Abstract
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 (AUC0−12h), 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.
Highlights
Insulin resistance (IR) is a root cause of type 2 diabetes mellitus (T2DM) and represents an efficient therapeutic target (Colca, 2015)
In 2010, Choi et al found that cyclin-dependent kinase 5 (CDK5)-mediated phosphorylation at serine 273 of peroxisome proliferator-activated receptor γ (PPARγ) is a critical link between obesity and insulin resistance. pSer273PPARγ inhibition selectively induces expression of specific subsets of PPARγ target genes that are responsible for insulin sensitization instead of adipogenic related genes, and constitutes another potential mechanism underlying the anti-diabetic effects of sPPARγMs (Choi et al, 2010), this has not been systematically demonstrated (Malapaka et al, 2012; Weidner et al, 2013)
We first sought to identify and confirm a dose of INT131 that resulted in equivalent insulin sensitivity to that of 10 mg kg−1 RSG, a dose commonly used in rodent studies(Chen et al, 2009; Zhang et al, 2013), for further use in our pharmacokinetic assays and molecular studies
Summary
Insulin resistance (IR) is a root cause of type 2 diabetes mellitus (T2DM) and represents an efficient therapeutic target (Colca, 2015). Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), a ligand-dependent transcription factor, ameliorates IR by controlling the expression of genes responsible for adipocyte differentiation, lipid metabolism, glucose homeostasis, and Tissue Selective Distribution of INT131 inflammation in insulin target tissues (Lehrke and Lazar, 2005; Ahmadian et al, 2013). The quantities or types of cofactors present in different cells affect this process, leading to tissueor cell-specific gene expression. PSer273PPARγ inhibition selectively induces expression of specific subsets of PPARγ target genes that are responsible for insulin sensitization instead of adipogenic related genes, and constitutes another potential mechanism underlying the anti-diabetic effects of sPPARγMs (Choi et al, 2010), this has not been systematically demonstrated (Malapaka et al, 2012; Weidner et al, 2013). SPPARγM-mediated tissue-selective PPARγ activation and gene expression related to selective PPARγ regulation in ameliorating IR remain to be elucidated
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