CMHX008,a PPAR γ partial agonist,enhances insulin sensitivity with minor influences on bone loss  

作　　者：Yi Hou Xuemei Cao Xiangnan Hu Xinyu Li Xiaoqin Shi Hongying Wang Chuan Peng Jiayu Li Jibin Li Qifu Li Chaodong Wu Xiaoqiu Xiao 

机构地区：[1]Department of Endocrinology,The First Affiliated Hospital of Chongqing Medical University,Chongqing,400016,China [2]College of Pharmacy,Chongqing Medical University,China [3]The Chongqing Key Laboratory of Translational Medicine in Major Metabolic Diseases,The First Affiliated Hospital of Chongqing Medical University,Chongqing,400016,China [4]Department of Nutrition and Food Hygiene,School of Public Health and Management,Chongqing Medical University,Chongqing,400016,China [5]Canada-China-New Zealand Joint Laboratory of Maternal and Fetal Medicine,Chongqing Medical University,Chongqing,400016,China [6]Department of Nutrition and Food Science,Texas A&M University,College Station,TX,77843,USA

出　　处：《Genes & Diseases》2018年第3期290-299,共10页基因与疾病（英文）

基　　金：supported by the National Natural Science Foundation of China(81270947 and 81570763,to XX);the National Program on Key Basic Research Project of China(973 Program,2012CB517505,to XX);the Fundamental Science and Advanced Technology Research of Chongqing(Major Project,CSTC2015jcyjB0146);Chongqing Graduate Student Research Innovation Fund(CYB15095,to HY)。

摘　　要：Traditional thiazolidinediones(TZDs),such as rosiglitazone,are peroxisome proliferator-activated receptor g(PPARg)potent agonists that can be used to treat type 2 diabetes but carry unwanted effects,including increased risk for fracture.The present work aimed to compare the insulin-sensitizing efficacies and bone-loss side effects of CMHX008,a novel TZDs-like PPARg partial agonist,with those of rosiglitazone.A TR-FRET PPARg competitive binding assay was used to compare the binding affinity between CMHX008 and rosiglitazone.Mice were administered vehicle,CMHX008 or rosiglitazone for 16 weeks.Mesenchymal stem cells(MSCs)were used to examine differences in differentiation into osteoblasts after compounds treatment.TR-FRET showed lower affinity to PPARg by CMHX008 compared with rosiglitazone.Mice treated with CMHX008 showed insulin sensitization similar to that of mice treated with rosiglitazone,which was related to the significant inhibition of PPARg Ser273 phosphorylation and improved insulin sensitivity by facilitating the phosphorylation of insulin receptor and Akt in adipose tissues.Micro-CT and histomorphometric analyses demonstrated that the degree of trabecular bone loss after treatment with CMHX008 was weaker than that observed with rosiglitazone,as evidenced by consistent changes in BV/TV,Tb.N,Tb.Th,Tb.Sp,and the mineral apposition rate.MSCs treated with CMHX008 showed higher ALP activity and mRNA levels of bone formation markers than did cells treated with rosiglitazone in the osteoblast differentiation test.Thus,CMHX008 showed insulin-sensitizing effects similar to those of rosiglitazone with a lower risk of bone loss,suggesting that PPARg sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.

关 键 词：OSTEOBLASTS Peroxisome proliferator-activated receptor g THIAZOLIDINEDIONES TR-FRET Type 2 diabetes mellitus 

分 类 号：R58[医药卫生—内分泌]