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Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator
The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs) are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447729/ https://www.ncbi.nlm.nih.gov/pubmed/28611668 http://dx.doi.org/10.3389/fphar.2017.00317 |
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author | Xie, Xinni Chen, Wei Zhang, Ning Yuan, Mei Xu, Cheng Zheng, Zhibing Li, Hua Wang, Lili |
author_facet | Xie, Xinni Chen, Wei Zhang, Ning Yuan, Mei Xu, Cheng Zheng, Zhibing Li, Hua Wang, Lili |
author_sort | Xie, Xinni |
collection | PubMed |
description | The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs) are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM in the context of tissue selective compound distribution and PPARγ regulation. First, 30 mg kg(−1) INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg(−1) rosiglitazone (RSG) in both db/db and DIO mice using the oral glucose and insulin tolerance tests. Similar to RSG, INT131 significantly increased brown adipose tissue (BAT) mass and adipocyte size and up-regulated the expression of BAT-specific genes. Compared with RSG, INT131 exhibited greater potency in inducing white adipose tissue (WAT) browning, decreasing adipocyte size, and increasing BAT-specific and function-related gene expression in subcutaneous WAT (sWAT). However, it did not induce hepatomegaly or hepatic steatosis, which is associated with lower levels of lipogenic genes expression. Pharmacokinetic analysis reveals that in contrast with RSG, INT131 shows higher Cmax, and much longer residency time (AUC(0−12h)), as well relatively lower elimination rate in adipose tissues and skeletal muscle, this demonstrated INT131 distributed predominantly in adipose tissue. Whereas, INT131 was less abundant in the liver. These results thus suggest that the tissue-selective distribution underlies INT131's selective PPARγ modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPARγM to address the insulin resistance of diabetes. |
format | Online Article Text |
id | pubmed-5447729 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-54477292017-06-13 Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator Xie, Xinni Chen, Wei Zhang, Ning Yuan, Mei Xu, Cheng Zheng, Zhibing Li, Hua Wang, Lili Front Pharmacol Pharmacology The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor γ modulators (sPPARγMs) are still not completely known. Here, the representative sPPARγM, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPARγM in the context of tissue selective compound distribution and PPARγ regulation. First, 30 mg kg(−1) INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg(−1) rosiglitazone (RSG) in both db/db and DIO mice using the oral glucose and insulin tolerance tests. Similar to RSG, INT131 significantly increased brown adipose tissue (BAT) mass and adipocyte size and up-regulated the expression of BAT-specific genes. Compared with RSG, INT131 exhibited greater potency in inducing white adipose tissue (WAT) browning, decreasing adipocyte size, and increasing BAT-specific and function-related gene expression in subcutaneous WAT (sWAT). However, it did not induce hepatomegaly or hepatic steatosis, which is associated with lower levels of lipogenic genes expression. Pharmacokinetic analysis reveals that in contrast with RSG, INT131 shows higher Cmax, and much longer residency time (AUC(0−12h)), as well relatively lower elimination rate in adipose tissues and skeletal muscle, this demonstrated INT131 distributed predominantly in adipose tissue. Whereas, INT131 was less abundant in the liver. These results thus suggest that the tissue-selective distribution underlies INT131's selective PPARγ modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPARγM to address the insulin resistance of diabetes. Frontiers Media S.A. 2017-05-30 /pmc/articles/PMC5447729/ /pubmed/28611668 http://dx.doi.org/10.3389/fphar.2017.00317 Text en Copyright © 2017 Xie, Chen, Zhang, Yuan, Xu, Zheng, Li and Wang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Pharmacology Xie, Xinni Chen, Wei Zhang, Ning Yuan, Mei Xu, Cheng Zheng, Zhibing Li, Hua Wang, Lili Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator |
title | Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator |
title_full | Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator |
title_fullStr | Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator |
title_full_unstemmed | Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator |
title_short | Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator |
title_sort | selective tissue distribution mediates tissue-dependent pparγ activation and insulin sensitization by int131, a selective pparγ modulator |
topic | Pharmacology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5447729/ https://www.ncbi.nlm.nih.gov/pubmed/28611668 http://dx.doi.org/10.3389/fphar.2017.00317 |
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