Mapping of early signaling events in tumor necrosis factor-alpha -mediated lipolysis in human fat cells.
Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine with a proposed role in obesity-related insulin resistance. This could be mediated by increased lipolysis in adipose tissue resulting in elevated free fatty acid levels. The early intracellular signals entailed in TNF-alpha-mediated lipolysis are unknown but may involve members of the mitogen-activated protein kinase (MAPK) family. We investigated the possible contribution of MAPK in TNF-alpha-induced lipolysis in human preadipocytes. TNF-alpha activated the three mammalian MAPK, p44/42, JNK, and p38, in a distinct time- and concentration-dependent manner. TNF-alpha also induced a concentration-dependent stimulation of lipolysis with a more than 3-fold increase at the maximal dose. Lipolysis was completely inhibited by blockers specific for p44/42 (PD98059) and JNK (dimetylaminopurine) but was not affected by the p38 blocker SB203580. Use of receptor-specific TNF-alpha mutants showed that activation of MAPK is entirely mediated by the TNFR1 receptor. The results in human preadipocytes differed from those obtained in murine 3T3-L1 adipocytes in which all three MAPK were constitutively active. Thus, studies of intracellular signaling pathways obtained in different cellular contexts should be interpreted with caution. In conclusion, although TNF-alpha activates all three known MAPK in human preadipocytes, only p44/42 and JNK appear to be involved in the regulation of lipolysis.
Ryden
Mikael
M
Lipid laboratory, Department of Medicine and Surgery, Karolinska Institute, Huddinge University Hospital, S-141 86 Huddinge, Stockholm, Sweden.
Dicker
Andrea
A
van Harmelen
Vanessa
V
Hauner
Hans
H
Brunnberg
Martin
M
Perbeck
Leif
L
Lonnqvist
Fredrik
F
Arner
Peter
P
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I; D015398:Signal Transduction / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*
D015703:Antigens, CD; D004791:Enzyme Inhibitors; D005419:Flavonoids; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; C001020:N(6),N(6)-dimethyladenine; D020928:Mitogen-Activated Protein Kinases; D000225:Adenine; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one