Novel genes regulated by the insulin sensitizer rosiglitazone during adipocyte differentiation.
Thiazolidinediones (TZDs) are a new class of compounds that improve insulin sensitivity in type 2 diabetic patients as well as in rodent models of this disease. These compounds act as ligands for a member of the nuclear hormone receptor superfamily, peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which is highly expressed in adipose tissue and, moreover, has been shown to play an important role in adipocyte differentiation. The strong correlation between the antidiabetic activity of TZDs and their ability to activate PPAR-gamma suggests that PPAR-gamma, through downstream-regulated genes, mediates the effects of TZDs. In this report, we present the isolation and characterization of 81 genes, encoding proteins of known function, differentially expressed during TZD-stimulated differentiation of 3T3-L1 cells. By the use of different reverse- Northern blot techniques, the differential expression of 50 of these genes could be verified, and 21 genes were specifically regulated by a potent TZD during the course of adipocyte differentiation, whereas no effect of a PPAR-gamma antagonist could be observed in mature adipocytes. The differential expression of a large fraction of the isolated genes was also shown to occur in white adipose tissue of ob/ob mice treated with rosiglitazone; combined, our results suggest that an important effect of rosiglitazone in adipose tissue is based on activation of PPAR-gamma in preexisting preadipocytes found among the mature adipocytes, resulting in subsequent adipocyte differentiation.
Albrektsen
Tatjana
T
Department of Molecular Genetics, Novo Nordisk, Bagsvaerd, Denmark.
Frederiksen
Klaus Stensgaard
KS
Holmes
William E
WE
Boel
Esper
E
Taylor
Karen
K
Fleckner
Jan
J
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D017931:DNA Primers; D004798:Enzymes / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000502:physiology*; D007668:Kidney; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics; D000077154:Rosiglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D014158:Transcription, Genetic
D017931:DNA Primers; D004798:Enzymes; D007004:Hypoglycemic Agents; D007328:Insulin; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone