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Journal of Lipid Research, Vol. 44, 2320-2330, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Arachidonic acid-dependent inhibition of adipocyte differentiation requires PKA activity and is associated with sustained expression of cyclooxygenases

Rasmus K. Petersen^*,, Claus Jørgensen^*, Arild C. Rustan, Livar Frøyland^**, Karin Muller-Decker, Gerhard Furstenberger, Rolf K. Berge, Karsten Kristiansen^* and Lise Madsen^1,*,

^* Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark
BioLigands, International Science Park, Odense, Denmark
Department of Pharmacology, School of Pharmacy, University of Oslo, Oslo, Norway
^** National Institute of Nutrition and Seafood Research, Bergen, Norway
Section of Eicosanoids and Epithelial Tumor Development, Deutsches Krebsforschungszentrum, Heidelberg, Germany
Department of Clinical Biochemistry, Haukeland University Hospital, University of Bergen, Bergen, Norway

¹ To whom correspondence should be addressed. e-mail: lise.madsen{at}bmb.sdu.dk

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.

Abbreviations: Akt/PKB, protein kinase B; aP2, adipocyte lipid binding protein; COX, cyclooxygenase; DGAT, diacylglycerol acyltransferase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ERK1/2, extracellular signal-regulated kinases 1 and 2; MAPK, mitogen-activated protein kinase; MDI, methylisobutylxanthine, dexamethasone, and insulin; MIX, methylisobutylxanthine; PPAR, peroxisome proliferator-activated receptor; SD, standard deviation; TFIIB, transcription factor IIB

Supplementary key words mitogen-activated protein kinase • peroxisome proliferator-activated receptor • CCAAT/enhancer-binding protein • diacylglycerol acyltransferase • protein kinase A

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