Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling

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 Hua Tseng; Nobuo Sakaguchi; C. Ronald Kahn; Eiichi Araki

doi:10.1038/s41467-022-33842-4

Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling

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 Hua Tseng, Nobuo Sakaguchi, C. Ronald Kahn, Eiichi Araki

Research output: Contribution to journal › Article › peer-review

14 Scopus citations

Abstract

Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.

Original language	English
Article number	6092
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33842-4
State	Published - Dec 2022

Bibliographical note

Publisher Copyright:
© 2022, The Author(s).

Funding

We would like to thank T. Motoyoshi (K.I. Stainer) and Y. Takahashi from the International core-facility of advanced life science at Kumamoto University for excellent technical assistance. We are grateful to members of the Center for Animal Resources and Development in Kumamoto University for their important contributions to the experiments. This work was supported by Japan Society for the Promotion of Science KAKENHI Grant Numbers JP 18K16208, JP 21K08532, the grant for Basic Research of the Japan Diabetes Society (2018), a grant from Japan Diabetes Foundation, Nippon Boehringer Ingelheim Co., Ltd and Eli Lilly Japan, K.K. (2018), a grant from the MSD Life Science Foundation (2019), a grant from the Manpei Suzuki Diabetes Foundation (2022), a grant from the Takeda Foundation (2019), a grant from the Kanae Foundation (2018), a grant from the Suzuken Memorial Foundation (2018), a grant from the Ono Medical Research Foundation (2018), a grant from the Astellas Foundation for Research on Metabolic Disorders (2018), a grant from the Mochida Memorial Foundation for Medical and Pharmaceutical Research (2018) to M.S. W.C. was supported by NIH grants K01 DK120740.

Funders	Funder number
Japan Diabetes Society
Kanae Foundation for the Promotion of Medical Science
Center for Animal Resources and Development in Kumamoto University
MSD Life Science Foundation, Public Interest Incorporated Foundation
Astellas Foundation for Research on Metabolic Disorders
Suzuken Memorial Foundation
Takeda Science Foundation
Japan Diabetes Foundation
Boehringer Ingelheim Japan
National Institutes of Health (NIH)
Eli Lilly Japan
Mochida Memorial Foundation for Medical and Pharmaceutical Research
Ono Medical Research Foundation
Japan Society for the Promotion of Science	JP 18K16208, 21K08533, JP 21K08532
National Institute of Diabetes and Digestive and Kidney Diseases	K01DK120740, R01DK077097, R01DK128429, R01DK031036, P30DK036836
Manpei Suzuki Diabetes Foundation	2022

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-022-33842-4

Cite this

Sakaguchi, M., Okagawa, S., Okubo, Y., Otsuka, Y., Fukuda, K., Igata, M., Kondo, T., Sato, Y., Yoshizawa, T., Fukuda, T., Yamagata, K., Cai, W., Tseng, Y. H., Sakaguchi, N., Kahn, C. R., & Araki, E. (2022). Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling. Nature Communications, 13(1), Article 6092. https://doi.org/10.1038/s41467-022-33842-4

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title = "Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling",

abstract = "Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.",

author = "Masaji Sakaguchi and Shota Okagawa and Yuma Okubo and Yuri Otsuka and Kazuki Fukuda and Motoyuki Igata and Tatsuya Kondo and Yoshifumi Sato and Tatsuya Yoshizawa and Takaichi Fukuda and Kazuya Yamagata and Weikang Cai and Tseng, \{Yu Hua\} and Nobuo Sakaguchi and Kahn, \{C. Ronald\} and Eiichi Araki",

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doi = "10.1038/s41467-022-33842-4",

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Sakaguchi, M, Okagawa, S, Okubo, Y, Otsuka, Y, Fukuda, K, Igata, M, Kondo, T, Sato, Y, Yoshizawa, T, Fukuda, T, Yamagata, K, Cai, W, Tseng, YH, Sakaguchi, N, Kahn, CR & Araki, E 2022, 'Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling', Nature Communications, vol. 13, no. 1, 6092. https://doi.org/10.1038/s41467-022-33842-4

TY - JOUR

T1 - Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling

AU - Sakaguchi, Masaji

AU - Okagawa, Shota

AU - Okubo, Yuma

AU - Otsuka, Yuri

AU - Fukuda, Kazuki

AU - Igata, Motoyuki

AU - Kondo, Tatsuya

AU - Sato, Yoshifumi

AU - Yoshizawa, Tatsuya

AU - Fukuda, Takaichi

AU - Yamagata, Kazuya

AU - Cai, Weikang

AU - Tseng, Yu Hua

AU - Sakaguchi, Nobuo

AU - Kahn, C. Ronald

AU - Araki, Eiichi

PY - 2022/12

Y1 - 2022/12

N2 - Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.

AB - Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we investigate the role of phosphatase binding protein Alpha4 (α4) that is essential for the serine/threonine protein phosphatase 2A (PP2A) in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of α4 impairs insulin-induced Akt-mediated serine/threonine phosphorylation despite a decrease in the protein phosphatase 2A (PP2A) levels. Interestingly, loss of α4 also reduces insulin-induced insulin receptor tyrosine phosphorylation. This occurs through decreased association of α4 with Y-box protein 1, resulting in the enhancement of the tyrosine phosphatase protein tyrosine phosphatase 1B (PTP1B) expression. Moreover, adipocyte-specific knockout of α4 in male mice results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the α4 /Y-box protein 1(YBX1)-mediated pathway of insulin receptor signaling is involved in maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism.

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SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

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M1 - 6092

ER -

Phosphatase protector alpha4 (α4) is involved in adipocyte maintenance and mitochondrial homeostasis through regulation of insulin signaling

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

UN SDGs

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