TY - JOUR
T1 - Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases
AU - Petersen, Rasmus K
AU - Jørgensen, Claus
AU - Rustan, Arild C
AU - Frøyland, Livar
AU - Muller-Decker, Karin
AU - Furstenberger, Gerhard
AU - Berge, Rolf K
AU - Kristiansen, Karsten
AU - Madsen, Lise
N1 - Keywords: 3T3-L1 Cells; Acyltransferases; Adipocytes; Animals; Arachidonic Acid; Cell Differentiation; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diacylglycerol O-Acyltransferase; Fatty Acids; Indomethacin; Isoenzymes; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Prostaglandin-Endoperoxide Synthases; Triglycerides
PY - 2003
Y1 - 2003
N2 - Arachidonic acid inhibits adipocyte differentiation of 3T3-L1 cells via a prostaglandin synthesis-dependent pathway. Here we show that this inhibition requires the presence of a cAMP-elevating agent during the first two days of treatment. Suppression of protein kinase A activity by H-89 restored differentiation in the presence of arachidonic acid. Arachidonic acid treatment led to a prolonged activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 activity by the addition of U0126 rescued differentiation. Upon induction of differentiation, expression of cyclooxygenase-2 (COX-2) was transiently induced and then declined, whereas COX-1 expression declined gradually as differentiation progressed. Treatment with arachidonic acid led to sustained expression of COX-1 and COX-2. Omission of a cAMP-elevating agent or addition of H-89 or U0126 prevented sustained expression of COX-2. Unexpectedly, we observed that selective COX-1 or COX-2 inhibitors rescued adipocyte differentiation in the presence of arachidonic acid as effectively as did the nonselective COX-inhibitor indomethacin. De novo fatty acid synthesis, diacylglycerol acyltransferase (DGAT) activity, and triacylglycerol accumulation were repressed in cells treated with arachidonic acid. Indomethacin restored DGAT activity and triacylglycerol accumulation without restoring de novo fatty acid synthesis, resulting in an enhanced incorporation of arachidonic acid into cellular triacylglycerols.
AB - Arachidonic acid inhibits adipocyte differentiation of 3T3-L1 cells via a prostaglandin synthesis-dependent pathway. Here we show that this inhibition requires the presence of a cAMP-elevating agent during the first two days of treatment. Suppression of protein kinase A activity by H-89 restored differentiation in the presence of arachidonic acid. Arachidonic acid treatment led to a prolonged activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), and suppression of ERK1/2 activity by the addition of U0126 rescued differentiation. Upon induction of differentiation, expression of cyclooxygenase-2 (COX-2) was transiently induced and then declined, whereas COX-1 expression declined gradually as differentiation progressed. Treatment with arachidonic acid led to sustained expression of COX-1 and COX-2. Omission of a cAMP-elevating agent or addition of H-89 or U0126 prevented sustained expression of COX-2. Unexpectedly, we observed that selective COX-1 or COX-2 inhibitors rescued adipocyte differentiation in the presence of arachidonic acid as effectively as did the nonselective COX-inhibitor indomethacin. De novo fatty acid synthesis, diacylglycerol acyltransferase (DGAT) activity, and triacylglycerol accumulation were repressed in cells treated with arachidonic acid. Indomethacin restored DGAT activity and triacylglycerol accumulation without restoring de novo fatty acid synthesis, resulting in an enhanced incorporation of arachidonic acid into cellular triacylglycerols.
U2 - 10.1194/jlr.M300192-JLR200
DO - 10.1194/jlr.M300192-JLR200
M3 - Journal article
C2 - 12923227
SN - 0022-2275
VL - 44
SP - 2320
EP - 2330
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 12
ER -