Solid rationales are still present for the identification of synthetic
ligands to simultaneously target multiple
PPAR subtypes for the treatment of T2DM. The purpose of this study was to characterize the in vitro and in vivo differential effects of
chiglitazar, a non-TZD type of
PPAR pan-agonist currently in phase III clinic development in China, from PPARγ-selective agonist like
rosiglitazone.
Chiglitazar showed transactivating activity in each PPARα, γ, and δ subtype and upregulated the expression of PPARα and/or PPARδ downstream genes involved in the key processes of lipid metabolism and thermogenesis. Comparable
blood glucose lowering effect was observed between
chiglitazar and
rosiglitazone, but
chiglitazar did not significantly increase the
body weight in KKAy and fat pad weight in db/db mice.
Chiglitazar had high distribution in liver, pancreas, and skeleton muscles but was less present in kidney, heart, and adipose in rats. Heart weight increase was not observed in rats treated with
chiglitazar for 6 months at a dose as high as 45 mg kg(-1). The in vitro and in vivo differential features of
chiglitazar are informative and encouraging for the further development of this synthetic
ligand for the potential use in T2DM.