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Selective Tissue Distribution Mediates Tissue-Dependent PPAR? Activation and Insulin Sensitization by INT131, a Selective PPAR? Modulator.

ABSTRACT: The mechanisms underlying the enhancement of insulin sensitivity by selective peroxisome proliferator-activated receptor ? modulators (sPPAR?Ms) are still not completely known. Here, the representative sPPAR?M, INT131, was used as a probe to investigate the insulin-sensitizing mechanisms of sPPAR?M in the context of tissue selective compound distribution and PPAR? 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 PPAR? modulation. Compounds favoring adipose tissue may aid in development of better, safer sPPAR?M to address the insulin resistance of diabetes.

SUBMITTER: Xie X

PROVIDER: S-EPMC5447729 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator.

Xie Xinni X Chen Wei W Zhang Ning N Yuan Mei M Xu Cheng C Zheng Zhibing Z Li Hua H Wang Lili L

Frontiers in pharmacology 20170530

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<sup>-1</sup> INT131 was observed to produce an insulin-sensitizing effect comparable to that of 10 mg kg< ...[more]

PMID: 28611668

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Project description:Peroxisome proliferator-activated receptor-γ (PPARγ) ligands, including the insulin-sensitizing thiazolidinedione drugs, transcriptionally regulate hundreds of genes. Little is known about the relationship between PPARγ ligand-specific modulation of cellular mechanisms and insulin sensitization. We characterized the insulin sensitivity and multitissue gene expression profiles of lean and insulin-resistant, obese Zucker rats untreated or treated with one of four PPARγ ligands (pioglitazone, rosiglitazone, troglitazone, and AG-035029). We analyzed the transcriptional profiles of adipose tissue, skeletal muscle, and liver from the rats and determined whether ligand treatment insulin-sensitizing potency was related to ligand treatment-induced alteration of functional pathways. Ligand treatments improved insulin sensitivity in obese rats to varying degrees. Adipose tissue profiles revealed ligand treatment-selective modulation of inflammatory and branched-chain amino acid (BCAA) metabolic pathways, which correlated with ligand treatment-specific insulin-sensitizing potency. Skeletal muscle profiles showed that obese rats exhibited elevated expression of adipocyte and slow-twitch fiber markers, which further increased after ligand treatment, but the magnitude of the treatment-induced changes was not correlated with insulin sensitization. Although PPARγ ligand treatments heterogeneously improved dysregulated expression of cholesterol and fatty acid biosynthetic pathways in obese rat liver, these alterations were not correlated with ligand insulin-sensitizing potency. PPARγ ligand treatment-specific insulin-sensitizing potency correlated with modulation of adipose tissue inflammatory and BCAA metabolic pathways, suggesting a functional relationship between these pathways and whole body insulin sensitivity. Other PPARγ ligand treatment-induced functional pathway changes were detected in adipose tissue, skeletal muscle, and liver profiles but were not related to degree of insulin sensitization.

Dataset Information

Selective Tissue Distribution Mediates Tissue-Dependent PPAR? Activation and Insulin Sensitization by INT131, a Selective PPAR? Modulator.

Publications

Selective Tissue Distribution Mediates Tissue-Dependent PPARγ Activation and Insulin Sensitization by INT131, a Selective PPARγ Modulator.

Similar Datasets

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