TY - JOUR
T1 - An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ)
AU - Lehmann, Jürgen M.
AU - Moore, Linda B.
AU - Smith-Oliver, Tracey A.
AU - Wilkison, William O.
AU - Willson, Timothy M.
AU - Kliewer, Steven A.
PY - 1995/6/2
Y1 - 1995/6/2
N2 - 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 γ (PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPARγ with a K(d) 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 PPARγ is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compounds.
AB - 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 γ (PPARγ), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents, BRL49653, binds to PPARγ with a K(d) 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 PPARγ is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility that PPARγ is a target for the therapeutic actions of this class of compounds.
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U2 - 10.1074/jbc.270.22.12953
DO - 10.1074/jbc.270.22.12953
M3 - Article
C2 - 7768881
AN - SCOPUS:0029016829
SN - 0021-9258
VL - 270
SP - 12953
EP - 12956
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 22
ER -