S-equol Exerts Estradiol-Like Anorectic Action with Minimal Stimulation of Estrogen Receptor-α in Ovariectomized Rats

Abstract

Chronic estrogen replacement in ovariectomized rats attenuates food intake and enhances c-Fos expression in the suprachiasmatic nucleus (SCN), specifically during the light phase. S-equol, a metabolite of daidzein, has a strong affinity for estrogen receptor (ER)-β and exerts estrogenic activity. The purpose of the present study was to elucidate whether S-equol exerts an estrogen-like anorectic effect by modifying the regulation of the circadian feeding rhythm in ovariectomized rats. Ovariectomized female Wistar rats were divided into an estradiol (E2)-replaced group and cholesterol (vehicle; Veh)-treated group. These animals were fed either a standard diet or an S-equol-containing diet for 13 days. Then, the brain, uterus, and pituitary gland were collected along with blood samples. In the rats fed the standard diet, E2 replacement attenuated food intake (P < 0.001) and enhanced c-Fos expression in the SCN (P < 0.01) during the light phase. Dietary S-equol supplementation reduced food intake (P < 0.01) and increased c-Fos expression in the SCN (P < 0.01) in the Veh-treated rats but not in the E2-replaced rats during the light phase. Dietary S-equol did not alter ER-α expression in the medial preoptic area or the arcuate nucleus, nor did dietary S-equol affect pituitary gland weight or endometrial epithelial layer thickness. By contrast, E2 replacement not only markedly decreased ER-α expression in these brain areas (P < 0.001) but also increased both the pituitary gland weight (P < 0.001) and the endometrial epithelial layer thickness (P < 0.001). Thus, dietary S-equol acts as an anorectic by modifying the diurnal feeding pattern in a manner similar to E2 in ovariectomized rats; however, the mechanism of action is not likely to be mediated by ER-α. The data suggest a possibility that dietary S-equol could be an alternative to hormone replacement therapy for the prevention of hyperphagia and obesity with a lower risk of adverse effects induced by ER-α stimulation.

Fluoxetine Mimics the Anorectic Action of Estrogen and Its Regulation of Circadian Feeding in Ovariectomized Female Rats

“…These results indicate the potential that both E2 and FLX modify the circadian feeding rhythm by altering the activity of the SCN, specifically during the light phase. Similar to our findings in previous studies, we found in the present study that E2 enhanced c-Fos expression in the SCN during the light phase [23,24]. Additionally, the present study revealed that FLX enhanced c-Fos expression in the SCN during the light phase in a similar fashion as E2.…”

“…We confirmed the hypophagic effect of E2 in the present study. However, the effect was relatively small in the present study compared to the effect in our previous studies [23,24]. It is unclear why the hypophagic effect of E2 was smaller in the present study.…”

“…Thus, the regulation of circadian feeding rhythm plays a critical role in energy homeostasis, and its function can be related to neuronal activities in the SCN. Our previous studies have shown that estrogen replacement in ovariectomized rats reduces food intake and augments c-Fos expression in the SCN during the light phase but not the dark phase [23,24]. These findings suggest that circadian regulation of feeding behavior plays a critical role in estrogen-induced hypophagia by altering neuronal activity in the SCN.…”

“…Immunohistochemical staining for c-Fos in the SCN and IGL was performed on free-floating sections, as previously reported [23,29]. Briefly, after incubation with rabbit anti-c-Fos antiserum (1:4000; Sc-52, Santa Cruz Biotechnology, Dallas, TX, USA), the sections were incubated with biotinylated goat anti-rabbit IgG (1:400, BA-1000, Vector Laboratories, Burlingame, CA, USA), followed by processing with an avidin-biotinylated horse radish peroxidase complex (1:400; Vectastain ABC kit, Vector Laboratories, Burlingame, CA, USA).…”

Soy-Induced Fecal Metabolome Changes in Ovariectomized and Intact Female Rats: Relationship with Cardiometabolic Health

“…One possible mechanism by which the gut microbiome might affect host function is through production of unique bacterial metabolites 23 – 28 . One category of bacterial metabolites that are increased in animals and humans consuming a soy-rich diet and that might have important health benefits are the equols, in particular S-equol 29 – 31 . Metabolism of phytoestrogens by gut microbes may produce metabolites with more potent biological activity within the host than their parental compounds 32 .…”