Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-Ay Mice

Obesity is an established risk factor for colorectal cancer. Pioglitazone is a peroxisome proliferatoractivatedreceptorγ (PPARγ) agonist that induces differentiation in adipocytes and induces growth arrestand/or apoptosis in vitro in several cancer cell lines. In the present study, we investigated the effect ofpioglitazone on the development of azoxymethane-induced colon aberrant crypt foci (ACF) in KK-Ayobesity and diabetes model mice, and tried to clarify mechanisms by which the PPARγ ligand inhibitsACF development. Administration of 800 ppm pioglitazone reduced the number of colon ACF / mouseto 30% of those in untreated mice and improved hypertrophic changes of adipocytes in KK-Ay mice withsignificant reduction of serum triglyceride and insulin levels. Moreover, mRNA levels of adipocytokines,such as leptin, monocyte chemoattractant protein-1 and plasminogen activator inhibitor-1, in the visceralfat were decreased. PCNA immunohistochemistry revealed that pioglitazone treatment suppressed cellproliferation in the colorectal epithelium with elevation of p27 and p53 gene expression. These results suggestthat pioglitazone prevented obesity-associated colon carcinogenesis through improvement of dysregulatedadipocytokine levels and high serum levels of triglyceride and insulin, and increase of p27 and p53 mRNAlevels in the colorectal mucosa. These data indicate that pioglitazone warrants attention as a potentialchemopreventive agent against obesity-associated colorectal cancer.