Insulin-stimulated hepatic glycogen synthesis is central to glucose homeostasis. Here, we show that PPP1R3G, a regulatory subunit of protein phosphatase 1 (PP1), is directly phosphorylated by AKT. PPP1R3G phosphorylation fluctuates with fasting-refeeding cycle and is required for insulin-stimulated dephosphorylation, i.e., activation of glycogen synthase (GS) in hepatocytes. In this study, we demonstrate that knockdown of PPP1R3G significantly inhibits insulin response. The introduction of wild-type PPP1R3G, and not phosphorylation-defective mutants, increases hepatic glycogen deposition, blood glucose clearance, and insulin sensitivity in vivo. Mechanistically, phosphorylated PPP1R3G displays increased binding for, and promotes dephosphorylation of, phospho-GS. Furthermore, PPP1R3B, another regulatory subunit of PP1, binds to the dephosphorylated GS, thereby relaying insulin stimulation to hepatic glycogen deposition. Importantly, this PP1-mediated signaling cascade is independent of GSK3. Therefore, we reveal a regulatory axis consisting of insulin/AKT/PPP1R3G/PPP1R3B that operates in parallel to the GSK3-dependent pathway, controlling glycogen synthesis and glucose homeostasis in insulin signaling.

胰岛素刺激的肝糖原合成是葡萄糖稳态的关键。在这里，我们显示PPP1R3G，蛋白磷酸酶1（PP1）的调节亚基，被AKT直接磷酸化。PPP1R3G的磷酸化随禁食-再喂食周期而波动，是胰岛素刺激的去磷酸化（即肝细胞中糖原合酶（GS）的激活）所必需的。在这项研究中，我们证明敲低PPP1R3G可以显着抑制胰岛素反应。野生型PPP1R3G而非磷酸化缺陷型突变体的引入增加了体内肝糖原沉积，血糖清除率和胰岛素敏感性。从机理上讲，磷酸化的PPP1R3G与磷酸GS的结合力增强，并促进磷酸GS的去磷酸化。此外，PPP1R3B（PP1的另一个调节亚基）与去磷酸化的GS结合，从而将胰岛素刺激传递给肝糖原沉积。重要的是，此PP1介导的信号级联独立于GSK3。因此，我们揭示了一个由胰岛素/ AKT / PPP1R3G / PPP1R3B组成的调节轴，该轴与GSK3依赖性途径平行运作，控制胰岛素信号中的糖原合成和葡萄糖稳态。