2. Academic Validation
  3. HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes

HNF4α-TET2-FBP1 axis contributes to gluconeogenesis and type 2 diabetes

  • Elife. 2025 Jun 3:13:RP103663. doi: 10.7554/eLife.103663.
Hongchen Li # 1,  Xinchao Zhang # 1 2,  Xiaoben Liang # 1,  Shuyan Li 3,  Ziyi Cui 1,  Xinyu Zhao 1,  Kai Wang 4,  Bingbing Zha 4,  Haijie Ma 5,  Ming Xu 6 7,  Lei Lv 2,  Yanping Xu 1
Affiliations

Affiliations

  • 1 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.
  • 2 MOE Key Laboratory of Metabolism and Molecular Medicine, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
  • 3 Department of Radiation Oncology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4 Department of Endocrinology, Fifth People's Hospital of Shanghai, Fudan University, Shanghai, China.
  • 5 Cellular and Molecular Biology Laboratory, Affiliated Zhoushan Hospital of Wenzhou Medical University, Zhoushan, China.
  • 6 Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, United States.
  • 7 Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, United States.
  • # Contributed equally.
PMID: 40459008 DOI: 10.7554/eLife.103663
Abstract

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 TET2 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 FBP1 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.

Keywords

FBP1; HNF4α; TET2; cell biology; diabetes; gluconeogenesis; mouse.

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