Targets for TNF-alpha-induced lipolysis in human adipocytes.
BACKGROUND
Tumor necrosis factor-alpha (TNF-alpha)-induced lipolysis may be important for insulin resistance in both obesity and cachexia. In rodent cells TNF-alpha enhances lipolysis through down-regulation of the expression of the membrane proteins Galpha(i) and the lipid droplet-associated protein perilipin (PLIN). In human (but not murine) adipocytes TNF-alpha stimulates lipolysis through the mitogen activated protein kinases (MAPKs) p44/42 and JNK although it is unclear whether this is mediated via PLIN and/or Galpha(i).


METHODS
Galpha(i) and PLIN as down-stream effectors of MAPKs were assessed in human adipocytes stimulated with TNF-alpha in the absence or presence of specific MAPK inhibitors.


RESULTS
A 48-h incubation with TNF-alpha resulted in a pronounced increase in lipolysis, which was paralleled by a decrease in the mRNA and protein expression of PLIN. Both these effects were inhibited in a concentration-dependent manner in the presence of MAPK inhibitors specific for p44/42 (PD98059) and JNK (SP600125). However, TNF-alpha did not affect Galpha(i) mRNA or protein expression. Furthermore, experiments with pertussis toxin demonstrated that inhibition of Galpha(i) signaling did not affect TNF-alpha-mediated lipolysis.


CONCLUSIONS
Our results suggest that TNF-alpha-mediated lipolysis is dependent on down-regulation of PLIN expression via p44/42 and JNK. This could be an important mechanism for the development of insulin resistance in both obesity and cachexia. However, in contrast to findings in rodent cells, Galpha(i) does not appear to be essential for TNF-alpha-induced lipolysis in human adipocytes.
Rydén
Mikael
M
Department of Medicine M63, Karolinska Institutet, Karolinska University Hospital at Huddinge, 141 86 Stockholm, Sweden. mikael.ryden@medhs.ki.se
Arvidsson
Elisabet
E
Blomqvist
Lennart
L
Perbeck
Leif
L
Dicker
Andrea
A
Arner
Peter
P
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D002352:Carrier Proteins; D002454:Cell Differentiation; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008875:Middle Aged; D000070778:Perilipin-1; D037342:Pertussis Toxin / Q000494:pharmacology; D010750:Phosphoproteins / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D002352:Carrier Proteins; D008565:Membrane Proteins; D000070778:Perilipin-1; D010750:Phosphoproteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D037342:Pertussis Toxin