PPARα in Obesity: Sex Difference and Estrogen Involvement

Abstract

Peroxisome proliferator-activated receptor α (PPARα) 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, PPARα regulates the transcription of a number of genes critical for lipid and lipoprotein metabolism. PPARα 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 PPARα 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 PPARα. In female ovariectomized mice, 17β-estradiol inhibits the actions of fenofibrate on obesity through its suppressive effects on the expression of PPARα target genes, and these processes may be mediated by inhibiting the coactivator recruitment of PPARα. Thus, it is likely that PPARα functions on obesity may be enhanced in estrogen-deficient states.

Figure 1

Schematic structure of the functional domains of nuclear receptors. The activation domains AF-1 and AF-2 are located at the N-terminal and C-terminal regions, respectively. C domain is a highly conserved DNA-binding domain. D domain is a highly flexible hinge region. E/E domain is responsible for ligand-binding and converting nuclear receptors to active forms that bind DNA. Adapted from [29].

Figure 2

Activation and repression of nuclear receptor activity. (a) In the absence of ligand, nuclear receptors (NRs) are associated with corepressor complexes that bind Sin3 and histone deacetylase (HDAC), thereby turning off gene transcription. Some steroid receptors can recruit this complex when they are occupied by antagonists although they do not seem to be associated with corepressors in the unliganded state. (b) In the presence of ligand, NRs generally recruit coactivator complexes, PCAF histone acetyltransferase protein, general transcription factors, and RNA polymerase II to induce gene transcription. GTF: general transcription factor; RNA pol II: RNA polymerase II; PCAF: P300/CBP-associated factor.

Figure 3

The signaling pathways of P P A R α and estrogen receptors. (a) After activation by its respective ligands, PPARα heterodimerizes with retinoid X receptor and binds to direct repeat PPRE in the promoters of target genes to drive expression of target genes. (b) Estrogen-bound estrogen receptors recognize palindromic ERE to directly bind this DNA and ultimately increase gene expression. RXR: retinoid X receptor; PPRE: PPAR response element; ERE: estrogen response element; ERs: estrogen receptors.

Figure 4

Effects of fenofibrate on high fat diet-induced body weight gain (a) and WAT mass (b) in both sexes of C57BL/6 mice. Male and female C57BL/6 mice were received a low fat, high fat, or high fat diet supplemented with fenofibrate (0.05% w/w) for 13 weeks. Body weight at the end of the experiment are statistically different (P < .01) between high fat diet and high fat plus fenofibrate groups. #: Significantly different versus a low fat diet group, P < .05. ∗: Significantly different versus a high fat diet group, P < .01. Adapted from [20].

Figure 5

Differential regulation of body weight gain (a) and PPAR α target gene expression (b) by fenofibrate depending on the presence of ovaries. Female sham-operated (Sham) and ovariectomized (OVX) mice received a low fat, high fat, or fenofibrate-supplemented (FF; 0.05% w/w) high fat diet for 13 weeks. Body weights at the end of the treatment period are significantly different not only when comparing the low fat group to either the high fat (P < .05) or high fat plus FF (P < .01) groups in female Sham mice, but also when comparing the high fat group to either the low fat (P < .01) or high fat plus FF (P < .005) groups in female OVX mice. ∗: Significantly different versus the high fat group, P < .05. #: Significantly different versus the Sham group, P < .05. ACOX: acyl-CoA oxidase; HD: enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase; thiolase: 3-ketoacyl-CoA thiolase; apo C-III: apolipoprotein C-III. Adapted from [23].

Figure 6

Inhibition of PPARα reporter gene expression ((a) and (b)) and coactivator recruitment (c) by 17 β -estradiol. (a) NMu2Li cells were transiently transfected with expression plasmids for PPARα and PPRE₃-TK-Luc reporter. * Significantly different versus control group, P < .0001. #: Significantly different versus PPARα group P < .0001. @ Significantly different versus PPARα/Wy group, P < .001. (b) NMu2Li cells were transiently transfected with expression plasmids for PPRE₃-TK-Luc reporter and ERα or ERβ.∗: Significantly different versus control group, P < .05.#: Significantly different versus respective ER group, P < .01. (c) CV-1 cells were transiently transfected with expression plasmids for VP16-mPPARα, GAL-CBP, reporter plasmid pFR-Luc, and VP16-hERα or VP16-hERβ. #: Significantly different versus PPARα group, P < .01.∗: Significantly different versus PPARα/Wy group, P < .005. Adapted from [32].

Figure 7

Mechanism of inhibitory effect of 17β-estradiol on PPAR α -mediated regulation of obesity. (a) Competition between PPARα and estrogen receptors (ERs) for coactivator binding. 17β-estradiol-activated ERs can interfere with the PPRE binding of PPARα. (b) Inhibition of PPARα actions on obesity by E. E impairs the ability of PPARα ligands to reduce body weight gain and adiposity in female ovariectomized (OVX) mice. FF: fenofibrate; RA: 9 cis-retinoic acid; RXR: retinoid X receptor. Adapted from [33].