Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice.
Molecular mechanism of moderate insulin resistance in adiponectin-knockout mice.
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DOI：
10.1507/endocrj.k08e-093
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发表时间：
2008-06
影响因子：
2
通讯作者：
Wataru Yano;N. Kubota;S. Itoh;Tetsuya Kubota;M. Awazawa;M. Moroi;K. Sugi;Iseki Takamoto;H. Ogata
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文献类型：
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作者：
Wataru Yano;N. Kubota;S. Itoh;Tetsuya Kubota;M. Awazawa;M. Moroi;K. Sugi;Iseki Takamoto;H. Ogata
脂联素被认为是一种抗糖尿病的脂肪因子，抑制肝脏和骨骼肌中的脂肪生成并刺激脂肪酸氧化。尽管已知脂联素敲除（adipo（-/-））小鼠表现出胰岛素抵抗，但胰岛素抵抗和葡萄糖耐受不良的程度出乎意料地仅为中度。在这项研究中，adipo（-/-）小鼠表现出肝脏胰岛素抵抗，而不是肌肉胰岛素抵抗。胰岛素刺激的IRS-1和IRS-2磷酸化受损，IRS-2蛋白水平降低，胰岛素刺激的Akt磷酸化在adipo（-/-）小鼠肝脏中降低。然而，在这些小鼠中，尽管参与脂质燃烧的PPARalpha表达减少，但肝脏中的甘油三酯含量没有增加，因为诸如SREBP-1和SCD-1的脂肪生成基因的表达减少与瘦素敏感性增加相关。与此一致，在adipo（-/-）小鼠中观察到的SREBP-1和SCD-1下调不再观察到，并且在脂联素瘦素双敲除（adipo（-/-）ob/ob）小鼠中肝脏甘油三酯含量显着增加。另一方面，在adipo（-/-）小鼠中，骨骼肌中的甘油三酯含量显著降低，这可能是由于与瘦素敏感性增加相关的AMPK活性上调。事实上，这些小鼠骨骼肌中的这些表型在adipo（-/-）ob/ob小鼠中不再观察到。总之，adipo（-/-）小鼠显示肝脏中胰岛素信号传导受损，导致肝脏胰岛素抵抗，然而，在肝脏或骨骼肌中均未观察到甘油三酯含量增加，推测是由于瘦素敏感性增加。
Adiponectin has been proposed to act as an antidiabetic adipokine, suppressing gluconeogenesis and stimulating fatty acid oxidation in the liver and skeletal muscle. Although adiponectin-knockout (adipo(-/-)) mice are known to exhibit insulin resistance, the degrees of insulin resistance and glucose intolerance are unexpectedly only moderate. In this study, the adipo(-/-) mice showed hepatic, but not muscle, insulin resistance. insulin-stimulated phosphorylation of IRS-1 and IRS-2 was impaired, the IRS-2 protein level was decreased, and insulin-stimulated phosphorylation of Akt was decreased in the liver of the adipo(-/-) mice. However, the triglyceride content in the liver was not increased in these mice, despite the decrease in the PPARalpha expression involved in lipid combustion, since the expressions of lipogenic genes such as SREBP-1 and SCD-1 were decreased in association with the increased leptin sensitivity. Consistent with this, the down-regulation SREBP-1 and SCD-1 observed in the adipo(-/-) mice was no longer observed, and the hepatic triglyceride content was significantly increased in the adiponectin leptin double-knockout (adipo(-/-)ob/ob) mice. On the other hand, the triglyceride content in the skeletal muscle was significantly decreased in the adipo(-/-) mice, probably due to up-regulated AMPK activity associated with the increased leptin sensitivity. In fact, these phenotypes in the skeletal muscle of these mice were no longer observed in the adipo(-/-)ob/ob mice. In conclusion, adipo(-/-) mice showed impaired insulin signaling in the liver to cause hepatic insulin resistance, however, no increase in the triglyceride content was observed in either the liver or the skeletal muscle, presumably on account of the increased leptin sensitivity.