Control of muscle mitochondria by insulin entails activation of Akt2-mtNOS pathway: implications for the metabolic syndrome.
Control of muscle mitochondria by insulin entails activation of Akt2-mtNOS pathway: implications for the metabolic syndrome.
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DOI：
10.1371/journal.pone.0001749
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发表时间：
2008-03-12
期刊：
影响因子：
3.7
通讯作者：
Poderoso JJ
中科院分区：
文献类型：
--
作者：
Finocchietto P;Barreyro F;Holod S;Peralta J;Franco MC;Méndez C;Converso DP;Estévez A;Carreras MC;Poderoso JJ
在高胰岛素血症的代谢综合征中，线粒体抑制促进肌肉脂肪和糖原积累并加速其进展。在过去的十年中，一氧化氮（NO）作为一个典型的线粒体调节剂出现可逆地抑制citochrome氧化酶和氧利用。我们想知道胰岛素操纵的信号通路是否通过NO调节线粒体呼吸，以交替地释放完全的葡萄糖氧化为CO2和H2O或驱动葡萄糖储存为糖原。我们在这里说明，由易位nNOS（线粒体NOS）产生的NO是控制线粒体氧利用的胰岛素信号分子。我们通过皮下注射成年雄性大鼠长效人甘精胰岛素（在血浆中保持稳定数小时），引发高胰岛素-正常血糖非侵入性钳夹。在一个精确的浓度下，胰岛素增加了磷酸化Akt 2，它易位到线粒体并决定原位磷酸化和大量的协同mtNOS激活（+4-8倍，P<0.05），高NO，线粒体氧摄取和静息代谢率降低（-25至-60%，P<0.05）。通过在同一动物的两条腿中直接电穿孔siRNA nNOS或空载体来比较对腓肠肌的体内胰岛素代谢作用，证实在沉默的肌肉中，相对于载体处理的肌肉中的正常mtNOS，破坏的mtNOS允许更高的氧摄取和完全的（U-14 C）-葡萄糖利用（分别为37±3 vs 10±1 µ mol O2/h.g组织和13±1 vs 7.2±1 µmol 3 H2O/h.g组织，P<0.05），这将糖原合成限制了一半。这些证据表明，能量补充后，胰岛素通过NO抑制骨骼肌中的线粒体呼吸，NO允许底物以大分子形式沉积;在离散的高胰岛素血症时，持续的mtNOS激活可能导致线粒体功能障碍伴胰岛素抵抗和肥胖，因此导致代谢综合征的进展。
In the metabolic syndrome with hyperinsulinemia, mitochondrial inhibition facilitates muscle fat and glycogen accumulation and accelerates its progression. In the last decade, nitric oxide (NO) emerged as a typical mitochondrial modulator by reversibly inhibiting citochrome oxidase and oxygen utilization. We wondered whether insulin-operated signaling pathways modulate mitochondrial respiration via NO, to alternatively release complete glucose oxidation to CO2 and H2O or to drive glucose storage to glycogen. We illustrate here that NO produced by translocated nNOS (mtNOS) is the insulin-signaling molecule that controls mitochondrial oxygen utilization. We evoke a hyperinsulinemic-normoglycemic non-invasive clamp by subcutaneously injecting adult male rats with long-lasting human insulin glargine that remains stable in plasma by several hours. At a precise concentration, insulin increased phospho-Akt2 that translocates to mitochondria and determines in situ phosphorylation and substantial cooperative mtNOS activation (+4–8 fold, P<.05), high NO, and a lowering of mitochondrial oxygen uptake and resting metabolic rate (−25 to −60%, P<.05). Comparing in vivo insulin metabolic effects on gastrocnemius muscles by direct electroporation of siRNA nNOS or empty vector in the two legs of the same animal, confirmed that in the silenced muscles disrupted mtNOS allows higher oxygen uptake and complete (U-14C)-glucose utilization respect to normal mtNOS in the vector-treated ones (respectively 37±3 vs 10±1 µmolO2/h.g tissue and 13±1 vs 7.2±1 µmol 3H2O/h.g tissue, P<.05), which reciprocally restricted glycogen-synthesis by a half. These evidences show that after energy replenishment, insulin depresses mitochondrial respiration in skeletal muscle via NO which permits substrates to be deposited as macromolecules; at discrete hyperinsulinemia, persistent mtNOS activation could contribute to mitochondrial dysfunction with insulin resistance and obesity and therefore, to the progression of the metabolic syndrome.
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