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FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

Author

Listed:
  • Masaji Sakaguchi

    (Joslin Diabetes Center
    Harvard Medical School
    Kumamoto University)

  • Weikang Cai

    (Joslin Diabetes Center
    Harvard Medical School)

  • Chih-Hao Wang

    (Joslin Diabetes Center
    Harvard Medical School)

  • Carly T. Cederquist

    (Joslin Diabetes Center
    Harvard Medical School)

  • Marcos Damasio

    (Joslin Diabetes Center
    Harvard Medical School)

  • Erica P. Homan

    (Joslin Diabetes Center
    Harvard Medical School)

  • Thiago Batista

    (Joslin Diabetes Center
    Harvard Medical School)

  • Alfred K. Ramirez

    (Joslin Diabetes Center
    Harvard Medical School)

  • Manoj K. Gupta

    (Joslin Diabetes Center
    Harvard Medical School)

  • Martin Steger

    (Max Planck Institute of Biochemistry)

  • Nicolai J. Wewer Albrechtsen

    (Max Planck Institute of Biochemistry
    University of Copenhagen
    University of Copenhagen)

  • Shailendra Kumar Singh

    (The World Premier International Research Center Initiative Immunology Frontier Research Center)

  • Eiichi Araki

    (Kumamoto University)

  • Matthias Mann

    (Max Planck Institute of Biochemistry)

  • Sven Enerbäck

    (University of Gothenburg)

  • C. Ronald Kahn

    (Joslin Diabetes Center
    Harvard Medical School)

Abstract

A major target of insulin signaling is the FoxO family of Forkhead transcription factors, which translocate from the nucleus to the cytoplasm following insulin-stimulated phosphorylation. Here we show that the Forkhead transcription factors FoxK1 and FoxK2 are also downstream targets of insulin action, but that following insulin stimulation, they translocate from the cytoplasm to nucleus, reciprocal to the translocation of FoxO1. FoxK1/FoxK2 translocation to the nucleus is dependent on the Akt-mTOR pathway, while its localization to the cytoplasm in the basal state is dependent on GSK3. Knockdown of FoxK1 and FoxK2 in liver cells results in upregulation of genes related to apoptosis and down-regulation of genes involved in cell cycle and lipid metabolism. This is associated with decreased cell proliferation and altered mitochondrial fatty acid metabolism. Thus, FoxK1/K2 are reciprocally regulated to FoxO1 following insulin stimulation and play a critical role in the control of apoptosis, metabolism and mitochondrial function.

Suggested Citation

  • Masaji Sakaguchi & Weikang Cai & Chih-Hao Wang & Carly T. Cederquist & Marcos Damasio & Erica P. Homan & Thiago Batista & Alfred K. Ramirez & Manoj K. Gupta & Martin Steger & Nicolai J. Wewer Albrecht, 2019. "FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09418-0
    DOI: 10.1038/s41467-019-09418-0
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    Cited by:

    1. Hirofumi Nagao & Ashok Kumar Jayavelu & Weikang Cai & Hui Pan & Jonathan M. Dreyfuss & Thiago M. Batista & Bruna B. Brandão & Matthias Mann & C. Ronald Kahn, 2023. "Unique ligand and kinase-independent roles of the insulin receptor in regulation of cell cycle, senescence and apoptosis," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Masaji Sakaguchi & Shota Okagawa & Yuma Okubo & Yuri Otsuka & Kazuki Fukuda & Motoyuki Igata & Tatsuya Kondo & Yoshifumi Sato & Tatsuya Yoshizawa & Takaichi Fukuda & Kazuya Yamagata & Weikang Cai & Yu, 2022. "Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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