The Development of INT131 as a Selective PPAR Modulator: Approach to a Safer Insulin Sensitizer
Figure 4
PPARγ full agonists, but
not INT131, activate expression of a full agonist reporter gene, induce recruitment
of DRIP205 coactivator peptide to PAPRγ, and
cause lipid accumulation. (a) An
expression construct bearing a PPAR response element designed to be activated
by PPARγ full agonists was used to detect reporter
gene expression. Transfected HEK cells were exposed to a range of
concentrations of the indicated PPAR ligands, and expression measured. The
maximal expression stimulated by INT131 was about 10% that promoted by
rosiglitazone, pioglitazone, troglitazone, farglitazar, and BPx. (b) A homogenous time-resolved
fluorescence energy transfer (FRET) assay was used to measure association of a
DRIP205 coactivator peptide to PPARγ upon exposure to a range of concentrations
of the indicated PPAR ligands. The maximal association stimulated by INT131 was
about 20–25% that was promoted
by rosiglitazone, pioglitazone, troglitazone, farglitazar, and netoglitazone.
(c) Lipid accumulation was measured in
murine preadipocytes exposed to a range of concentrations of the indicated PPAR
ligands. The maximal lipid accumulation stimulated by INT131 was about 10% that
was promoted by rosiglitazone, pioglitazone, troglitazone, farglitazar, and BPx,
Data on file.
