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

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.

• Authors: 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
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 21 Pg. 11674-11684 (05 26 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 32393635 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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