Peroxisome proliferator-activated receptor (
PPAR) γ plays a major role in the regulation of
lipid and carbohydrate metabolism.
Pioglitazone is a PPARγ agonist that is widely used for the treatment of
type 2 diabetes mellitus. However, female patients have been reported to experience stronger efficacy and adverse effects than male patients. This study evaluated the effects of
sex hormones on PPARγ expression and activity in adipocytes. Mouse 3T3-L1 preadipocytes were used after being grown into matured adipocytes. The
sex hormones 17β-estradiol (E2),
testosterone (T), or 5α-androstan-17β-ol-3-one (
dihydrotestosterone; DHT) were added to the matured adipocytes and the cells were then maintained for short (24-72 h) or long (1- or 2-weeks) periods. E2 significantly upregulated PPARγ
protein expression in a concentration-dependent manner after extended exposure, whereas T and DHT did not have such an effect. When cells were co-treated with
pioglitazone and E2, PPARγ
protein expression significantly increased in an E2-dependent manner, whereas this expression seemed to be reduced by
pioglitazone mono-treatment and co-treatment with DHT at higher concentrations. The secretion levels of
adiponectin protein, a major
indicator of PPARγ activity, were significantly decreased by DHT, but were not affected by E2. Finally a
luciferase assay was performed using a
PPAR response element-Luk reporter gene. Transcriptional activity was not changed by any of single
sex hormone treatment, but was significantly downregulated by co-treatment with
pioglitazone and DHT. Taken together, our results suggest that
sex hormones may influence PPARγ expression and function, which may explain the observed sex-specific different effect of
pioglitazone.