Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice
Chronic blockade of nitric oxide synthesis reduces adiposity and improves insulin resistance in high fat-induced obese mice
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DOI：
10.1210/en.2006-1371
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发表时间：
2007-10-01
期刊：
影响因子：
4.8
通讯作者：
Hirata, Yukio
中科院分区：
文献类型：
--
作者：
Tsuchiya, Kyoichiro;Sakai, Haruna;Hirata, Yukio
小鼠中诱导型一氧化氮合酶（NOS）的基因缺失已被证明可改善高脂饮食（HFD）诱导的胰岛素抵抗。然而，内源性一氧化氮（NO）在肥胖相关的胰岛素抵抗的病理生理作用仍然存在争议。为了解决这个问题，我们研究了HFD诱导的肥胖小鼠的代谢表型，这些小鼠通过NOS抑制剂N（G）-硝基-L-精氨酸甲酯（L-NAME）慢性阻断NO合成。向六周龄雄性C57 BL/6 j小鼠自由提供标准饮食（SD）或HFD和具有或不具有L-NAME（100 mg/kg . d）12 wk。L-NAME治疗显著减弱了喂食SD或HFD的小鼠的体重增加，而不影响热量摄入。HFD喂养小鼠的L-NAME治疗改善了葡萄糖耐量和胰岛素敏感性。HFD喂养诱导NOS mRNA的表达，但不是其他两个NOS亚型，在白色脂肪组织（WAT）和骨骼肌。L-NAME处理上调HFD喂养小鼠棕色脂肪组织中的解偶联蛋白-1，但下调WAT中单核细胞趋化蛋白-1和CD 68 mRNA水平。HFD喂养上调瘦素mRNA水平，但相反下调脂联素mRNA水平在WAT，但这些影响不受L-NAME治疗。此外，L-NAME治疗还增加了HFD喂养小鼠骨骼肌中过氧化物酶体增殖物解偶联蛋白-3 mRNA水平。在L-NAME处理的小鼠中，HFD喂养后去甲肾上腺素的尿排泄增加。胰岛素刺激的酪氨酸磷酸化的胰岛素受体底物-1和丝氨酸磷酸化的Akt/Akt 2在比目鱼肌HFD喂养的小鼠显着受损，但逆转L-NAME治疗。总之，L-NAME在小鼠中的慢性NOS阻断改善HFD诱导的肥胖和葡萄糖耐受不良，伴随着减少脂肪炎症和改善骨骼肌中的胰岛素信号传导，表明内源性NO在肥胖相关的胰岛素抵抗的发展中起着调节作用。
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.