An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor 
(PPAR
) (*)
- Jürgen M. Lehmann(1),
- Linda B. Moore(1),
- Tracey A. Smith-Oliver(1),
- William O. Wilkison(2),
- Timothy M. Willson(3) and
- Steven A. Kliewer(1)(§)
- From the (1) Department of Cellular Biochemistry,
- (2) Department of Biochemistry, and
- (3) Department of Medicinal Chemistry, Glaxo Research Institute, Research Triangle Park, North Carolina 27709
- § To whom correspondence should be addressed. Tel.: 919-990-5601; Fax: 919-990-6147.
Abstract
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 
(PPAR
), a member of the nuclear receptor superfamily recently shown to function in adipogenesis. The most potent of these agents,
BRL49653, binds to PPAR
with a K
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
is a molecular target for the adipogenic effects of thiazolidinediones. Furthermore, these data raise the intriguing possibility
that PPAR
is a target for the therapeutic actions of this class of compounds.
Footnotes
-
↵* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
-
↵1 The abbreviations used are:
- PPAR
-
peroxisome proliferator-activated receptor
- NIDDM
-
non-insulin-dependent diabetes mellitus
- DME medium
-
Dulbecco's modified Eagle's medium
- CAT
-
chloramphenicol acetyltransferase
- tk
-
thymidine kinase
- GST
-
glutathione S-transferase.
- PPAR
- © 1995 by The American Society for Biochemistry and Molecular Biology, Inc.
