Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice

Zhi, Zhang; Park, Jae Whan; Ahn, In Sook; Diamante, Graciel; Sivakumar, Nilla; Arneson, Douglas; Yang, Xia; Veen, J. Edward Van; Correa, Stephanie M.

doi:10.7554/elife.63333

Cited by 21 publications

(17 citation statements)

References 101 publications

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“…This same dosing scheme was used for the experimental phenotyping studies. Due to the known effects of tamoxifen on bone metabolism, (18,19) we treated both experimental mice (Dmp1 CreERT2 Â Erα fl/fl ) and control animals (Dmp1 CreERT2 only) with tamoxifen.…”

Section: Tamoxifen Treatmentsmentioning

confidence: 99%

Skeletal Effects of Inducible ERα Deletion in Osteocytes in Adult Mice

Doolittle

Saul

Kaur

et al. 2020

Journal of Bone and Mineral Research

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Estrogen is known to regulate bone metabolism in both women and men, but substantial gaps remain in our knowledge of estrogen and estrogen receptor alpha (ERα) regulation of adult bone metabolism. Studies using global ERα‐knockout mice were confounded by high circulating sex‐steroid levels, and osteocyte/osteoblast‐specific ERα deletion may be confounded by ERα effects on growth versus the adult skeleton. Thus, we developed mice expressing the tamoxifen‐inducible CreERT2 in osteocytes using the 8‐kilobase (kb) Dmp1 promoter (Dmp1CreERT2). These mice were crossed with ERαfl//fl mice to create ERαΔOcy mice, permitting inducible osteocyte‐specific ERα deletion in adulthood. After intermittent tamoxifen treatment of adult 4‐month‐old mice for 1 month, female, but not male, ERαΔOcy mice exhibited reduced spine bone volume fraction (BV/TV (−20.1%, p = 0.004) accompanied by decreased trabecular bone formation rate (−18.9%, p = 0.0496) and serum P1NP levels (−38.9%, p = 0.014). Periosteal (+65.6%, p = 0.004) and endocortical (+64.1%, p = 0.003) expansion were higher in ERαΔOcy mice compared to control (Dmp1CreERT2) mice at the tibial diaphysis, reflecting the known effects of estrogen to inhibit periosteal apposition and promote endocortical formation. Increases in Sost (2.1‐fold, p = 0.001) messenger RNA (mRNA) levels were observed in trabecular bone at the spine in ERαΔOcy mice, consistent with previous reports that estrogen deficiency is associated with increased circulating sclerostin as well as bone SOST mRNA levels in humans. Further, the biological consequences of increased Sost expression were reflected in significant overall downregulation in panels of osteoblast and Wnt target genes in osteocyte‐enriched bones from ERαΔOcy mice. These findings thus establish that osteocytic ERα is critical for estrogen action in female, but not male, adult bone metabolism. Moreover, the reduction in bone formation accompanied by increased Sost, decreased osteoblast, and decreased Wnt target gene expression in ERαΔOcy mice provides a direct link in vivo between ERα and Wnt signaling. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Section: Tamoxifen Treatmentsmentioning

confidence: 99%

Skeletal Effects of Inducible ERα Deletion in Osteocytes in Adult Mice

Doolittle

Saul

Kaur

et al. 2020

Journal of Bone and Mineral Research

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“…One candidate tissue is the hypothalamus. In mice, hypothalamic ERα-dependent gene expression changes have been linked to common TAM side effects, including decreased movement ( Zhang et al, 2021 ), which could contribute to weight gain.…”

Section: Discussionmentioning

confidence: 99%

Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice

Smith

Saulsbery

Sarchet

et al. 2022

eNeuro

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“…In line with this, hypothalamic ablation of ERα blunts tamoxifen-induced inhibition of BAT thermogenesis and locomotion. These findings suggest that tamoxifen acts through ERα expressed by the MPOA neurons to impair energy expenditure and suppress metabolism-related genes ( 137 ).…”

Section: Estrogen In the Brainmentioning

confidence: 99%

Hypothalamic Estrogen Signaling and Adipose Tissue Metabolism in Energy Homeostasis

Irizarry

Jiang

et al. 2022

Front. Endocrinol.

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Obesity has become a global epidemic, and it is a major risk factor for other metabolic disorders such as type 2 diabetes and cardiometabolic disease. Accumulating evidence indicates that there is sex-specific metabolic protection and disease susceptibility. For instance, in both clinical and experimental studies, males are more likely to develop obesity, insulin resistance, and diabetes. In line with this, males tend to have more visceral white adipose tissue (WAT) and less brown adipose tissue (BAT) thermogenic activity, both leading to an increased incidence of metabolic disorders. This female-specific fat distribution is partially mediated by sex hormone estrogens. Specifically, hypothalamic estrogen signaling plays a vital role in regulating WAT distribution, WAT beiging, and BAT thermogenesis. These regulatory effects on adipose tissue metabolism are primarily mediated by the activation of estrogen receptor alpha (ERα) in neurons, which interacts with hormones and adipokines such as leptin, ghrelin, and insulin. This review discusses the contribution of adipose tissue dysfunction to obesity and the role of hypothalamic estrogen signaling in preventing metabolic diseases with a particular focus on the VMH, the central regulator of energy expenditure and glucose homeostasis.

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Estrogen receptor alpha in the brain mediates tamoxifen-induced changes in physiology in mice

Cited by 21 publications

References 101 publications

Skeletal Effects of Inducible ERα Deletion in Osteocytes in Adult Mice

Skeletal Effects of Inducible ERα Deletion in Osteocytes in Adult Mice

Oral and injected tamoxifen alter adult hippocampal neurogenesis in female and male mice

Hypothalamic Estrogen Signaling and Adipose Tissue Metabolism in Energy Homeostasis

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