Concentration-dependent stimulatory and inhibitory effect of troglitazone on insulin-induced fatty acid synthase expression and protein kinase B activity in 3T3-L1 adipocytes.
In order to study the effect of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist troglitazone on the insulin-induced expression of fatty acid synthase (FAS) in adipocytes, we generated a 3T3-L1 cell line stably expressing a FAS reporter gene construct. In this cell line, a low concentration of troglitazone (250 nM) increased the effect of insulin on the FAS promoter activity and the expression of FAS protein about 1.5- to 2-fold. Since the effect of insulin on the expression of FAS is believed to be mediated by activation of protein kinase B (PKB), we investigated the effect of troglitazone on the regulation of PKB. Troglitazone (250 nM) increased the maximal effect of insulin on PKB activity about twofold without significantly affecting its EC(50) (1.4+/-0.5 nM vs. 2.2+/-0.6 nM in controls). Higher concentrations of troglitazone (> or =1 microM) inhibited both insulin-stimulated PKB activity and expression of FAS. In summary, our data indicate a dual effect of troglitazone on the insulin-induced FAS gene expression in 3T3-L1 cells. The therapeutic, stimulatory effect is produced by low concentrations of troglitazone (250 nM), and is presumably mediated by enhanced activation of PKB.
Barthel
Andreas
A
Institut für Pharmakologie und Toxikologie, RWTH Aachen, 52057 Aachen, Germany, Andreas.Barthel@post.rwth-aachen.de
Krüger
Klaus-Dieter
KD
Roth
Richard A
RA
Joost
Hans-Georg
HG
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D000818:Animals; D002839:Chromans / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D064429:Fatty Acid Synthases / Q000096:biosynthesis* / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D017930:Genes, Reporter; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists; D000077288:Troglitazone
D002839:Chromans; D007004:Hypoglycemic Agents; D007328:Insulin; D011518:Proto-Oncogene Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D064429:Fatty Acid Synthases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000077288:Troglitazone