FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

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 Albrechtsen; Shailendra Kumar Singh; Eiichi Araki; Matthias Mann; Sven Enerbäck; C. Ronald Kahn

doi:10.1038/s41467-019-09418-0

FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

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 Albrechtsen, Shailendra Kumar Singh, Eiichi Araki, Matthias Mann, Sven Enerbäck, C. Ronald Kahn

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84 Scopus citations

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.

Original language	English
Article number	1582
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-09418-0
State	Published - Dec 1 2019

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

The authors would like to thank Ryan C. Kunz and Steve P. Gygi from the Taplin Mass Spectrometry Facility in the Department of Cell Biology at Harvard Medical School for their important help in analysis of the proteins associated with the insulin receptor. The Joslin Diabetes Center DRC Genomics and Bioinformatics Core (P30 DK36836) Jonathan M. Dreyfuss and Hui Pan also provided important help. This work was supported by NIH grants R01 DK031036 and R01 DK033201 (to C.R.K.). M.S. was supported by MSD Life Science Foundation, Takeda Science Foundation and Center for Metabolic Regulation of Healthy Aging.

Funders	Funder number
MSD Life Science Foundation, Public Interest Incorporated Foundation
Takeda Science Foundation
National Institutes of Health (NIH)
Japan Society for the Promotion of Science Fund for the Promotion of Joint International Research	19K16691, 18K16208
National Institute of Diabetes and Digestive and Kidney Diseases	K01DK120740, R01DK082659, R01DK031036, P30DK036836, R01DK055545, R01DK033201
Fundação para a Ciência e Tecnologia I.P.	PTDC/CCI-INF/6762/2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General
General Physics and Astronomy

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Cite this

Sakaguchi, M., Cai, W., Wang, C. H., Cederquist, C. T., Damasio, M., Homan, E. P., Batista, T., Ramirez, A. K., Gupta, M. K., Steger, M., Wewer Albrechtsen, N. J., Singh, S. K., Araki, E., Mann, M., Enerbäck, S., & Kahn, C. R. (2019). FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism. Nature Communications, 10(1), Article 1582. https://doi.org/10.1038/s41467-019-09418-0

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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.",

author = "Masaji Sakaguchi and Weikang Cai and Wang, \{Chih Hao\} and Cederquist, \{Carly T.\} and Marcos Damasio and Homan, \{Erica P.\} and Thiago Batista and Ramirez, \{Alfred K.\} and Gupta, \{Manoj K.\} and Martin Steger and \{Wewer Albrechtsen\}, \{Nicolai J.\} and Singh, \{Shailendra Kumar\} and Eiichi Araki and Matthias Mann and Sven Enerb{\"a}ck and Kahn, \{C. Ronald\}",

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Sakaguchi, M, Cai, W, Wang, CH, Cederquist, CT, Damasio, M, Homan, EP, Batista, T, Ramirez, AK, Gupta, MK, Steger, M, Wewer Albrechtsen, NJ, Singh, SK, Araki, E, Mann, M, Enerbäck, S & Kahn, CR 2019, 'FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism', Nature Communications, vol. 10, no. 1, 1582. https://doi.org/10.1038/s41467-019-09418-0

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AU - Sakaguchi, Masaji

AU - Cai, Weikang

AU - Wang, Chih Hao

AU - Cederquist, Carly T.

AU - Damasio, Marcos

AU - Homan, Erica P.

AU - Batista, Thiago

AU - Ramirez, Alfred K.

AU - Gupta, Manoj K.

AU - Steger, Martin

AU - Wewer Albrechtsen, Nicolai J.

AU - Singh, Shailendra Kumar

AU - Araki, Eiichi

AU - Mann, Matthias

AU - Enerbäck, Sven

AU - Kahn, C. Ronald

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

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FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

Abstract

Bibliographical note

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ASJC Scopus subject areas

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