An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma).
Thiazolidinedione derivatives are antidiabetic agents that increase the insulin sensitivity of target tissues in animal models of non-insulin-dependent diabetes mellitus. In vitro, thiazolidinediones promote adipocyte differentiation of preadipocyte and mesenchymal stem cell lines; however, the molecular basis for this adipogenic effect has remained unclear. Here, we report that thiazolidinediones are potent and selective activators of peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPAR gamma with a Kd of approximately 40 nM. Treatment of pluripotent C3H10T1/2 stem cells with BRL49653 results in efficient differentiation to adipocytes. These data are the first demonstration of a high affinity PPAR ligand and provide strong evidence that PPAR gamma is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPAR gamma is a target for the therapeutic actions of this class of compounds.
Lehmann
J M
JM
Department of Cellular Biochemistry, Glaxo Research Institute, Research Triangle Park, North Carolina 27709, USA.
Moore
L B
LB
Smith-Oliver
T A
TA
Wilkison
W O
WO
Willson
T M
TM
Kliewer
S A
SA
D017667:Adipocytes / Q000166:cytology; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D008809:Mice, Inbred C3H; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D000077154:Rosiglitazone; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism*; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000378:metabolism*
D007004:Hypoglycemic Agents; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone