Evidence for a common mechanism of action for fatty acids and thiazolidinedione antidiabetic agents on gene expression in preadipose cells.
In diabetic rodents, thiazolidinediones are able to improve insulin sensitivity of target tissues and to reverse, at least partially, the diabetic state. The effects of these drugs on phenotypic expression in various tissues, including adipose tissue, have been reported. We report here that a new thiazolidinedione compound, BRL 49653, exerts, in preadipose cells, potent effects on the expression of genes encoding proteins involved in fatty acid metabolism. These effects of BRL 49653 in Ob 1771 preadipose cells are similar, in terms of kinetics, reversibility, specificity of genes affected, and requirement for protein synthesis, to those already described for natural or nonmetabolizable fatty acids. Moreover, when used at submaximally effective concentrations, BRL49653 and 2-bromopalmitate act in an additive manner to induce gene expression in preadipose cells, but this additivity of effects is lost when one of the compounds is used at a maximally effective concentration. These observations, suggesting similar mechanisms of action for thiazolidinediones and fatty acids, are strongly supported by the demonstration that (i) both molecules activate, in a heterogolous trans-activation assay, the same nuclear receptor of the steroid/thyroid hormone nuclear receptor superfamily and (ii) transfection of 3T3-C2 fibroblasts with an expression vector for this nuclear receptor confers thiazolidinedione inducibility of adipocyte lipid-binding protein gene expression.
Ibrahimi
A
A
Centre de Biochimie, UMR 134 CNRS, Université de Nice-Sophia Antipolis, Faculté des Sciences, France.
Teboul
L
L
Gaillard
D
D
Amri
E Z
EZ
Ailhaud
G
G
Young
P
P
Cawthorne
M A
MA
Grimaldi
P A
PA
D016475:3T3 Cells; D000273:Adipose Tissue / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007700:Kinetics; D051379:Mice; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010168:Palmitates / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D045162:Thiazolidinediones
D002352:Carrier Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D010168:Palmitates; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C022776:2-bromopalmitate