Institute for Diabetes, Obesity, and Metabolism.
Biochemistry and Molecular Biophysics Graduate Group, and.
J Clin Invest. 2024 Jan 30;134(7):e173782. doi: 10.1172/JCI173782.
In response to a meal, insulin drives hepatic glycogen synthesis to help regulate systemic glucose homeostasis. The mechanistic target of rapamycin complex 1 (mTORC1) is a well-established insulin target and contributes to the postprandial control of liver lipid metabolism, autophagy, and protein synthesis. However, its role in hepatic glucose metabolism is less understood. Here, we used metabolomics, isotope tracing, and mouse genetics to define a role for liver mTORC1 signaling in the control of postprandial glycolytic intermediates and glycogen deposition. We show that mTORC1 is required for glycogen synthase activity and glycogenesis. Mechanistically, hepatic mTORC1 activity promotes the feeding-dependent induction of Ppp1r3b, a gene encoding a phosphatase important for glycogen synthase activity whose polymorphisms are linked to human diabetes. Reexpression of Ppp1r3b in livers lacking mTORC1 signaling enhances glycogen synthase activity and restores postprandial glycogen content. mTORC1-dependent transcriptional control of Ppp1r3b is facilitated by FOXO1, a well characterized transcriptional regulator involved in the hepatic response to nutrient intake. Collectively, we identify a role for mTORC1 signaling in the transcriptional regulation of Ppp1r3b and the subsequent induction of postprandial hepatic glycogen synthesis.
进食后，胰岛素会促进肝糖原合成，以帮助调节全身葡萄糖稳态。雷帕霉素靶蛋白复合物 1（mTORC1）是一个成熟的胰岛素靶点，有助于调节餐后肝脏脂质代谢、自噬和蛋白质合成。然而，其在肝糖代谢中的作用尚未完全阐明。在此，我们利用代谢组学、同位素示踪和小鼠遗传学来定义肝脏 mTORC1 信号在控制餐后糖酵解中间产物和糖原沉积中的作用。我们发现 mTORC1 对于糖原合酶活性和糖异生是必需的。在机制上，肝 mTORC1 活性促进了 Ppp1r3b 的进食依赖性诱导，该基因编码一种对糖原合酶活性很重要的磷酸酶，其多态性与人类糖尿病有关。在缺乏 mTORC1 信号的肝脏中重新表达 Ppp1r3b 可增强糖原合酶活性并恢复餐后糖原含量。mTORC1 对 Ppp1r3b 的转录调控是由 FOXO1 介导的，FOXO1 是一种参与营养摄入后肝脏反应的已被充分研究的转录调节因子。综上所述，我们确定了 mTORC1 信号在 Ppp1r3b 的转录调控和随后诱导餐后肝糖原合成中的作用。
