The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production
The importance of the AMPK gamma 1 subunit in metformin suppression of liver glucose production
复制标题
DOI：
10.1038/s41598-020-67030-5
复制
发表时间：
2020-06-26
影响因子：
4.6
通讯作者：
He, Ling
中科院分区：
文献类型：
--
作者：
An, Hongying;Wang, Yu;He, Ling
二甲双胍用于治疗 2 型糖尿病患者已有 60 多年的历史，然而，其作用机制仍不完全清楚。我们之前的报告表明，肝脏特异性敲除 AMPK 催化 α 1 和 α 2 亚基的高脂饮食 (HFD) 喂养的小鼠在长期二甲双胍治疗后表现出显着更高的空腹血糖水平，并且比 floxed AMPK 催化 α 1 和 α 2 小鼠产生更多的葡萄糖，并且二甲双胍促进功能性 AMPK α β γ 异三聚体复合物的形成。在当前的研究中，我们测试了每个调节γ亚基亚型对二甲双胍作用的重要性。我们发现，gamma 1 的消耗，而不是gamma 2 或gamma 3 的消耗，显着降低了二甲双胍对 AMPK 的激活。 γ1 亚基耗尽的高脂饮食小鼠对二甲双胍对肝脏葡萄糖产生的抑制具有抵抗力。此外，我们确定了γ1亚基中每个调节性胱硫醚-β-合酶（CBS）结构域在二甲双胍作用中的作用，并发现CBS1或CBS4的缺失消除了二甲双胍对T172处AMPKα磷酸化和肝细胞中葡萄糖产生抑制的作用。我们的数据表明，γ1 亚基是二甲双胍控制肝细胞葡萄糖代谢所必需的。此外，在人类和动物模型中，二甲双胍治疗导致体重减轻，我们发现用二甲双胍治疗的小鼠体重增加的减少并不是直接归因于能量消耗的增加。
Metformin has been used to treat patients with type 2 diabetes for over 60 years, however, its mechanism of action is still not completely understood. Our previous reports showed that high-fat-diet (HFD)-fed mice with liver-specific knockout of both AMPK catalytic alpha 1 and alpha 2 subunits exhibited significantly higher fasting blood glucose levels and produced more glucose than floxed AMPK catalytic alpha 1 and alpha 2 mice after long-term metformin treatment, and that metformin promotes the formation of the functional AMPK alpha beta gamma heterotrimeric complex. We tested the importance of each regulatory gamma subunit isoform to metformin action in this current study. We found that depletion of gamma 1, but not gamma 2 or gamma 3, drastically reduced metformin activation of AMPK. HFD-fed mice with depletion of the gamma 1 subunit are resistant to metformin suppression of liver glucose production. Furthermore, we determined the role of each regulatory cystathionine-beta -synthase (CBS) domain in the gamma 1 subunit in metformin action and found that deletion of either CBS1 or CBS4 negated metformin's effect on AMPK alpha phosphorylation at T172 and suppression of glucose production in hepatocytes. Our data indicate that the gamma 1 subunit is required for metformin's control of glucose metabolism in hepatocytes. Furthermore, in humans and animal models, metformin treatment leads to the loss of body weight, we found that the decrease in body weight gain in mice treated with metformin is not directly attributable to increased energy expenditure.