The CB1 endocannabinoid system modulates adipocyte insulin sensitivity
The CB1 endocannabinoid system modulates adipocyte insulin sensitivity
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DOI：
10.1038/oby.2008.309
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发表时间：
2008-08-01
期刊：
影响因子：
6.9
通讯作者：
McGraw, Timothy E.
中科院分区：
文献类型：
--
作者：
Motaghedi, Roja;McGraw, Timothy E.
越来越多的证据表明，内源性大麻素系统通过对外周组织的直接作用以及调节食欲的中枢作用来调节能量代谢。在这里，我们研究了大麻素受体1(CB1)信号对脂肪细胞中胰岛素作用的影响。我们检测了天然CB1激动剂2-花生四烯酸甘油(2-AG)和合成CB1拮抗剂SR141716对培养脂肪细胞胰岛素作用的影响。我们使用葡萄糖转运体GLUT4到质膜(PM)的移位来衡量胰岛素的作用。2-AG激活CB1受体可促进胰岛素敏感性，而SR141716拮抗则降低胰岛素敏感性。在没有胰岛素或高剂量胰岛素的情况下，这两种药物都没有影响GLUT4的易位。与这些结果一致，我们发现胰岛素刺激的蛋白激酶Akt的磷酸化被2-AG增加，被SR141716减弱，在没有胰岛素或添加高剂量胰岛素的情况下不受影响。这些数据提供了CB1受体和胰岛素敏感性之间的功能和分子联系，因为胰岛素刺激的Akt磷酸化是GLUT4转位到PM所必需的2-AG的致敏作用可被SR141716和百日咳毒素所阻断，提示其作用是通过CB1受体介导的。重要的是，2-AG、SR141716单独或联合最大剂量胰岛素对GLUT4易位和Akt磷酸化都没有影响。这些数据与一个模型一致，在该模型中，内源性大麻素系统设定脂肪细胞胰岛素反应的敏感性，而不是直接调节GLUT4或Akt磷酸化的重新分布。
Mounting evidence suggests that the endocannabinoid system regulates energy metabolism through direct effects on peripheral tissues as well as central effects that regulate appetite. Here we examined the effect of cannabinoid receptor 1 (CB1) signaling on insulin action in fat cells. We examined effects of the natural CB1 agonist, 2-Arachidonoylglycerol (2-AG), and the synthetic CB1 antagonist, SR141716, on insulin action in cultured adipocytes. We used translocation of glucose transporter GLUT4 to plasma membrane (PM) as a measure of insulin action. 2-AG activation of the CB1 receptor promoted insulin sensitivity whereas antagonism by SR141716 reduced insulin sensitivity. Neither drug affected GLUT4 translocation in the absence of insulin or with high doses of insulin. Consistent with these results we found that insulin-stimulated phosphorylation of the protein kinase Akt was increased by 2-AG, attenuated by SR141716, and unaffected in the absence of insulin or by addition of high-dose insulin. These data provide a functional and molecular link between the CB1 receptor and insulin sensitivity, because insulin-stimulated phosphorylation of Akt is required for GLUT4 translocation to the PM. The sensitizing effects of 2-AG were abrogated by SR141716 and Pertussis toxin, indicating that the effects are mediated by CB1 receptor. Importantly, neither 2-AG nor SR141716 alone or in combination with maximal dose of insulin had effects on GLUT4 translocation and Akt phosphorylation. These data are consistent with a model in which the endocannabinoid system sets the sensitivity of the insulin response in adipocytes rather than directly regulating the redistribution of GLUT4 or Akt phosphorylation.