Ha E, Yim S V, Jung K H, Yoon S H, Zheng L T, Kim M J, Hong S J, Choe B K, Baik H H, Chung J H, Kim J W
Department of Biochemistry, College of Medicine, Kyung Hee University, Seoul, Republic of Korea.
Pharmacogenomics J. 2006 Sep-Oct;6(5):327-32. doi: 10.1038/sj.tpj.6500366. Epub 2006 Jan 17.
The use of topiramate (TPM) in the treatment of binge-eating disorder, bulimia nervosa, and antipsychotic-induced weight gain has recently increased, however, the exact molecular basis for its effects on body weight reduction and improved glucose homeostasis, is yet to be elucidated. Here we investigated the effect and signaling pathway of TPM on glucose uptake in L6 rat skeletal muscle cells, which account for >70% of glucose disposal in the body. Intriguingly, we found that TPM (10 microM) stimulated the rate of glucose uptake up to twofold increase. And TPM-stimulated glucose transport was inhibited with the overexpression of dominant-negative form of AMP-activated protein kinase (AMPK), an important mediator in glucose transport, implicating that AMPK-mediated pathway is involved. The TPM-stimulated glucose transport was blocked by SB203580, a specific inhibitor of AMPK downstream mediator, p38 mitogen-activated protein kinase (MAPK) protein. LY294002, an inhibitor of phosphatidylinositol (PI) 3-kinase, which is another crucial mediator in independent glucose transport pathway, did not inhibit TPM-stimulated glucose transport. We also found that TPM increased the phosphorylation level of AMPK and p38 MAPK, whereas no effect on the activity of PI 3-kinase of TPM, when assessed by PI 3-kinase assay, was observed. These results together suggest that TPM stimulates glucose transport, not via PI 3-kinase mediated, but via AMPK-mediated pathway in skeletal muscle cells, thereby contributing to the body weight regulation and glucose homeostasis.
托吡酯（TPM）在治疗暴饮暴食症、神经性贪食症和抗精神病药物引起的体重增加方面的应用近来有所增加，然而，其减轻体重和改善葡萄糖稳态的确切分子基础仍有待阐明。在此，我们研究了TPM对L6大鼠骨骼肌细胞葡萄糖摄取的影响及其信号通路，L6大鼠骨骼肌细胞对体内>70%的葡萄糖代谢起作用。有趣的是，我们发现TPM（10微摩尔）可使葡萄糖摄取速率刺激增加高达两倍。并且，通过过表达葡萄糖转运重要调节因子——AMP激活蛋白激酶（AMPK）的显性负性形式，可抑制TPM刺激的葡萄糖转运，这表明涉及AMPK介导的信号通路。TPM刺激的葡萄糖转运被SB203580阻断，SB203580是AMPK下游调节因子p38丝裂原活化蛋白激酶（MAPK）的特异性抑制剂。磷脂酰肌醇（PI）3激酶抑制剂LY294002并未抑制TPM刺激的葡萄糖转运，PI 3激酶是独立葡萄糖转运途径中的另一个关键调节因子。我们还发现，通过PI 3激酶活性检测评估时，TPM增加了AMPK和p38 MAPK的磷酸化水平，而对TPM的PI 3激酶活性无影响。这些结果共同表明，TPM在骨骼肌细胞中刺激葡萄糖转运不是通过PI 3激酶介导，而是通过AMPK介导的信号通路，从而有助于体重调节和葡萄糖稳态。
