PPAR alpha in Obesity: Sex Difference and Estrogen Involvement

Peroxisome proliferator-activated receptor alpha ( PPAR alpha) is a member of the steroid hormone receptor superfamily and is well known to act as the molecular target for lipid-lowering drugs of the fibrate family. At the molecular level, PPAR alpha regulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPAR alpha activators are further shown to reduce body weight gain and adiposity, at least in part, due to the increase of hepatic fatty acid oxidation and the decrease in levels of circulating triglycerides responsible for adipose cell hypertrophy and hyperplasia. However, these effects of the PPAR alpha ligand fenofibrate on obesity are regulated with sexual dimorphism and seem to be influenced by the presence of functioning ovaries, suggesting the involvement of ovarian steroids in the control of obesity by PPAR alpha. In female ovariectomized mice, 17 beta-estradiol inhibits the actions of fenofibrate on obesity through its suppressive effects on the expression of PPAR alpha target genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPAR alpha. Thus, it is likely that PPAR alpha functions on obesity may be enhanced in estrogen-deficient states.