title: Eicosapentaenoic acid upregulates VEGF-A through both GPR120 and PPARγ mediated pathways in 3T3-L1 adipocytes.
abstract: Vascular endothelial growth factor-A (VEGF-A) released from adipocytes promotes angiogenesis; and thereby ameliorates the local hypoxia-induced adipose inflammation and insulin resistance. Here, we newly found that eicosapentaenoic acid (EPA) upregulated both mRNA expression and release of VEGF-A in mature 3T3-L1 adipocytes. Silencing mRNA of G-protein coupled receptor 120 (GPR120) and specific inhibition of peroxisome proliferator-activated receptor γ (PPARγ) by GW9662 respectively attenuated the EPA-induced augmentation of VEGF-A release by adipocytes. Furthermore, transfection of GPR120 gene alone and PPARγ gene alone to HEK293 cells respectively increased the promoter activity of VEGF-A as assessed by luciferase reporter assay, which was further augmented when both genes were co-transfected. Promoter deletion analysis and chromatin immunoprecipitation assay revealed that co-transfection of GPR120 enhanced EPA-induced PPARγ binding to PPAR-response element in VEGF-A promoter region. Thus, by the synchronized activation of a membrane receptor GRP120 and a nuclear receptor PPARγ, EPA enhances VEGF-A production in adipocytes.
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Arif U
authors.initials: AU
authors.lastname: Hasan
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Electronic address: komori@med.kagawa-u.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kumi
authors.initials: K
authors.lastname: Konishi
authors.affiliation: Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Junsuke
authors.initials: J
authors.lastname: Igarashi
authors.affiliation: Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kamitori
authors.affiliation: Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Yamaguchi
authors.affiliation: Department of Pharmaco-Bio-Informatics, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Tsukamoto
authors.affiliation: Department of Biochemistry, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Uyama
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noma
authors.affiliation: Department of Cell Physiology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tokuda
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D047495:PPAR gamma / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D015118:Eicosapentaenoic Acid; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; C498007:FFAR4 protein, mouse
keywords: Cytokines; Diabetes; G proteins; Obesity; Protein kinases/MAP kinase; ω-3 fatty acids