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Tumor Necrosis Factor- Stimulates Lipolysis in Differentiated Human Adipocytes Through Activation of Extracellular Signal-Related Kinase and Elevation of Intracellular cAMP

¹ Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA
² Section of Biochemical Physiology, Pulmonary-Critical Care Medicine NHLBI, National Institutes of Health, Bethesda, MD.

Tumor necrosis factor- (TNF-) stimulates lipolysis in human adipocytes. However, the mechanisms regulating this process are largely unknown. We demonstrate that TNF- increases lipolysis in differentiated human adipocytes by activation of mitogen-activated protein kinase kinase (MEK), extracellular signal-related kinase (ERK), and elevation of intracellular cAMP. TNF- activated ERK and increased lipolysis; these effects were inhibited by two specific MEK inhibitors, PD98059 and U0126. TNF- treatment caused an electrophoretic shift of perilipin from 65 to 67 kDa, consistent with perilipin hyperphosphorylation by activated cAMP-dependent protein kinase A (PKA). Coincubation with TNF- and MEK inhibitors caused perilipin to migrate as a single 65-kDa band. Consistent with the hypothesis that TNF- induces perilipin hyperphosphorylation by activating PKA, TNF- increased intracellular cAMP 1.7-fold, and the increase was abrogated by PD98059. Furthermore, H89, a specific PKA inhibitor, blocked TNF--induced lipolysis and the electrophoretic shift of perilipin, suggesting a role for PKA in TNF--induced lipolysis. Finally, TNF- decreased the expression of cyclic-nucleotide phosphodiesterase 3B (PDE3B) by 50%, delineating a mechanism by which TNF- could increase intracellular cAMP. Cotreatment with PD98059 restored PDE3B expression. These studies suggest that in human adipocytes, TNF- stimulates lipolysis through activation of MEK-ERK and subsequent increase in intracellular cAMP.

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