The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B 4 axis

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2020-05, Vol.117 (21), p.11674-11684
Main Authors: Hosooka, Tetsuya, Hosokawa, Yusei, Matsugi, Kaku, Shinohara, Masakazu, Senga, Yoko, Tamori, Yoshikazu, Aoki, Chikako, Matsui, Sho, Sasaki, Tsutomu, Kitamura, Tadahiro, Kuroda, Masashi, Sakaue, Hiroshi, Nomura, Kazuhiro, Yoshino, Kei, Nabatame, Yuko, Itoh, Yoshito, Yamaguchi, Kanji, Hayashi, Yoshitake, Nakae, Jun, Accili, Domenico, Yokomizo, Takehiko, Seino, Susumu, Kasuga, Masato, Ogawa, Wataru
Format: Article
Language:English
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Summary:Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass. Neither circulating levels of adiponectin and leptin nor inflammatory markers in adipose tissue differed between A-PDK1KO and A-PDK1/FoxO1KO mice. Lipidomics and microarray analyses revealed that leukotriene B (LTB ) levels in plasma and in adipose tissue as well as the expression of 5-lipoxygenase (5-LO) in adipose tissue were increased and restored in A-PDK1KO mice and A-PDK1/FoxO1KO mice, respectively. Genetic deletion of the LTB receptor BLT1 as well as pharmacological intervention to 5-LO or BLT1 ameliorated insulin resistance in A-PDK1KO mice. Furthermore, insulin was found to inhibit LTB production through down-regulation of 5-LO expression via the PDK1-FoxO1 pathway in isolated adipocytes. Our results indicate that insulin signaling in adipocytes negatively regulates the production of LTB via the PDK1-FoxO1 pathway and thereby maintains systemic insulin sensitivity.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1921015117