MULTIPLE SIGNALING PATHWAYS INVOLVED IN THE STIMULATION OF FATTY-ACID AND GLYCOGEN-SYNTHESIS BY INSULIN IN RAT EPIDIDYMAL FAT-CELLS
MULTIPLE SIGNALING PATHWAYS INVOLVED IN THE STIMULATION OF FATTY-ACID AND GLYCOGEN-SYNTHESIS BY INSULIN IN RAT EPIDIDYMAL FAT-CELLS
复制标题
DOI：
10.1042/bj3110595
复制
发表时间：
1995-10-15
影响因子：
4.1
通讯作者：
DENTON, RM
中科院分区：
文献类型：
--
作者：
MOULE, SK;EDGELL, NJ;DENTON, RM
我们已经研究了参与刺激糖原和脂肪酸合成的胰岛素在大鼠脂肪细胞中使用渥曼青霉素，磷脂酰肌醇3-激酶的抑制剂，和雷帕霉素，它阻止激活p70核糖体S6蛋白激酶（p70（S6 K））的信号通路。胰岛素降低了糖原合成酶激酶-3的活性，这在观察到的糖原合成酶刺激中可能是重要的。发现这两种作用对渥曼青霉素的抑制敏感。胰岛素刺激葡萄糖合成脂肪酸涉及三个过程的激活，即葡萄糖摄取、乙酰辅酶A。羧化酶和丙酮酸脱氢酶。而渥曼青霉素在很大程度上消除了胰岛素对葡萄糖利用和乙酰辅酶A羧化酶活性的影响，它对丙酮酸脱氢酶的刺激没有影响。虽然表皮生长因子刺激有丝分裂原活化蛋白激酶在更大程度上比胰岛素，它是无法模仿胰岛素对糖原合成酶，糖原合成酶激酶-3，葡萄糖利用，乙酰辅酶A羧化酶或丙酮酸脱氢酶的影响。雷帕霉素对胰岛素刺激这些参数也没有任何明显的作用，尽管它确实阻断了胰岛素对p70（S6 K）的作用。我们得出结论，磷脂酰肌醇3-激酶的活性是必需的胰岛素对糖原合成，葡萄糖摄取和乙酰辅酶A羧化酶的影响，但不参与丙酮酸脱氢酶的信号转导。然而，丝裂原活化蛋白激酶或p70（S6 K）的活化似乎不足以刺激脂肪酸或糖原合成。总之，似乎至少有四种不同的信号通路参与胰岛素对大鼠脂肪细胞的影响。
We have investigated the signalling pathways involved in the stimulation of glycogen and fatty acid synthesis by insulin in rat fat cells using wortmannin, an inhibitor of phosphatidylinositol 3-kinase, and rapamycin, which blocks activation of p70 ribosomal S6 protein kinase (p70(S6K)). Insulin produced a decrease in the activity of glycogen synthase kinase-3 which is likely to be important in the observed stimulation of glycogen synthase. Both of these actions were found to be sensitive to inhibition by wortmannin. Activation of three processes is involved in the stimulation of fatty acid synthesis from glucose by insulin, namely glucose uptake, acetyl-CoA. carboxylase and pyruvate dehydrogenase. Whereas wortmannin largely abolished the effects of insulin on glucose utilization and acetyl-CoA carboxylase activity, it was without effect on the stimulation of pyruvate dehydrogenase. Although epidermal growth factor stimulated mitogen-activated protein kinase to a greater extent than insulin, it was unable to mimic the effect of insulin on glycogen synthase, glycogen synthase kinase-3, glucose utilization, acetyl-CoA carboxylase or pyruvate dehydrogenase. Rapamycin also failed to have any appreciable effect on stimulation of these parameters by insulin, although it did block the effect of insulin on p70(S6K). We conclude that the activity of phosphatidylinositol 3-kinase is required for the effects of insulin on glycogen synthesis, glucose uptake and acetyl-CoA carboxylase, but is not involved in signalling to pyruvate dehydrogenase. Activation of mitogen-activated protein kinase or p70(S6K), however, does not appear to be sufficient to bring about the stimulation of fatty acid or glycogen synthesis. Altogether it seems likely that at least four distinct signalling pathways are involved in the effects of insulin on rat fat cells.