Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Sasayama, Daimei; Sugiyama, Nobuhiro; Yonekubo, Shigeru; Pawlak, Akiko; Murasawa, Hiroyasu; Nakamura, Mie; Hayashi, Morimoto; Ogawa, Takashi; Moro, Makoto; Washizuka, Shinsuke; Amano, Naoji; Hongo, Kazuhiro; Ohnota, Hideki

doi:10.1038/s41598-017-04946-5

Cited by 23 publications

(19 citation statements)

References 40 publications

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“…In the ovariectomized animals fed with the control diet, we found no significant effects on the depressive-like behaviors measured in the FST. While these results agree with previous reports in rodents utilizing the same behavioral paradigm 12,19–21 , other studies have found ovariectomy to induce depressive-like behaviors 11,17,18 . These contradictory fiings may be attributed to methodological discrepancies among these studies.…”

Section: Discussionsupporting

confidence: 93%

High-fat diet intake induces depressive-like behavior in ovariectomized rats

Boldarine

Pedroso

Neto

et al. 2019

Sci Rep

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This study tested the effects of ovariectomy, allied or not to high-fat feeding and estradiol replacement, on hormonal, metabolic and behavioral parameters, to explore the connection of obesity and depression after menopause. Wistar rats were either ovariectomized or sham-operated and fed with either standard chow or lard-enriched diet for twelve weeks. Sub-groups of ovariectomized rats received estradiol replacement. Depressive-like behaviors were assessed by the forced swim test and locomotor activity was assessed by the elevated plus maze test. Ovariectomy alone increased body weight gain and feed efficiency and induced hyperleptinemia and glucose intolerance while it increased caloric intake and body adiposity only marginally. High-fat intake alone induced obesity and, in combination with ovariectomy, accentuated the ovariectomy-induced alterations. Estradiol replacement attenuated the hormonal alterations only in chow-fed rats. Ovariectomy combined with high-fat intake induced depressive-like behaviors, which were marginally attenuated by estradiol. Depressive-like behaviors were associated with metabolic and body composition parameters and with estrogen status. The data indicate that the vulnerability to develop depression after menopause is influenced by high-fat intake. It is suggested that weight management is a crucial issue in postmenopausal women, probably having a beneficial role in preventing the appearance of mental health problems.

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Section: Discussionsupporting

confidence: 93%

High-fat diet intake induces depressive-like behavior in ovariectomized rats

Boldarine

Pedroso

Neto

et al. 2019

Sci Rep

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“…The inhibitory effect of estradiol on food intake has been previously established ( Blaustein and Wade, 1976 ; Eckel, 2004 ). This anorexic effect of estrogen is further supported by the prevention of weight loss in ovariectomized animals ( Sasayama et al, 2017 ). A significantly reduced BW gain observed in the E 2 L1000 treatment group relative to TV group in our study could be partly due to this anorexic effect of E 2 .…”

Section: Discussionmentioning

confidence: 95%

Chemoprevention of LA7-Induced Mammary Tumor Growth by SM6Met, a Well-Characterized Cyclopia Extract

et al. 2018

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Breast cancer (BC) is the leading cause of cancer-related deaths in women. Chemoprevention of BC by using plant extracts is gaining attention. SM6Met, a well-characterized extract of Cyclopia subternata with reported selective estrogen receptor subtype activity, has shown tumor suppressive effects in a chemically induced BC model in rats, which is known to be estrogen responsive. However, there is no information on the estrogen sensitivity of the relatively new orthotopic model of LA7 cell-induced mammary tumors. In the present study, the potential chemopreventative and side-effect profile of SM6Met on LA7 cell-induced tumor growth was evaluated, as was the effects of 17β-estradiol and standard-of-care (SOC) endocrine therapies, such as tamoxifen (TAM), letrozole (LET), and fulvestrant (FUL). Tumor growth was observed in the tumor-vehicle control group until day 10 post tumor induction, which declined afterward on days 12–14. SM6Met suppressed tumor growth to the same extent as TAM, while LET, but not FUL, also showed substantial anti-tumor effects. Short-term 17β-estradiol treatment reduced tumor volume on days prior to day 10, whereas tumor promoting effects were observed during long-term treatment, which was especially evident at later time points. Marked elevation in serum markers of liver injury, which was further supported by histological evaluation, was observed in the vehicle-treated tumor control, TAM, LET, and long-term 17β-estradiol treatment groups. Alterations in the lipid profiles were also observed in the 17β-estradiol treatment groups. In contrast, SM6Met did not augment the increase in serum levels of liver injury biomarkers caused by tumor induction and no effect was observed on lipid profiles. In summary, the results from the current study demonstrate the chemopreventative effect of SM6Met on mammary tumor growth, which was comparable to that of TAM, without eliciting the negative side-effects observed with this SOC endocrine therapy. Furthermore, the results of this study also showed some responsiveness of LA7-induced tumors to estrogen and SOC endocrine therapies. Thus, this model may be useful in evaluating potential endocrine therapies for hormone responsive BC.

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“…Moreover, recent reports have demonstrated that female mice lacking ERβ leads to dysregulation of brain-derived neurotrophic factor and serotonin signaling and decrease synaptic plasticity in the HPC, which could predispose the brain to a state of depression ( Chhibber et al, 2017 ). Likewise, ERβ-selective ligand reduces depressive-like behavior in ovariectomized mice ( Sasayama et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Effects of Estrogen Therapy on the Serotonergic System in an Animal Model of Perimenopause Induced by 4-Vinylcyclohexen Diepoxide (VCD)

Pestana-Oliveira

Kalil

Leite

et al. 2018

eNeuro

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Chronic exposure to 4-vinylcycloxene diepoxide (VCD) in rodents accelerates the natural process of ovarian follicular atresia modelling perimenopause in women. We investigated why estrogen therapy is beneficial for symptomatic women despite normal or high estrogen levels during perimenopause. Female rats (28 d) were injected daily with VCD or oil for 15 d; 55-65 d after the first injection, pellets of 17β-estradiol or oil were inserted subcutaneously. Around 20 d after, the rats were euthanized (control rats on diestrus and estradiol-treated 21 d after pellets implants). Blood was collected for hormone measurement, the brains were removed and dorsal raphe nucleus (DRN), hippocampus (HPC), and amygdala (AMY) punched out for serotonin (5-HT), estrogen receptor β (ERβ), and progesterone receptor (PR) mRNA level measurements. Another set of rats was perfused for tryptophan hydroxylase (TPH) immunohistochemistry in the DRN. Periestropausal rats exhibited estradiol levels similar to controls and a lower progesterone level, which was restored by estradiol. The DRN of periestropausal rats exhibited lower expression of PR and ERβ mRNA and a lower number of TPH cells. Estradiol restored the ERβ mRNA levels and number of serotonergic cells in the DRN caudal subregion. The 5-HT levels were lower in the AMY and HPC in peristropausal rats, and estradiol treatment increased the 5-HT levels in the HPC and also increased ERβ expression in this area. In conclusion, estradiol may improve perimenopause symptoms by increasing progesterone and boosting serotonin pathway from the caudal DRN to the dorsal HPC potentially through an increment in ERβ expression in the DRN.

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Novel oestrogen receptor β-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice

Cited by 23 publications

References 40 publications

High-fat diet intake induces depressive-like behavior in ovariectomized rats

High-fat diet intake induces depressive-like behavior in ovariectomized rats

Chemoprevention of LA7-Induced Mammary Tumor Growth by SM6Met, a Well-Characterized Cyclopia Extract

Effects of Estrogen Therapy on the Serotonergic System in an Animal Model of Perimenopause Induced by 4-Vinylcyclohexen Diepoxide (VCD)

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