Type 2 diabetes mellitus is often treated with
insulin-sensitizing drugs called
thiazolidinediones (TZD), which improve
insulin resistance and
glycemic control. Despite their effectiveness in treating diabetes, these drugs provide little protection from eminent
cardiovascular disease associated with diabetes. Here we demonstrate how
chiglitazar, a configuration-restricted non-TZD
peroxisome proliferator-activated receptor (
PPAR) pan agonist with moderate transcription activity, preferentially regulates ANGPTL4 and PDK4, which are involved in
glucose and lipid metabolism. CDK5-mediated phosphorylation at
serine 273 (S273) is a unique regulatory mechanism reserved for PPARγ, and this event is linked to
insulin resistance in
type 2 diabetes mellitus. Our data demonstrates that
chiglitazar modulates gene expression differently from two TZDs,
rosiglitazone and
pioglitazone, via its configuration-restricted binding and phosphorylation inhibition of PPARγ.
Chiglitazar induced significantly greater expression of ANGPTL4 and PDK4 than
rosiglitazone and
pioglitazone in different cell models. These increased expressions were dependent on the phosphorylation status of PPARγ at S273. Furthermore, ChIP and AlphaScreen assays showed that phosphorylation at S273 inhibited promoter binding and cofactor recruitment by PPARγ. Based on these results, activities from pan agonist
chiglitazar can be an effective part of a long-term therapeutic strategy for treating
type 2 diabetes in a more balanced action among its targeted organs.