Dataset Information

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

ACCESS DATA

Publications

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

Similar Datasets

Project description:It has been recently reported that the patients with non-alcoholic fatty liver diseases (NAFLD) had accompanied with cardiac dysfunction. However, an animal model of steatohepatitis related cardiomyopathy has not been reported. In the current study, we have developed a mouse model of steatohepatitis-related cardiomyopathy and examined whether a selective PPARα modulator, pemafibrate would improve both steatohepatitis and cardiomyopathy. C57Bl/6 male mice were fed 1. normal chow diet (C group), 2. high fat/high cholesterol/high sucrose/bile acid diet (N group), or 3. N with pemafibrate 0.1 mg/kg (NP group) for three or eight weeks, respectively. Cardiac function was evaluated by ultra-high magnetic field 7-Tesla magnetic resonance imaging (7T-MRI). Even at the eight weeks, we have detected cholesterol crystals, free cholesterol accumulation in liver, followed by macrophage infiltration and fibrosis as wells as activation of NLRP3, caspase-1 and IL-1βmRNA. At the same time in heart, the ratio of heart to body was increased in N group compared to C group. Left ventricular (LV) ejection fraction (LVEF) was moderately decreased in N group compared to C group (50.2±2.8 vs 59.8±2.1, p<0.05). LV circumferential strain and radial strain are focally attenuated in N group, suggesting the early lesion of myocardial damages. mRNA expression of Nlrp3, Caspase1 and Il1b were enhanced in N group, followed by increased protein levels of Caspase-1 and Asc. Rna-sequence analysis revealed that NOD-like receptor and PI3 kinase-AKT pathways were up-regulated, suggesting hypertrophic phenotypes. in N group. Importantly, NLRP3 inflammasome activation were suppressed both in liver and heart in NP group, suggesting pemafibrate had the beneficial effect on steatohepatitis and cardiomyopathy. In addition, four week treatment by pemafibrate improved steatohepatitis and cardiomyopathy after development for eight week. We have first developed the animal model of steatohepatitis-related cardiomyopathy, characterized by the activation of NLRP3 inflammasome pathway both in liver and heart. Steatohepatitis-related cardiomyopathy displayed moderate reduction of LVEF and focal impairment of LV strain by 7T-MRI. Pemafibrate suppressed steatohepatitis, hepatic fibrosis and cardiomyopathy.

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

OmicsDI is part of the ELIXIR infrastructure

Tweets