The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B4 axis

Tetsuya Hosooka; Yusei Hosokawa; Kaku Matsugi; Masakazu Shinohara; Yoko Senga; Yoshikazu Tamori; Chikako Aoki; Sho Matsui; Tsutomu Sasaki; Tadahiro Kitamura; Masashi Kuroda; Hiroshi Sakaue; Kazuhiro Nomura; Kei Yoshino; Yuko Nabatame; Yoshito Itoh; Kanji Yamaguchi; Yoshitake Hayashi; Jun Nakae; Domenico Accili; Takehiko Yokomizo; Susumu Seino; Masato Kasuga; Wataru Ogawa

doi:10.1073/pnas.1921015117

The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B₄ axis

Proc Natl Acad Sci U S A. 2020 May 26;117(21):11674-11684. doi: 10.1073/pnas.1921015117. Epub 2020 May 11.

Authors

Tetsuya Hosooka¹, Yusei Hosokawa¹, Kaku Matsugi¹, Masakazu Shinohara^{2

3}, Yoko Senga¹, Yoshikazu Tamori^{1

4}, Chikako Aoki¹, Sho Matsui⁵, Tsutomu Sasaki⁵, Tadahiro Kitamura⁵, Masashi Kuroda⁶, Hiroshi Sakaue⁶, Kazuhiro Nomura¹, Kei Yoshino¹, Yuko Nabatame¹, Yoshito Itoh⁷, Kanji Yamaguchi⁷, Yoshitake Hayashi⁸, Jun Nakae⁹, Domenico Accili¹⁰, Takehiko Yokomizo¹¹, Susumu Seino¹², Masato Kasuga¹³, Wataru Ogawa¹⁴

Affiliations

¹ Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan.
² Division of Epidemiology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan.
³ The Integrated Center for Mass Spectrometry, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan.
⁴ Department of Internal Medicine, Chibune General Hospital, 555-0001 Osaka, Japan.
⁵ Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 371-8512 Maebashi, Japan.
⁶ Department of Nutrition and Metabolism, Institute of Biomedical Sciences, Tokushima University Graduate School, 770-8503 Tokushima, Japan.
⁷ Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, 602-8566 Kyoto, Japan.
⁸ Division of Molecular Medicine and Medical Genetics, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan.
⁹ Department of Internal Medicine, Keio University School of Medicine, 160-8582 Tokyo, Japan.
¹⁰ Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, NY 10032.
¹¹ Department of Biochemistry, Juntendo University School of Medicine, 113-8421 Tokyo, Japan.
¹² Division of Molecular and Metabolic Medicine, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan.
¹³ The Institute for Adult Diseases, Asahi Life Foundation, 103-0002 Tokyo, Japan.
¹⁴ Division of Diabetes and Endocrinology, Kobe University Graduate School of Medicine, 650-0017 Kobe, Japan; ogawa@med.kobe-u.ac.jp.

Abstract

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 B₄ (LTB₄) 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 LTB₄ 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 LTB₄ 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 LTB₄ via the PDK1-FoxO1 pathway and thereby maintains systemic insulin sensitivity.

Keywords: 5-lipoxygenase; FoxO1; PDK1; insulin resistance; leukotriene B4.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3-Phosphoinositide-Dependent Protein Kinases* / genetics
3-Phosphoinositide-Dependent Protein Kinases* / metabolism
Adipocytes / metabolism*
Animals
Arachidonate 5-Lipoxygenase / metabolism*
Cells, Cultured
Forkhead Box Protein O1* / genetics
Forkhead Box Protein O1* / metabolism
Insulin Resistance* / genetics
Insulin Resistance* / physiology
Leukotriene B4 / metabolism
Male
Mice
Mice, Knockout
Signal Transduction / genetics

Substances

Forkhead Box Protein O1
Foxo1 protein, mouse
Leukotriene B4
Arachidonate 5-Lipoxygenase
3-Phosphoinositide-Dependent Protein Kinases
Pdpk1 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding