TNF‐α induction of lipolysis is mediated through activation of the extracellular signal related kinase pathway in 3T3‐L1 adipocytes

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Abstract
Tumor necrosis factor-α (TNF-α) increases adipocyte lipolysis after 6–12 h of incubation. TNF-α 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-α-induced lipolysis, 3T3-L1 adipocytes were treated with the cytokine (10 ng/ml), in the presence or absence of PD98059 or U0126 (100 µM), specific inhibitors of ERK activity. We demonstrated that U0126 or PD98059 blocked TNF-α-induced ERK activity and decreased TNF-α-induced lipolysis by 65 or 76% respectively. The peroxisome-proliferator-activated receptor γ (PPARγ) agonists, rosiglitazone (ros), and 15-deoxy-Δ-12,14- prostaglandin J2 (PGJ2) have been demonstrated to block TNF-α-induced lipolysis. Pretreatment of adipocytes with these agents almost totally blocked TNF-α-induced ERK activation and reduced lipolysis by greater than 90%. TNF-α also stimulated JNK activity, which was not affected by PD98059 or PPARγ agonist treatment. The expression of perilipin, previously proposed to contribute to the mechanism of lipolysis, is diminished in response to TNF-α treatment. Pretreatment of adipocytes with PD98059 or ros significantly blocked the TNF-α-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-α-induced lipolysis.