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

Endocrinology and Metabolism

14 Citations (Scopus)

15 Downloads (Pure)

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
Number of pages	17
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-019-09418-0
Publication status	Published - 1 Dec 2019

Access to Document

10.1038/s41467-019-09418-0Licence: CC BY

OA-FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolismFinal published version, 4.24 MBLicence: CC BY

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

Sakaguchi, M, Cai, W, Wang, C-H, 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

@article{20ddb44eed64428484b2addfc25deb0e,

title = "FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism",

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 Chih-Hao Wang 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}",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-09418-0",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "nature publishing group",

number = "1",

}

TY - JOUR

T1 - FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

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.

AB - 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.

U2 - 10.1038/s41467-019-09418-0

DO - 10.1038/s41467-019-09418-0

M3 - Journal article

C2 - 30952843

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1582

ER -

FoxK1 and FoxK2 in insulin regulation of cellular and mitochondrial metabolism

Abstract

Access to Document

Fingerprint

Cite this