The availability of high-affinity agonists for
peroxisome proliferator-activated receptor-beta/delta (
PPARbeta/delta) has led to significant advances in our understanding of the functional role of
PPARbeta/delta. In this study, a new
PPARbeta/delta antagonist, 4-chloro-N-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)
benzamide (
GSK3787), was characterized using in vivo and in vitro models. Orally administered
GSK3787 caused antagonism of 4-[2-(3-fluoro-4-trifluoromethyl-phenyl)-4-methyl-thiazol-5-ylmethylsulfanyl]-2-methyl-phenoxy}-
acetic acid (
GW0742)-induced up-regulation of Angptl4 and Adrp
mRNA expression in wild-type mouse colon but not in
Pparbeta/delta-null mouse colon.
Chromatin immunoprecipitation (ChIP) analysis indicates that this correlated with reduced promoter occupancy of
PPARbeta/delta on the Angptl4 and Adrp genes. Reporter assays demonstrated antagonism of
PPARbeta/delta activity and weak antagonism and agonism of
PPARgamma activity but no effect on
PPARalpha activity. Time-resolved fluorescence resonance energy transfer assays confirmed the ability of
GSK3787 to modulate the association of both
PPARbeta/delta and
PPARgamma coregulator
peptides in response to
ligand activation, consistent with reporter assays. In vivo and in vitro analysis indicates that the efficacy of
GSK3787 to modulate
PPARgamma activity is markedly lower than the efficacy of
GSK3787 to act as a
PPARbeta/delta antagonist.
GSK3787 antagonized
GW0742-induced expression of Angptl4 in mouse fibroblasts, mouse keratinocytes, and human
cancer cell lines. Cell proliferation was unchanged in response to either
GW0742 or
GSK3787 in human
cancer cell lines. Results from these studies demonstrate that
GSK3787 can antagonize
PPARbeta/delta in vivo, thus providing a new strategy to delineate the functional role of a receptor with great potential as a therapeutic target for the treatment and prevention of disease.