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.
Adipose tissue plays important roles not only in storing fat but also in maintaining metabolic homeostasis by regulating hundreds of biological signaling events and the secretion of various cytokines. One of the central regulators of adipocyte differentiation is peroxisome proliferator-activated receptor γ (PPARγ), which promotes downstream transcriptional activities, such as adiponectin. Disruption of homeostasis leads to the onset of metabolic diseases such as type 2 diabetes and other triggers for metabolic syndrome. Males and post-menopausal females are more likely to be affected with metabolic diseases than pre-menopausal females, suggesting that sex hormones might be involved in the pathogenesis and development of metabolic diseases. Indeed, 17β-estradiol, testosterone, dihydrotestosterone, and their receptors clearly play a role in adipose regulation: they can alter fat distribution and can modify the expression and activities of PPARγ and its downstream adipocytokines. Furthermore, sex hormones affect inflammatory factors such as nitric oxygen, nitric oxygen synthase, and their surrounding components. Sex hormones are also suggested to be involved with sex differences in the efficacy of the PPARγ agonist thiazolidinediones. Therefore, thorough investigation of how sex hormone-dependent regulation of metabolic homeostasis occurs is necessary in order to develop individualized clinical therapies optimized with regard to each patient's biological condition and drug sensitivities.
We investigated the influence of the cytosine-adenine (CA) dinucleotide repeat polymorphism in intron 6 of estrogen receptor β (ERβ) gene on rheumatoid arthritis (RA) risk. One hundred and ninety-three RA patients and 77 control subjects with osteoarthritis (OA) were recruited. The CA repeat polymorphism was assayed by a dye-terminator cycle sequencing analysis. No statistically significant difference in the mean number of CA repeats between the RA and OA patients was observed (RA: 21.47, OA: 21.23, P = 0.324). The alleles were categorized according to the number of repeats: short (S, ≦ ≧ 21) and long (L, 22), in which the genotypes SS, SL, and LL were observed. No significant differences were observed for the allele and genotype distributions of this polymorphism in both patient groups. The RA patients were classified according to RA severity: mild (least erosive disease) and severe (more erosive and mutilating disease). Again, no significant difference in genotype frequency between these groups was observed, even after stratifying by sex. The present study indicates that additional studies are needed to clarify the roles of this polymorphism, estrogen, and ER in the development of autoimmune diseases.
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