title: GPR120 in adipocytes has differential roles in the production of pro-inflammatory adipocytokines.
abstract: How nutritional excess leads to inflammatory responses in metabolic syndrome is not well characterized. Here, we evaluated the effects of ω-3 polyunsaturated fatty acid specific G-protein coupled receptor 120 (GPR120) activation on inflammatory pathways in adipocytes, and the influence of this process on macrophage migration. Using 3T3-L1 adipocytes, we found that agonizing GPR120 using its synthetic ligand, GSK137647, attenuated both basal and lipopolysaccharide-induced production of interleukin-6 (IL-6) and C-C motif chemokine ligand 2 (CCL2). Moreover, the intervention reduced the phosphorylation of nuclear factor kappa B inhibitor alpha (IκBα) and nuclear translocation of nuclear factor kappa-B p65 subunit (p65). Furthermore, the silencing of GPR120 itself reduced IL-6 and CCL2 mRNA expression. Inhibition of protein kinase C (PKC) augmented the down-regulatory effect of GSK137647 on IL-6 and CCL2 mRNA. Using a luciferase assay to measure promoter activity of the IL-6 gene in mouse embryonic fibroblasts, we demonstrated that exogenous transfection of GPR120 alone reduced the promoter activity, which was augmented by GSK137647. Inhibition of PKC further reduced the promoter activity. Nevertheless, RAW 264.7 macrophages grown in conditioned medium collected from GSK137647-treated adipocytes attenuated the expressions of matrix metalloproteinases-9 and -3, and tissue inhibitor of metalloproteinase-1. Conditioned medium also inhibited the lipopolysaccharide-induced migration of these macrophages. Taken together, these findings provide critical evidence that although GPR120 is associated with a PKC-mediated pro-inflammatory pathway, the direct inhibitory effects of GPR120 on the nuclear factor kappa B pathway are anti-inflammatory. Moreover, GPR120 activity can attenuate the adipocyte-mediated enhanced production of extracellular matrix-modulating factors in macrophages and can reduce their migration by a paracrine mechanism.
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan; Department of Pharmacology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan. Electronic address: ahasan@med.kagawa-u.ac.jp.
authors.forename: Arif Ul
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.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
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 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 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 Biochemistry, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Tsuboi
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 Pharmacology, Faculty of Medicine, Kagawa University, 1750-1, Ikenobe, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Nishiyama
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*; D054392:Adipokines / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D034622:RNA Interference; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D054392:Adipokines; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C498007:FFAR4 protein, mouse; D018836:Inflammation Mediators; D015850:Interleukin-6; D008070:Lipopolysaccharides; D043562:Receptors, G-Protein-Coupled; C560825:Timp1 protein, mouse; D019715:Tissue Inhibitor of Metalloproteinase-1; D051996:Transcription Factor RelA; D000072000:NF-KappaB Inhibitor alpha; D011493:Protein Kinase C; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9
keywords: Extracellular matrix remodeling factor; Obesity; Protein kinase C; Toll-like receptors; ω-3 polyunsaturated fatty acids