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.

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Our previous study demonstrated that chronic estrogen replacement in ovariectomized rats reduces food intake and augments c-Fos expression in the suprachiasmatic nucleus (SCN), specifically during the light phase. Here, we hypothesized that serotonergic neurons in the central nervous system (CNS), which have anorectic action and play a role in regulating circadian rhythm, mediate the light phase-specific anorectic action of estrogen, and that selective serotonin reuptake inhibitors (SSRIs) mimic the hypophagic action of estrogen. Female Wistar rats were ovariectomized and treated with estradiol (E2) or cholesterol by subcutaneously implanting a silicon capsule containing E2 or cholesterol. Then, half of the cholesterol-treated rats were injected with the SSRI fluoxetine (5 mg/kg) (FLX group), while the remaining rats in the cholesterol-treated group (CON group) and all those in the E2 group were injected with saline subcutaneously twice daily at the onsets of the light and dark phases. Both E2 and FLX reduced food intake during the light phase but not the dark phase, and reduced body weight gain. In addition, both E2 and FLX augmented the c-Fos expression in the SCN, specifically during the light phase. These data indicate that FLX exerts estrogen-like antiobesity and hypophagic actions by modifying circadian feeding patterns, and suggest that estrogen regulates circadian feeding rhythm via serotonergic neurons in the CNS.

We examined the effect of orchiectomy on food intake and lateral hypothalamic neuron fs activity during glucoprivation induced by i.v. 2‐deoxy‐D‐glucose (2DG) administration in male rats. Rats (7W) were bilaterally orchiectomized (OrX) or sham‐operated (Sham). 2DG (400 mg/kg) was infused two weeks after the operation and food intake was measured for 3 hours after the injection. The same experiment was performed for immunohistochemical examination of c‐Fos and orexin A expression in the perifornical area (PFA) and arcuate nucleus (Arc). Glucoprivation induced food intake, and food intake in OrX rats was larger than Sham rats, and food intake was inversely correlated with plasma testosterone concentration. Glucoprivation stimulated c‐Fos expression in the orexin A neurons at the PFA, and c‐Fos expression in the Arc. The number and fraction of c‐Fos expressed orexin A neurons was significantly higher in OrX rats than Sham rats. The number of c‐Fos ir cells in the Arc was also higher in OrX rats than Sham rats. These data indicate that testosterone attenuates food intake induced by reduced glucose availability via attenuated perifornical orexin A neuron's activity and Arc neuron's activity.

Estrogen replacement in ovariectomized (OVX) rats reduces food intake specifically during the light phase. To test the hypothesis that enhanced response to photic stimulation during the light phase is involved in the mechanism for the anorexigenic and anti‐obesity effects of estrogen, we examined the effects of exposure to a constant dark environment (DD) and estrogen replacement on food intake and body weight change in OVX rats. Female Wistar rats were ovariectomized and implanted with either an estradiol (E2) or a cholesterol (Veh) capsule. Rats were then exposed to DD for 2 weeks. Other rats exposed to the12 h/12 h‐light/dark cycle condition (LD) served as control. Exposure to DD increased food intake during the subjective day but did not during the subjective night, and increased daily food intake in the E2 group. These changes occurred without phase shifting. DD exposure did not alter food intake either during the subjective day or night in the Veh group. Physical activity was increased by DD exposure during the subjective day in the both groups, and significantly decreased during the subjective night in the Veh group. Body weight gain under DD in the both groups was larger compared with that under LD. These data indicate that the anorexigenic effect of estrogen is dependent on the light environment, while photic stimulation attenuates body weight gain regardless of E2 replacement or physical activity.