Abstract
Several lines of evidence have supported a link between obesity and inflammation. The present study investigated the capacity of leptin and globular adiponectin to affect tumor necrosis factor alpha (TNF-alpha) production in murine peritoneal macrophages. Leptin stimulated TNF-alpha production at mRNA as well as protein levels in a dose- and time-dependent manner. Intracellular cAMP concentration was increased and protein kinase A (PKA) was activated with the treatment of leptin, subsequently downstream MAPK signal proteins, ERK1/2 and p38, were phosphorylated. Specific inhibitors for the signal proteins, Rp cAMPS, H89, PD98059, and U0126, or SB203580, suppressed the signaling pathway and TNF-alpha expression. Although gAd partially increased cAMP concentration and PKA activity, it directly reduced leptin-induced ERK1/2 and p38 MAPK phosphorylation thus inhibiting TNF-alpha production. In conclusion, leptin promotes inflammation by stimulating TNF-alpha production, which is mediated by cAMP-PKA-ERK1/2 and p38 MAPK pathways. gAd inhibited leptin-induced TNF-alpha production through suppressing phosphorylation of ERK1/2 and p38 pathways.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adiponectin / pharmacology*
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Animals
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Butadienes / pharmacology
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Cyclic AMP / immunology
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Cyclic AMP / metabolism*
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Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
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Cyclic AMP-Dependent Protein Kinases / immunology
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Cyclic AMP-Dependent Protein Kinases / metabolism*
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Drug Interactions
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Enzyme Activation
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Flavonoids / pharmacology
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Imidazoles / pharmacology
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Isoquinolines / pharmacology
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Leptin / antagonists & inhibitors*
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Leptin / pharmacology
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MAP Kinase Kinase 4 / antagonists & inhibitors
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MAP Kinase Kinase 4 / immunology
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MAP Kinase Kinase 4 / metabolism
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MAP Kinase Signaling System / immunology*
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Macrophages, Peritoneal / enzymology
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Macrophages, Peritoneal / immunology*
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Male
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Mice
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / immunology
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Mitogen-Activated Protein Kinase 3 / metabolism
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Nitriles / pharmacology
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Phosphorylation
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Protein Kinase Inhibitors / pharmacology
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Pyridines / pharmacology
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfonamides / pharmacology
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Tumor Necrosis Factor-alpha / biosynthesis*
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / immunology
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p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
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p38 Mitogen-Activated Protein Kinases / immunology
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Adiponectin
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Butadienes
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Flavonoids
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Imidazoles
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Isoquinolines
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Leptin
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Nitriles
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Protein Kinase Inhibitors
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Pyridines
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Sulfonamides
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Tumor Necrosis Factor-alpha
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U 0126
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 3
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p38 Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
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SB 203580
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one