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 and Eiichi Araki
Additional contact information
Masaji Sakaguchi: Kumamoto University
Shota Okagawa: Kumamoto University
Yuma Okubo: Kumamoto University
Yuri Otsuka: Kumamoto University
Kazuki Fukuda: Kumamoto University
Motoyuki Igata: Kumamoto University
Tatsuya Kondo: Kumamoto University
Yoshifumi Sato: Kumamoto University
Tatsuya Yoshizawa: Kumamoto University
Takaichi Fukuda: Kumamoto University
Kazuya Yamagata: Kumamoto University
Weikang Cai: New York Institute of Technology College of Osteopathic Medicine
Yu-Hua Tseng: Harvard Medical School
Nobuo Sakaguchi: Kumamoto University
C. Ronald Kahn: Harvard Medical School
Eiichi Araki: Kumamoto University

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33842-4

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DOI: 10.1038/s41467-022-33842-4

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