Perrin Christophe, Knauf Claude, Burcelin Rémy
Unité Mixte de Recherche 5018, Centre National de la Recherche Scientifique-Paul Sabatier University and Institut Federatif de Recherche 31, Rangueil Hospital, L1 Building, 31403 Toulouse, France.
Endocrinology. 2004 Sep;145(9):4025-33. doi: 10.1210/en.2004-0270. Epub 2004 Jun 10.
The AMP-activated kinase has been proposed to be an important intracellular energy sensor because the enzyme controls lipid and glucose oxidation. In the corresponding knockout mice, insulin-stimulated muscle glycogen synthesis and glucose tolerance are reduced. In addition, these mice excrete catecholamines in excess, suggesting that the central and autonomic nervous systems are impaired. Indeed, in the brain, fuel sensor mechanisms have been described, and recently, evidence has shown that the AMP-activated kinase could control food intake. We show in this study that the intracerebroventricular infusion of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a pharmacological AMP-activated kinase activator, increased insulin-stimulated muscle glycogen synthesis and insulin sensitivity during a hyperinsulinemic clamp. Similarly, we infused AICAR in the brain of fasted mice, i.e. when insulinemia was low, and showed that muscle glycogen synthesis was also increased. We then studied the effect of a cerebral infusion of the peripheral signals, i.e. insulin and glucose, known to be detected by the brain. The cerebral infusion of insulin increased muscle glycogen synthesis. This effect was blunted by the coinfusion of glucose, which induced insulin resistance. Importantly, the cerebral injections of AICAR, insulin, and glucose were associated with variations in the phosphorylation state of the AMP-activated kinase in the hypothalamus. In conclusion, our data showed for the first time that 1) the brain is sensitive to insulin and glucose for the regulation of muscle glycogen synthesis; and 2) the cerebral infusion of AICAR enhances insulin sensitivity. Although the above mechanisms are correlated with the regulation of AMP-activated kinase, the direct involvement of the enzyme in the mechanism remains to be demonstrated.
AMP激活的蛋白激酶被认为是一种重要的细胞内能量传感器，因为该酶可控制脂质和葡萄糖氧化。在相应的基因敲除小鼠中，胰岛素刺激的肌肉糖原合成及葡萄糖耐量降低。此外，这些小鼠会过量分泌儿茶酚胺，提示中枢和自主神经系统受损。实际上，在大脑中已描述了燃料传感机制，最近有证据表明AMP激活的蛋白激酶可控制食物摄入。我们在本研究中表明，脑室内注入5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICAR），一种药理学上的AMP激活的蛋白激酶激活剂，在高胰岛素钳夹期间可增加胰岛素刺激的肌肉糖原合成及胰岛素敏感性。同样，我们在禁食小鼠的大脑中注入AICAR，即当胰岛素水平较低时，结果显示肌肉糖原合成也增加。然后我们研究了向大脑注入已知可被大脑检测到的外周信号（即胰岛素和葡萄糖）的作用。向大脑注入胰岛素可增加肌肉糖原合成。葡萄糖的共同注入会减弱这种作用，葡萄糖会诱导胰岛素抵抗。重要的是，向大脑注射AICAR、胰岛素和葡萄糖与下丘脑AMP激活的蛋白激酶的磷酸化状态变化有关。总之，我们的数据首次表明：1）大脑对胰岛素和葡萄糖敏感，可调节肌肉糖原合成；2）向大脑注入AICAR可增强胰岛素敏感性。尽管上述机制与AMP激活的蛋白激酶的调节相关，但该酶在该机制中的直接作用仍有待证实。
