Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions
Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions
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DOI：
10.1038/nm1557
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发表时间：
2007-03-01
期刊：
影响因子：
82.9
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Yamauchi, Toshimasa;Nio, Yasunori;Kadowaki, Takashi
脂联素作为一种抗糖尿病和抗动脉粥样硬化的脂肪因子发挥着重要作用。AdipoR1和AdipoR2在体外作为脂联素的受体，它们在肥胖中的减少似乎与脂联素敏感性的降低相关。在这里，我们发现腺病毒介导的AdipoR1和R2在Lepr（-/-）小鼠肝脏中的表达分别增加了AMP激活蛋白激酶（AMPK）激活和过氧化物酶体增殖物激活受体（PPAR）-α信号通路。AMPK的激活减少了糖尿病的发生，而在这两种情况下，受体的表达增加了脂肪酸的氧化，并导致糖尿病的改善。或者，AdipoR1的靶向破坏导致脂联素诱导的AMPK活化的消除，而AdipoR2的靶向破坏导致PPAR-alpha信号通路的活性降低。同时破坏AdipoR1和R2消除了脂联素的结合和作用，导致组织甘油三酯含量增加，炎症和氧化应激，从而导致胰岛素抵抗和明显的葡萄糖耐受不良。因此，AdipoR1和R2是脂联素在体内的主要受体，在体内糖脂代谢、炎症和氧化应激的调节中发挥重要作用。
Adiponectin plays a central role as an antidiabetic and antiatherogenic adipokine. AdipoR1 and AdipoR2 serve as receptors for adiponectin in vitro, and their reduction in obesity seems to be correlated with reduced adiponectin sensitivity. Here we show that adenovirus-mediated expression of AdipoR1 and R2 in the liver of Lepr(-/-) mice increased AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor (PPAR)-alpha signaling pathways, respectively. Activation of AMPK reduced gluconeogenesis, whereas expression of the receptors in both cases increased fatty acid oxidation and lead to an amelioration of diabetes. Alternatively, targeted disruption of AdipoR1 resulted in the abrogation of adiponectin-induced AMPK activation, whereas that of AdipoR2 resulted in decreased activity of PPAR-alpha signaling pathways. Simultaneous disruption of both AdipoR1 and R2 abolished adiponectin binding and actions, resulting in increased tissue triglyceride content, inflammation and oxidative stress, and thus leading to insulin resistance and marked glucose intolerance. Therefore, AdipoR1 and R2 serve as the predominant receptors for adiponectin in vivo and play important roles in the regulation of glucose and lipid metabolism, inflammation and oxidative stress in vivo.