Inhibition of the actions of peroxisome proliferator-activated receptor a on obesity by estrogen

Objective: To determine whether the major ovarian factor estrogen modulates peroxisome proliferator-activated receptor (PPAR) a actions on obesity and to investigate the mechanism by which estrogen regulates PPAR alpha actions. Research Methods and Procedures: Female ovariectomized mice were randomly divided into four groups (n = 8/group). After they were treated with combinations of high fat, fenofibrate (FF), or 17 beta-estradiol (E) for 13 weeks, variables and determinants of obesity and lipid metabolism were measured using in vivo and in vitro approaches. Results: When female ovariectomized mice were given a high-fat diet with either FF or E, body weight gain and white adipose tissue mass were significantly reduced and serum lipid profiles were improved compared with control mice fed a high-fat diet alone. When mice were concomitantly treated with FF and E, however, E reversed the effects of FF on body weight gain, serum lipid profiles, and hepatic PPAR alpha target gene expression. Consistent with the in vivo data, E not only decreased basal levels of PPAR alpha reporter gene activation but also significantly decreased Wy 14,643-induced luciferase reporter activity. In addition, inhibition of PPARa functions by E did not seem to occur by interfering with the DNA binding of PPAR alpha. Discussion: Our results demonstrate that in vivo and in vitro treatment of estrogen inhibited the actions of FF-activated PPAR alpha on obesity and lipid metabolism through changes in the expression of PPAR alpha target genes, providing evidence that FF does not regulate obesity in female mice with functioning ovaries.