Mechanism by which a novel non-thiazolidinedione peroxisome proliferator-activated receptor ? agonist, FK614, ameliorates insulin resistance in Zucker fatty rats

Aim:  The aim of this study was to examine the mechanism by which a novel non-thiazolidinedione (TZD) peroxisome proliferator-activated receptor (PPAR) γ agonist, FK614, ameliorates insulin resistance in Zucker fatty rats. Methods:  FK614 (1, 3.2 or 10 mg/kg) and a TZD PPARγ 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 PPARγ 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. Results:  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-α, 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. Conclusion:  This study suggests the possibility that FK614 induces adipocyte differentiation in Zucker fatty rats by stimulating PPARγin vivo, thereby changing the character of WAT and improving insulin sensitivity throughout the body.