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

Traditional thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) 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-sensitizin...

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Autores principales: Hou, Yi, Cao, Xuemei, Hu, Xiangnan, Li, Xinyu, Shi, Xiaoqin, Wang, Hongying, Peng, Chuan, Li, Jiayu, Li, Jibin, Li, Qifu, Wu, Chaodong, Xiao, Xiaoqiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Chongqing Medical University 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176219/
https://www.ncbi.nlm.nih.gov/pubmed/30320193
http://dx.doi.org/10.1016/j.gendis.2018.05.004
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author Hou, Yi
Cao, Xuemei
Hu, Xiangnan
Li, Xinyu
Shi, Xiaoqin
Wang, Hongying
Peng, Chuan
Li, Jiayu
Li, Jibin
Li, Qifu
Wu, Chaodong
Xiao, Xiaoqiu
author_facet Hou, Yi
Cao, Xuemei
Hu, Xiangnan
Li, Xinyu
Shi, Xiaoqin
Wang, Hongying
Peng, Chuan
Li, Jiayu
Li, Jibin
Li, Qifu
Wu, Chaodong
Xiao, Xiaoqiu
author_sort Hou, Yi
collection PubMed
description Traditional thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ partial agonist, with those of rosiglitazone. A TR-FRET PPARγ 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 PPARγ 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 PPARγ 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 PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties.
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spelling pubmed-61762192018-10-12 CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss Hou, Yi Cao, Xuemei Hu, Xiangnan Li, Xinyu Shi, Xiaoqin Wang, Hongying Peng, Chuan Li, Jiayu Li, Jibin Li, Qifu Wu, Chaodong Xiao, Xiaoqiu Genes Dis Article Traditional thiazolidinediones (TZDs), such as rosiglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ partial agonist, with those of rosiglitazone. A TR-FRET PPARγ 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 PPARγ 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 PPARγ 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 PPARγ sparing eliminates the skeletal side effects of TZDs while maintaining their insulin-sensitizing properties. Chongqing Medical University 2018-06-06 /pmc/articles/PMC6176219/ /pubmed/30320193 http://dx.doi.org/10.1016/j.gendis.2018.05.004 Text en © 2018 Chongqing Medical University. Production and hosting by Elsevier B.V. http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Article
Hou, Yi
Cao, Xuemei
Hu, Xiangnan
Li, Xinyu
Shi, Xiaoqin
Wang, Hongying
Peng, Chuan
Li, Jiayu
Li, Jibin
Li, Qifu
Wu, Chaodong
Xiao, Xiaoqiu
CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
title CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
title_full CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
title_fullStr CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
title_full_unstemmed CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
title_short CMHX008, a PPARγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
title_sort cmhx008, a pparγ partial agonist, enhances insulin sensitivity with minor influences on bone loss
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6176219/
https://www.ncbi.nlm.nih.gov/pubmed/30320193
http://dx.doi.org/10.1016/j.gendis.2018.05.004
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