Despite being the frontline therapy for type 2 diabetes, the mechanisms of action of the biguanide drug metformin are still being discovered. In particular, the detailed molecular interplays between the AMPK and the mTORC1 pathway in the hepatic benefits of metformin are still ill defined. Metformin-dependent activation of AMPK classically inhibits mTORC1 via TSC/RHEB, but several lines of evidence suggest additional mechanisms at play in metformin inhibition of mTORC1. Here we investigated the role of direct AMPK-mediated serine phosphorylation of RAPTOR in a new Raptor^AA mouse model, in which AMPK phospho-serine sites Ser722 and Ser792 of RAPTOR were mutated to alanine. Metformin treatment of primary hepatocytes and intact murine liver requires AMPK regulation of both RAPTOR and TSC2 to fully inhibit mTORC1, and this regulation is critical for both the translational and transcriptional response to metformin. Transcriptionally, AMPK and mTORC1 were both important for regulation of anabolic metabolism and inflammatory programs triggered by metformin treatment. The hepatic transcriptional response in mice on high-fat diet treated with metformin was largely ablated by AMPK deficiency under the conditions examined, indicating the essential role of this kinase and its targets in metformin action in vivo.

中文翻译：

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Raptor 和 TSC2 的 AMPK 调节介导二甲双胍对合成代谢和炎症转录控制的影响。

尽管双胍类药物二甲双胍是 2 型糖尿病的一线治疗方法，但其作用机制仍在探索中。特别是，二甲双胍对肝脏的益处中 AMPK 和 mTORC1 通路之间的详细分子相互作用仍不清楚。二甲双胍依赖性 AMPK 激活通常通过 TSC/RHEB 抑制 mTORC1，但一些证据表明二甲双胍抑制 mTORC1 的过程中还有其他机制。在这里，我们研究了 RAPTOR 直接 AMPK 介导的丝氨酸磷酸化在新的Raptor ^AA中的作用小鼠模型，其中 RAPTOR 的 AMPK 磷酸丝氨酸位点 Ser722 和 Ser792 突变为丙氨酸。二甲双胍治疗原代肝细胞和完整小鼠肝脏需要 RAPTOR 和 TSC2 的 AMPK 调节以完全抑制 mTORC1，并且这种调节对于二甲双胍的翻译和转录反应至关重要。从转录角度来看，AMPK 和 mTORC1 对于调节合成代谢和二甲双胍治疗引发的炎症程序都很重要。在接受二甲双胍治疗的高脂饮食小鼠中，在所检测的条件下，AMPK 缺陷很大程度上消除了其肝脏转录反应，表明该激酶及其靶标在二甲双胍体内作用中的重要作用。