3-(2-4-dichlorobenzyl)-2-methyl-n-(pentylsulfonyl)-3-h-benzimidazole-5-carboxamide and Obesity

The aim of this study was to examine the mechanism by which a novel non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) gamma agonist, FK614, ameliorates insulin resistance in Zucker fatty rats.. FK614 (1, 3.2 or 10 mg/kg) and a TZD PPARgamma agonist, pioglitazone (1, 3.2 or 10 mg/kg), were orally administered to Zucker fatty rats (genetically obese and insulin resistant) once a day for 14 days, and an oral glucose tolerance test was performed. The expression levels of various genes in the white adipose tissue (WAT) of Zucker fatty rats treated with FK614 (3.2 mg/kg), pioglitazone (10 mg/kg) and another TZD PPARgamma agonist, rosiglitazone (3.2 mg/kg), were determined using a real-time reverse transcription-polymerase chain reaction method. Morphometric analysis of the WAT of Zucker fatty rats treated with FK614 (3.2 mg/kg) and pioglitazone (10 mg/kg) was performed. Glucose transport activity in the isolated soleus muscle of FK614-treated Zucker fatty rats was also investigated.. FK614 and pioglitazone both improved glucose tolerance in Zucker fatty rats. FK614 significantly increased the expression levels of acyl CoA oxidase, a PPAR-responsive gene, and adipocyte fatty acid-binding protein (aP2), an adipocyte differentiation marker gene, in epididymal WAT. It also significantly decreased the level of gene expression of tumour necrosis factor-alpha, an insulin resistance-inducing factor in retroperitoneal WAT, as did pioglitazone and rosiglitazone. FK614 and pioglitazone both significantly increased the total number of adipocytes and decreased their average size in WAT, mainly by increasing the number of small adipocytes. Additionally, administration of FK614 to Zucker fatty rats enhanced insulin sensitivity for glucose uptake in the soleus muscle.. This study suggests the possibility that FK614 induces adipocyte differentiation in Zucker fatty rats by stimulating PPARgammain vivo, thereby changing the character of WAT and improving insulin sensitivity throughout the body.

Topics: Acyl-CoA Oxidase; Adipocytes, White; Adipose Tissue; Administration, Oral; Animals; Benzimidazoles; Biological Transport; Cell Count; Cell Size; Epididymis; Fatty Acid-Binding Proteins; Gene Expression; Glucose; Glucose Tolerance Test; Hypoglycemic Agents; Insulin Resistance; Male; Muscle, Skeletal; Obesity; Pioglitazone; PPAR gamma; Rats; Rats, Zucker; Rosiglitazone; Thiazolidinediones

Adipogenesis is an important process for the improvement of insulin resistance by peroxisome proliferator-activated receptor (PPAR) gamma agonists, such as rosiglitazone and pioglitazone. FK614 [3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3-Hbenzimidazole-5-carboxamide] is a structurally novel class of PPARgamma agonist that improves insulin sensitivity in animal models of type 2 diabetes. Herein, we characterize FK614, a selective PPARgamma modulator (SPPARM) with differential properties affecting the regulation of fat cell function. FK614 behaves as a partial agonist in inducing the interaction of PPARgamma with both transcriptional coactivators, cAMP response element-binding protein-binding protein and steroid receptor coactivator-1, but as a full agonist with both PPAR-binding protein and PPAR-interacting protein, which are required for PPARgamma-mediated adipogenesis. In the differentiating 3T3-L1 adipocytes, the levels of adipose fatty acid-binding protein (aP2) mRNA expression and triglyceride accumulation induced by FK614 were as efficacious as those of rosiglitazone and pioglitazone. In contrast, the effect of FK614 on aP2 gene expression in mature adipocytes was less than that of the other PPARgamma agonists. Furthermore, the long-term treatment of mature adipocytes with rosiglitazone and pioglitazone reduced the expression of phosphodiesterase 3B, the down-regulation of which has an important role in the development of insulin resistance; however, FK614 had no such effect in mature adipocytes. Thus, FK614 behaves as an SPPARM with differential effects on the activation of PPARgamma at each stage of adipocyte differentiation. The stage-dependent selectivity of FK614 may contribute to its enhanced insulin sensitization in differentiating adipocytes and to reduced insulin resistance at the stage of adipocyte hypertrophy.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; 3T3 Cells; Adipocytes; Animals; Benzimidazoles; Cell Differentiation; Chlorocebus aethiops; Collagen; Cyclic Nucleotide Phosphodiesterases, Type 3; Gels; Gene Expression; Hypoglycemic Agents; Insulin Resistance; Mice; Obesity; Pioglitazone; Plasmids; PPAR gamma; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Rosiglitazone; Thiazolidinediones; Triglycerides