ABSTRACT
To determine whether the PPARalpha agonist fenofibrate regulates obesity and lipid metabolism with sexual dimorphism, we examined the effects of fenofibrate on body weight, white adipose tissue (WAT) mass, circulating lipids, and the expression of PPARalpha target genes in both sexes of high fat diet-fed C57BL/6J mice. Both sexes of mice fed a high-fat diet for 14 weeks exhibited increases in body weight, visceral WAT mass, as well as serum triglycerides and cholesterol, although these effects were more pronounced among males. Feeding a high fat diet supplemented with fenofibrate (0.05% w/w) reduced all of these effects significantly in males except serum cholesterol level. Females on a fenofibrate-enriched high fat diet had reduced serum triglyceride levels, albeit to a smaller extent compared to males, but did not exhibit decreases in body weight, WAT mass, and serum cholesterol. Fenofibrate treatment resulted in hepatic induction of PPAR alpha target genes encoding enzymes for fatty acid beta-oxidation, the magnitudes of which were much higher in males compared to females, as evidenced by results for acyl-CoA oxidase, a first enzyme of the beta-oxidation system. These results suggest that observed sexually dimorphic effects on body weight, WAT mass and serum lipids by fenofibrate may involve sexually related elements in the differential activation of PPARalpha.
Subject(s)
Animals , Female , Male , Mice , Adipose Tissue/drug effects , Body Composition/drug effects , Body Weight/drug effects , Diet , Dietary Fats/pharmacology , Gene Expression Regulation/drug effects , Lipids/blood , Liver/drug effects , Mice, Inbred C57BL , Obesity/metabolism , Organ Size/drug effects , Fenofibrate/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Sex Characteristics , Time Factors , Transcription Factors/agonistsABSTRACT
Backgroand: In our previous study, it was demonstrated that estradiol-dependent prostaglandin synthesis may be mediated by cAMP elevation during the process of iplantation in rats. The present study was undertaken to investigate if estradio1, a hydrophobic molecule could interact with uterine plasma membrane, thereby influencing adenylate cyclase and cAMP. Methods: The specific binding of [3H]estradiol to plasma membrane prepared from rat uterus has been identified and characterized. Results: The association of [3H]estradiol to plasma membrane preparations reached equilibrium at 24 hrs. [3H]estradiol binding was directly proportional to the concentration of plasma membrane preparations and its binding was temperature-sensitive. This binding was saturable, reversible and binding site was one type with high affinity(Kd=0.16+0.03 nM) and high binding capacity(Bmax= 2.03 + 0.38pmol/mg protein). The dissociation constant was estimated as 1.6*10(-10)M. In a competition assay, binding was specific for estrogenic compounds. When 100% specific binding was detennined in the presence of 3*10(-6) M diethylstilbestrol, 17B-estradiol and tamoxifen displaced specific binding by 115% and 23%, respectively. Neither progesterone nor cortisol at 500-fold excess displaced the specific binding. Conclusion: These data suggest the presence of specific binding sites on the plasma membrane for estradiol in the rat uterus.