Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1
Adiponectin and AdipoR1 regulate PGC-1α and mitochondria by Ca2+ and AMPK/SIRT1
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DOI：
10.1038/nature08991
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发表时间：
2010-04-29
期刊：
影响因子：
64.8
通讯作者：
Kadowaki, Takashi
中科院分区：
文献类型：
--
作者：
Iwabu, Masato;Yamauchi, Toshimasa;Kadowaki, Takashi
脂联素是一种抗糖尿病的脂肪因子。其受体具有七跨膜拓扑结构，氨基末端位于细胞内，这与G蛋白偶联受体相反。在这里，我们提供了脂联素通过脂联素受体1（AdipoR 1）诱导细胞外Ca 2+内流的证据，这是随后激活Ca 2 +/钙调蛋白依赖性蛋白激酶激酶β（CaMKK β）、AMPK和SIRT 1、增加过氧化物酶体增殖物激活受体γ共激活因子-1 α（PGC-1 α）的表达和减少乙酰化以及增加肌细胞线粒体所必需的。此外，肌肉特异性破坏AdipoR 1抑制脂联素介导的细胞内Ca 2+浓度的增加，并降低脂联素对CaMKK，AMPK和SIRT 1的激活。抑制AdipoR 1还导致PGC-1 α表达和脱乙酰化减少，线粒体含量和酶减少，I型氧化肌纤维减少，骨骼肌中氧化应激解毒酶减少，这与胰岛素抵抗和运动耐力降低有关。肥胖症患者脂联素和AdipoR 1水平降低可能与糖尿病患者线粒体功能障碍和胰岛素抵抗有关。
Adiponectin is an anti-diabetic adipokine. Its receptors possess a seven-transmembrane topology with the amino terminus located intracellularly, which is the opposite of G-protein-coupled receptors. Here we provide evidence that adiponectin induces extracellular Ca2+ influx by adiponectin receptor 1 (AdipoR1), which was necessary for subsequent activation of Ca2+/calmodulin-dependent protein kinase kinase beta (CaMKK beta), AMPK and SIRT1, increased expression and decreased acetylation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), and increased mitochondria in myocytes. Moreover, muscle-specific disruption of AdipoR1 suppressed the adiponectin-mediated increase in intracellular Ca2+ concentration, and decreased the activation of CaMKK, AMPK and SIRT1 by adiponectin. Suppression of AdipoR1 also resulted in decreased PGC-1 alpha expression and deacetylation, decreased mitochondrial content and enzymes, decreased oxidative type I myofibres, and decreased oxidative stress-detoxifying enzymes in skeletal muscle, which were associated with insulin resistance and decreased exercise endurance. Decreased levels of adiponectin and AdipoR1 in obesity may have causal roles in mitochondrial dysfunction and insulin resistance seen in diabetes.