title: TNF-alpha induction of lipolysis is mediated through activation of the extracellular signal related kinase pathway in 3T3-L1 adipocytes.
abstract: Tumor necrosis factor-alpha (TNF-alpha) increases adipocyte lipolysis after 6-12 h of incubation. TNF-alpha has been demonstrated to activate mitogen-activated protein (MAP) kinases including extracellular signal-related kinase (ERK) and N-terminal-c-Jun-kinase (JNK) in different cell types. To determine if the MAP kinases have a role in TNF-alpha-induced lipolysis, 3T3-L1 adipocytes were treated with the cytokine (10 ng/ml), in the presence or absence of PD98059 or U0126 (100 micromoles), specific inhibitors of ERK activity. We demonstrated that U0126 or PD98059 blocked TNF-alpha-induced ERK activity and decreased TNF-alpha-induced lipolysis by 65 or 76% respectively. The peroxisome-proliferator-activated receptor gamma (PPARgamma) agonists, rosiglitazone (ros), and 15-deoxy-Delta-(12,14)- prostaglandin J(2) (PGJ2) have been demonstrated to block TNF-alpha-induced lipolysis. Pretreatment of adipocytes with these agents almost totally blocked TNF-alpha-induced ERK activation and reduced lipolysis by greater than 90%. TNF-alpha also stimulated JNK activity, which was not affected by PD98059 or PPARgamma agonist treatment. The expression of perilipin, previously proposed to contribute to the mechanism of lipolysis, is diminished in response to TNF-alpha treatment. Pretreatment of adipocytes with PD98059 or ros significantly blocked the TNF-alpha-induced reduction of perilipin A protein level as determined by Western analysis. These data suggest that activation of the ERK pathway is an early event in the mechanism of TNF-alpha-induced lipolysis.
authors.affiliation: The Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, Massachusetts 02111, USA. sandra.souza@tufts.edu
authors.forename: Sandra C
authors.initials: SC
authors.lastname: Souza
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Palmer
authors.forename: You Hou
authors.initials: YH
authors.lastname: Kang
authors.forename: Mia T
authors.initials: MT
authors.lastname: Yamamoto
authors.forename: Kizito V
authors.initials: KV
authors.lastname: Muliro
authors.forename: K Eric
authors.initials: KE
authors.lastname: Paulson
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Greenberg
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D002352:Carrier Proteins; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D048031:JNK Mitogen-Activated Protein Kinases; D008066:Lipolysis / Q000187:drug effects*; D048670:MAP Kinase Kinase 4; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000096:biosynthesis / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D002070:Butadienes; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D009570:Nitriles; D000070778:Perilipin-1; D010750:Phosphoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C113580:U 0126; D000077154:Rosiglitazone; C037112:9-deoxy-delta-9-prostaglandin D2; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D015230:Prostaglandin D2; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one