Li Hongchen, Zhang Xinchao, Liang Xiaoben, Li Shuyan, Cui Ziyi, Zhao Xinyu, Wang Kai, Zha Bingbing, Ma Haijie, Xu Ming, Lv Lei, Xu Yanping
Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China.
MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Elife. 2025 Jun 3;13:RP103663. doi: 10.7554/eLife.103663.
The control of gluconeogenesis is critical for glucose homeostasis and the pathology of type 2 diabetes (T2D). Here, we uncover a novel function of TET2 in the regulation of gluconeogenesis. In mice, both fasting and a high-fat diet (HFD) stimulate the expression of TET2, and knockout impairs glucose production. Mechanistically, FBP1, a rate-limiting enzyme in gluconeogenesis, is positively regulated by TET2 in liver cells. TET2 is recruited by HNF4α, contributing to the demethylation of the promoter and activating its expression in response to glucagon stimulation. Moreover, metformin treatment increases the phosphorylation of HNF4α on Ser313, which prevents its interaction with TET2, thereby decreasing the expression level of FBP1 and ameliorating the pathology of T2D. Collectively, we identify an HNF4α-TET2-FBP1 axis in the control of gluconeogenesis, which contributes to the therapeutic effect of metformin on T2D and provides a potential target for the clinical treatment of T2D.
糖异生的调控对于葡萄糖稳态和2型糖尿病（T2D）的病理过程至关重要。在此，我们揭示了TET2在糖异生调控中的新功能。在小鼠中，禁食和高脂饮食（HFD）均刺激TET2的表达，而敲除TET2会损害葡萄糖生成。机制上，糖异生的限速酶FBP1在肝细胞中受到TET2的正向调控。TET2被HNF4α招募，促进启动子的去甲基化，并在胰高血糖素刺激下激活其表达。此外，二甲双胍治疗增加了HNF4α在Ser313位点的磷酸化，这阻止了它与TET2的相互作用，从而降低FBP1的表达水平并改善T2D的病理状况。总体而言，我们确定了一个在糖异生调控中的HNF4α-TET2-FBP1轴，这有助于二甲双胍对T2D的治疗作用，并为T2D的临床治疗提供了一个潜在靶点。
