In VitroandIn VivoCharacterizations of Chiglitazar, a Newly Identified PPAR Pan-Agonist

Abstract

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 thein vitroandin vivodifferential 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, andδsubtype and upregulated the expression of PPARαand/or PPARδdownstream 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 indb/dbmice. 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. Thein vitroandin vivodifferential features of chiglitazar are informative and encouraging for the further development of this synthetic ligand for the potential use in T2DM.