Inhibition of the Actions of Peroxisome Proliferator‐activated Receptor α on Obesity by Estrogen

Abstract

JEONG, SUNHYO AND MICHUNG YOON. Inhibition of the actions of peroxisome proliferator-activated receptor ␣ on obesity by estrogen. Obesity. 2007;15:1430 -1440. Objective: To determine whether the major ovarian factor estrogen modulates peroxisome proliferator-activated receptor (PPAR) ␣ actions on obesity and to investigate the mechanism by which estrogen regulates PPAR␣ actions. Research Methods and Procedures: Female ovariectomized mice were randomly divided into four groups (n ϭ 8/group). After they were treated with combinations of high fat, fenofibrate (FF), or 17␤-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␣ target gene expression. Consistent with the in vivo data, E not only decreased basal levels of PPAR␣ reporter gene activation but also significantly decreased Wy14,643-induced luciferase reporter activity. In addition, inhibition of PPAR␣ functions by E did not seem to occur by interfering with the DNA binding of PPAR␣. Discussion: Our results demonstrate that in vivo and in vitro treatment of estrogen inhibited the actions of FFactivated PPAR␣ on obesity and lipid metabolism through changes in the expression of PPAR␣ target genes, providing evidence that FF does not regulate obesity in female mice with functioning ovaries.

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…However, in the context of obesity, estrogen appears to inhibit the actions of PPAR-␣ by an unknown mechanism. 103 Considering that PPAR-␣ plays a central role in determining circulating FFA and lipid characteristics, these studies provide a direct link between cellular lipid balance, cardiac disease, and sex. In addition, estrogen is strongly implicated as a central mediator of this sex difference.…”

Fenofibrate inhibits adipocyte hypertrophy and insulin resistance by activating adipose PPARα in high fat diet-induced obese mice

“…Mice were divided randomly into three groups (n = 5/group), one of which received a low fat diet (4.5% fat, w/w, CJ, Korea). Another group received a high fat diet containing 35% fat (w/w, Research Diets, New Brunswick, NJ), and the final group was fed the same high fat diet supplemented with fenofibrate (0.05%, w/w) for seven weeks (Jeong et al, 2004b;Jeong and Yoon, 2007). The composition of high fat diet is shown in Supplemental Data Table S1.…”

17β-Estradiol inhibition of PPARγ-induced adipogenesis and adipocyte-specific gene expression

“…In particular, 17β-estradiol (E) has been recognized as a major factor in regulating adipose tissue metabolism in females. Ovariectomy in rodents leads to weight gain, primarily in the form of adipose tissue, which is reversed by physiologic E replacement [15,16] . Loss of circulating E is associated with an increase in adiposity during menopause, whereas postmenopausal women who receive E replacement therapy do not display the characteristic abdominal weight gain pattern usually associated with menopause [17] .…”