyte chemoattractant protein 1; Monocytes; Muscle, Skeletal - enzymology; Muscle, Skeletal - metabolism; Muscles; Musculoskeletal system; NG-Nitroarginine methyl ester; NG-Nitroarginine Methyl Ester - administration & dosage; NG-Nitroarginine Methyl Ester - pharmacology; Nitrates - urine; Nitric oxide; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitric-oxide synthase; Nitrites - urine; Norepinephrine; Obesity; Obesity - etiology; Obesity - metabolism; Obesity - pathology; Obesity - physiopathology; Organ Size - drug effects; Phenotypes; Phosphorylation; Proteins; Proteins - metabolism; Signal Transduction - drug effects; Skeletal muscle; Synthesis; Tyrosine; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2006-1371

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.