The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B <sub>4</sub> 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
Abstract
Significance Recent studies have implicated LTB 4 in inflammation in adipose tissue and in the subsequent development of insulin resistance. The mechanism by which LTB 4 is produced in adipose tissue has remained unknown, however. We now reveal that insulin regulates LTB 4 production in adipocytes via a PDK1–FoxO1–5-LO pathway and thereby maintains systemic insulin sensitivity. Whereas signaling pathways of insulin and LTB 4 have been extensively investigated, a cross-talk between these two signaling pathways has not been reported. We also reveal that LTB 4 exists in plasma at concentrations sufficient to activate its receptor BLT1 and that the plasma concentration of LTB 4 correlated with insulin resistance in human, implying that LTB 4 is a mediator of organ cross-talk.