The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B 4 axis
| العنوان: | The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase–leukotriene B 4 axis |
|---|---|
| المؤلفون: | Kei Yoshino, Yuko Nabatame, Masakazu Shinohara, Kazuhiro Nomura, Yoshitake Hayashi, Kaku Matsugi, Wataru Ogawa, Kanji Yamaguchi, Hiroshi Sakaue, Tsutomu Sasaki, Sho Matsui, Tadahiro Kitamura, Yusei Hosokawa, Takehiko Yokomizo, Yoshikazu Tamori, Jun Nakae, Domenico Accili, Tetsuya Hosooka, Masato Kasuga, Chikako Aoki, Yoko Senga, Susumu Seino, Masashi Kuroda, Yoshito Itoh |
| المصدر: | Proceedings of the National Academy of Sciences. 117:11674-11684 |
| بيانات النشر: | Proceedings of the National Academy of Sciences, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | medicine.medical_specialty, Multidisciplinary, biology, Adiponectin, Leukotriene B4, Insulin, medicine.medical_treatment, Leptin, Adipose tissue, FOXO1, medicine.disease, chemistry.chemical_compound, Insulin receptor, Endocrinology, Insulin resistance, chemistry, Internal medicine, medicine, biology.protein |
| الوصف: | 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. |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::5331483681979a2d19929553a57de793 https://doi.org/10.1073/pnas.1921015117 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........5331483681979a2d19929553a57de793 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
|---|