title: 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.
authors.affiliation: Department of Clinical and Molecular Endocrinology, Tokyo Medical and Dental University Graduate School, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. ktsuchiya.cme@tmd.ac.jp
authors.forename: Kyoichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Haruna
authors.initials: H
authors.lastname: Sakai
authors.forename: Noriko
authors.initials: N
authors.lastname: Suzuki
authors.forename: Fumiko
authors.initials: F
authors.lastname: Iwashima
authors.forename: Takanobu
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Shichiri
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hirata
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000652:urine; D004041:Dietary Fats / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005951:Glucose Tolerance Test; D007249:Inflammation / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008660:Metabolism / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology; D009566:Nitrates / Q000652:urine; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009573:Nitrites / Q000652:urine; D009765:Obesity / Q000209:etiology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D009929:Organ Size / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002395:Catecholamines; D004041:Dietary Fats; D004791:Enzyme Inhibitors; D007328:Insulin; D007527:Isoenzymes; D009566:Nitrates; D009573:Nitrites; D011506:Proteins; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester