CMHX008, a Novel Thiazolidinedione-Like PPARγ Partial Agonist, Enhances Insulin Sensitivity with Minor Influences on Bone Loss

Abstract

Objective: Traditional thiazolidinediones (TZDs), rosiglitazone for instance, are peroxisome proliferator-activated receptor γ (PPARγ) potent agonists and can treat type 2 diabetes but carry unwanted effects including increased risk for fracture. Here we compared insulin-sensitizing efficacies and bone-loss side effects of CMHX008, a novel TZDs-like PPARγ partial agonist, with rosiglitazone. Methods: TR-FRET PPARγ competitive binding assay was used to compare the binding affinity between CMHX0and rosiglitazone. High fat diet fed and ob/ob mice were administered with vehicle, CMHX0or rosiglitazone. Bone marrow mesenchymal stem cells (BMMSCs) were used to examine differences in differentiation into osteoblasts after treated with CMHX0and rosiglitazone. Results: TR-FRET showed lower affinity to PPARγ by CMHX0compared with rosiglitazone. Mice treated with CMHX0for 16 weeks had the comparable effect of insulin sensitization as rosiglitazone, which was related to significant inhibition on PPARγ Ser 273 phosphorylation and improved insulin sensitivity by facilitating phosphorylation insulin receptor and AKT in adipose tissues. Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treated with CMHX0was weaker than rosiglitazone as evidence by consistent changes in BV/TV, Tb.N, Tb.Th, Tb.Sp, and mineral apposition rate. BMMSCs treated with CMHX0showed higher ALP activity and mRNA levels of bone formation markers than those treated by rosiglitazone in osteoblast differentiation test. Conclusion: PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties. CMHX0shared the comparable insulin-sensitizing effects as rosiglitazone with lower risk of bone loss. Disclosure X. Xiao: None. Y. Hou: None. X. Cao: None. J. Li: None.