Enhancement of adipocyte differentiation by an insulin-sensitizing agent.
The thiazolidinediones are a class of novel antidiabetic compounds that enhance the response of target tissues to insulin. Pioglitazone, a thiazolidinedione analog, lowers blood glucose and insulin levels in rodent models of non-insulin-dependent diabetes mellitus. We have studied the effect of pioglitazone on 3T3-L1 cells, a cell line that undergoes differentiation from a preadipocyte fibroblastic morphology to that of an adipocyte. Pioglitazone treatment of preadipocytes enhanced the insulin- or insulin-like growth factor-1 (IGF-I)-regulated differentiation (monitored by the rate of lipogenesis or triglyceride accumulation), whereas treatment of the cells in the absence of insulin or IGF-I resulted in no apparent change in the cellular phenotype. Pioglitazone caused both a leftward shift and enhanced maximum response for the IGF-I-regulated differentiation of the cells, consistent with the idea that the drug enhances the sensitivity of cells to polypeptide hormones. A series of pioglitazone analogs were tested in this system, and variations in activity relative to that of the parent compound were observed. A study of the time required for the drug to exert an effect on differentiation revealed that an increased rate of lipogenesis occurred 16-24 hr after drug treatment in appropriately staged cells. An increased rate of glucose transport and increased activity of lipogenic enzymes were noted in a time frame that correlated with the change in lipogenesis. Analysis of mRNA abundance for Glut-4, lipoprotein lipase, and glucose-6-phosphate dehydrogenase showed that pioglitazone enhanced the insulin induction of these mRNA species. Thus, pioglitazone, in combination with insulin or IGF-I, appears to be exerting effects on the cellular phenotype by eliciting changes in the expression of genes that regulate metabolic pathways leading to the acquisition of the differentiated phenotype.
Kletzien
R F
RF
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Clarke
S D
SD
Ulrich
R G
RG
D016475:3T3 Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005954:Glucosephosphate Dehydrogenase / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis; D008071:Lipoprotein Lipase / Q000378:metabolism; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D010641:Phenotype; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014280:Triglycerides / Q000378:metabolism
D007004:Hypoglycemic Agents; D007328:Insulin; D008055:Lipids; D009004:Monosaccharide Transport Proteins; D012333:RNA, Messenger; D013844:Thiazoles; D045162:Thiazolidinediones; D014280:Triglycerides; D007334:Insulin-Like Growth Factor I; D005954:Glucosephosphate Dehydrogenase; D008071:Lipoprotein Lipase; D000077205:Pioglitazone