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The role of hypothalamic estrogen receptors in metabolic regulation
Open accessAbstract
Estrogens regulate key features of metabolism, including food intake, body weight, energy expenditure, insulin sensitivity, leptin sensitivity, and body fat distribution. There are two 'classical' estrogen receptors (ERs): estrogen receptor alpha (ERS1) and estrogen receptor beta (ERS2). Human and murine data indicate ERS1 contributes to metabolic regulation more so than ESR2. For example, there are human inactivating mutations of ERS1 which recapitulate aspects of the metabolic syndrome in both men and women. Much of our understanding of the metabolic roles of ERS1 was initially uncovered in estrogen receptor α-null mice (ERS1(-/-)); these mice display aspects of the metabolic syndrome, including increased body weight, increased visceral fat deposition and dysregulated glucose intolerance. Recent data further implicate ERS1 in specific tissues and neuronal populations as being critical for regulating food intake, energy expenditure, body fat distribution and adipose tissue function. This review will focus predominantly on the role of hypothalamic ERs and their critical role in regulating all aspects of energy homeostasis and metabolism.
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“Robust evidence exists that demonstrates the important roles estrogen and progesterone have in regulating substrate metabolism [20,24,66,70,80,82,84,154–159].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [66]
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“Estrogen actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution [22,66,67].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [66]
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“Estrogen actions in pancreatic islet β-cells also regulate insulin secretion, nutrient homeostasis, and survival [66,69,70].”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [66]
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“Estrogen, specifically 17β-estradiol, promotes lipolysis and increases fatty acid availability while decreasing the rate of gluconeogenesis with muscle and liver glycogen sparing.”
From International society of sports nutrition position stand: nutritional concerns of the female athlete (2023) · cites this paper as [66]
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Trivedi, C. J., Shan, X., Tung, Y. L., Kabra, D. G., Holland, J., Amburgy, S. E., Heppner, K. M., Kirchner, H., Yeo, G. S. H., & Pérez–Tilve, D. (2015) · Endocrinology · doi:10.1210/en.2014-1781 · Cited by 17
Ansarin, A., Mahdavi, A. M., Javadivala, Z., Shanehbandi, D., Zarredar, H., & Ansarin, K. (2023) · Molecular Biology Reports · doi:10.1007/s11033-023-08887-3 · Cited by 17
“First, activation of the GH signaling pathway by STAT5 phosphorylation [22, 64, 73, 74] and second, activation of sex hormone pathways by decreasing AR [22, 75, 76] and enhancing ESR1 [22, 77, 78] and estradiol levels [22, 45, 79] that lead to feminized liver gene expression [22].”
BackgroundLöfberg, I. E., Karppinen, J. E., Laatikainen‐Raussi, V., Lehti, M., Hackney, A. C., Ihalainen, J. K., & Taipale, R. S. (2024) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000003518 · Cited by 17
“The hypothesized physiological reason for these variations is that E2 may inhibit appetite in the late follicular phase (47) via a complex process involving hypothalamic E2 neurons and their regulatory role in energy homeostasis (48).”
E2 Regulates Epigenetic Signature on Neuroglobin Enhancer-Promoter in Neuronal Cells
Guglielmotto, M., Reineri, S., Iannello, A., Ferrero, G., Vanzan, L., Miano, V., Ricci, L., Tamagno, E., Bortoli, M. D., & Cutrupi, S. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00147 · Cited by 18
“Epigenetic changes under E2 control have an impact on memory consolidation and energy expenditure in hypothalamus (Zhao et al., 2010; Frick et al., 2011; Frank et al., 2014; Frontiers in Cellular Neuroscience | www.frontiersin.org 1 June 2016 | Volume 10 | Article 147 López and Tena-Sempere, 2015).”
BackgroundVelasco, C., Conde‐Sieira, M., Comesaña, S., Chivite, M., Míguez, J. M., & Soengas, J. L. (2021) · Journal of Experimental Biology · doi:10.1242/jeb.242360 · Cited by 18
Rui, W., Zou, Y., Lee, J., Nambiar, S. M., Lin, J., Zhang, L., Yang, Y., & Dai, G. (2016) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.115.231316 · Cited by 16
“The pivotal roles of estrogen signaling in the metabolic network were thoroughly reviewed by several groups recently (Roepke, 2009; Barros and Gustafsson, 2011; Mauvais-Jarvis et al., 2013; Frank et al., 2014; Kim et al., 2014; Palmer and Clegg, 2015).”
BackgroundJaimes-Hoy, L., Pérez-Maldonado, A., Bahena, E. N., Guarneros, N. D. L. C., Rodríguez-Rodríguez, A., Charli, J., Soberón, X., & Joseph‐Bravo, P. (2021) · Endocrinology · doi:10.1210/endocr/bqab110 · Cited by 16
Rapid Jetlag Resetting of Behavioral, Physiological, and Molecular Rhythms in Proestrous Female Mice
Pilorz, V., Kolms, B., & Oster, H. (2020) · Journal of Biological Rhythms · doi:10.1177/0748730420965291 · Cited by 15
“Hence, although it is generally accepted that timing of events is SCN dependent, it is also likely that peripheral oscillators expressing ERs may play a role in the timing and stabilization of clocks and metabolic rhythms in the brain and the periphery (Frank et al., 2014; Rando and Wahli, 2011; Yan and Silver, 2015).”
BackgroundMenstrual Cycle Tracking in Sports Research: Challenges, Progress, and Future Directions
Dole, A., Beaven, C. M., & Sims, S. T. (2023) · Physiologia · doi:10.3390/physiologia3040044 · Cited by 19
“E2 actions in hypothalamic nuclei differentially control food intake, energy expenditure, and white adipose tissue distribution [1–4].”
BackgroundFarinetti, A., Marraudino, M., Ponti, G., Panzica, G., & Gotti, S. (2018) · Cell and Tissue Research · doi:10.1007/s00441-018-2896-9 · Cited by 14
Sexually Dimorphic Effect of Genistein on Hypothalamic Neuronal Differentiation in Vitro
Marraudino, M., Farinetti, A., Arévalo, M., Gotti, S., Panzica, G., & García‐Segura, L. M. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20102465 · Cited by 14
“Phytoestrogens, in particular genistein, which is able to interact with the estrogen-dependent neural pathways in complex and multidirectional ways [4,5], may interfere with the endocrine system, leading to permanent alterations of estrogen sensitive circuits [6].”
BackgroundPannia, E., Hammoud, R., Simonian, R., Arning, E., Ashcraft, P., Wasek, B. L., Bottiglieri, T., Pausová, Z., Kubant, R., & Anderson, G. H. (2020) · Nutrients · doi:10.3390/nu13010048 · Cited by 13
“While mRNA levels of Crh2, Prlhr, Prhr, Kiss1, Esr1, and Gabre were significantly down-regulated in ARC of MTHF dams compared to FA dams at parturition, mRNA levels of Gabra4, Gabrd, Drd2, Grm2 and Cck were significantly up-regulated in MTHF dams (Figure 4A, p 0.05) corroborating RNAseq results.”
BackgroundInfluentialIrsik, D. L., Romero-Aleshire, M. J., Chavez, E. M., Fallet, R. W., Brooks, H. L., Carmines, P. K., & Lane, P. H. (2018) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00231.2017 · Cited by 14
“The impact of estrogen on body weight maintenance involves not only regulation of glucose homeostasis but also food consumption, energy expenditure, fat deposition, and hepatic gluconeogenesis and glycogenolysis (1, 10, 25).”
BackgroundOvariectomy Interferes with Proteomes of Brown Adipose Tissue in Rats
Chou, T.-J., Lu, C., Liao, C., Chiang, C., Huang, C., & Huang, K. (2022) · International Journal of Medical Sciences · doi:10.7150/ijms.66996 · Cited by 14
“Low levels of estrogen, occurring due to menopause, ovarian insufficiency, or ovariectomy (Ovx), are associated with decreased energy expenditure and increased food intake, likely leading to weight gain and obesity in the long term [6, 7].”
BackgroundCarrillo, B., Collado, P., Díaz, F., Chowen, J. A., Grassi, D., & Pinos, H. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.11.008 · Cited by 12
Interactions between estradiol, diabetes, and brain aging and the risk for cognitive impairment
Hugenschmidt, C. E., Duran, T., & Espeland, M. A. (2021) · Climacteric · doi:10.1080/13697137.2021.1877652 · Cited by 13
Andreoli, M. F., Stoker, C., Rossetti, M. F., Lazzarino, G. P., Luque, E. H., & Ramos, J. G. (2016) · Nutrition Research · doi:10.1016/j.nutres.2016.05.003 · Cited by 12
“Estrogens also regulate key aspects of metabolism, including food intake, body weight and insulin sensitivity [8].”
BackgroundIdentification of an ionic mechanism for ERα-mediated rapid excitation in neurons
Yu, M., Yin, N., Feng, B. C., Gao, P., Yu, K., Liu, H., Liu, H., Li, Y., Ginnard, O. Z. B., Conde, K., et al. (2024) · Science Advances · doi:10.1126/sciadv.adp0696 · Cited by 10
Gardini, E., Fiacco, S., Mernone, L., & Ehlert, U. (2020) · Nature and Science of Sleep · doi:10.2147/nss.s256102 · Cited by 10
The Role of Beta-Endorphin in Food Deprivation-Mediated Increases in Food Intake and Binge-Eating
Tolentino, L., Iqbal, A., Rahman, S., & Lutfy, K. (2023) · Brain Sciences · doi:10.3390/brainsci13020212 · Cited by 10
“Furthermore, knocking out the αER on POMC neurons leads to increased food consumption and body weight in female but not male mice [24].”
BackgroundCortes, L. R., Sturgeon, H., & Forger, N. G. (2023) · Hormones and Behavior · doi:10.1016/j.yhbeh.2023.105348 · Cited by 9
Xu, P., Li, S., Wu, Q., Yang, L.-X., Na, Z., Zhu, C., Liu, P., Li, N., & Zou, L. (2023) · Fitoterapia · doi:10.1016/j.fitote.2023.105497 · Cited by 9
Song, X., Xu, W., Li, Z., Zhang, X., Liu, C., Han, K., Chen, L., Shi, Y., Xu, C., Han, D., et al. (2024) · Neuroendocrinology · doi:10.1159/000539238 · Cited by 9
“Interestingly, the activation of 5-HT2CR was found to promote ER α synthesis in the hypothalamus, which may result in estrogen-induced obesity [64, 65].”
Dimorphic effect of 17β-oestradiol on pathology and oxidative stress in experimental malaria
Aguilar-Castro, J., Cervantes-Candelas, L. A., Buendía-González, F. O., Nolasco-Pérez, T. D. J., López-Padilla, M. S., Fernández-Rivera, O., Cervantes‐Sandoval, A., & Legorreta‐Herrera, M. (2019) · Immunobiology · doi:10.1016/j.imbio.2019.11.008 · Cited by 9
Coyoy-Salgado, A., Segura-Uribe, J. J., Gallardo, J. M., Estrada-Cruz, N. A., Camacho‐Arroyo, I., & Guerra‐Araiza, C. (2020) · Brain Research · doi:10.1016/j.brainres.2020.147096 · Cited by 10
Drewe, J., Boonen, G., & Culmsee, C. (2022) · Phytomedicine · doi:10.1016/j.phymed.2022.154060 · Cited by 10
Ghasemzadeh‐Hasankolaei, M., Elcombe, C. S., Powls, S., Lea, R. G., Sinclair, K. D., Padmanabhan, V., Evans, N. P., & Bellingham, M. (2023) · Journal of Neuroendocrinology · doi:10.1111/jne.13358 · Cited by 8
“For this study, punches from the mPOA, AHA, PVN, rostral ARC, and caudal ARC were studied.”
BackgroundInfluentialGenistein during Development Alters Differentially the Expression of POMC in Male and Female Rats
Fernández‐García, J. M., Carrillo, B., Tezanos, P., Collado, P., & Pinos, H. (2021) · Metabolites · doi:10.3390/metabo11050293 · Cited by 8
The role of ovarian hormone dynamics in metabolic phenotype and gene expression in female mice
Ouldibbat, L., Rocks, D., Sampson, B., & Kundaković, M. (2025) · Hormones and Behavior · doi:10.1016/j.yhbeh.2025.105693 · Cited by 7
Gregory, S., Bridgeman, K., Darwin, H., Barbato, M., Booi, L., Serrat, A. B., Chadha, A. S., Farina, F. R., Jenkins, N. D., Jutila, O. I., et al. (2025) · Alzheimer s & Dementia · doi:10.1002/alz.70873 · Cited by 8
Sudomotor and vasomotor activity during the menstrual cycle with global heating
PETROFSKY, J. S., Lee, H., & Khowailed, I. A. (2015) · Clinical Physiology and Functional Imaging · doi:10.1111/cpf.12309 · Cited by 7
“The effect may be seen in changes in overall sympathetic activity during the menstrual cycle as there are oestrogen receptors in the hypothalamus (Frank et al., 2014) and other areas of the autonomic nervous system.”
BackgroundGeneration and characterization of an estrogen receptor alpha‐iCre knock‐in mouse
Park, C. J., Chen, G., Koo, Y., Lin, P.-C. P., Cacioppo, J. A., Prohaska, H., & Ko, C. J. (2017) · genesis · doi:10.1002/dvg.23084 · Cited by 7
Ohlsson, C., Farman, H. H., Gustafsson, K. L., Wu, J., Henning, P., Windahl, S. H., Sjögren, K., Gustafsson, J.-Α., Movérare‐Skrtic, S., & Lagerquist, M. K. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00018.2020 · Cited by 7
The avian central roles of alpha and beta oestrogen receptors on food intake
Motaghi, S., Jonaidi, H., Talebifard, H., & Chavoshizadeh, M. (2021) · Journal of Animal Physiology and Animal Nutrition · doi:10.1111/jpn.13578 · Cited by 7
Systems Toxicology of Bisphenol A: Mechanistic Overlap in Metabolic and Reproductive Disruption
Bhardwaj, S., & Misra, S. (2026) · Journal of Applied Toxicology · doi:10.1002/jat.70127 · Cited by 6
“This complex network of glands (including the hypothalamus and peripheral organs such as the liver, pancreas, and adipose tissue) (Frank et al. 2014; Lopez and Tena-Sempere 2015; Mahboobifard et al. 2022) release specific hormones into the bloodstream.”
Iqbal, A., Hamid, A., Ahmad, S. M., & Lutfy, K. (2023) · Life · doi:10.3390/life13030619 · Cited by 6
“Furthermore, knocking out the αER on POMC neurons leads to an increase in food consumption and body weight in female but not male mice [21].”
BackgroundLin, J.-Y., Stone, B. T., Rahamim, O. M., Craddock, A. E., & Katz, D. B. (2026) · eNeuro · doi:10.1523/eneuro.0225-25.2026 · Cited by 5
“Previous research has demonstrated that another factor playing a key role in regulating food consumption across the estrous cycle is negative postingestive feedback (Eckel, 2004).”
InfluentialAssociation of sex hormones with metabolic syndrome among Egyptian males
Ahmed, I., Mahdy, M. M. M., Orabi, H. E., & Abdelazeem, E. M. (2017) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2017.07.042 · Cited by 5
Zurita‐Cruz, J. N., Villasís-Keever, M. Á., Damasio‐Santana, L., Manuel‐Apolinar, L., Nishimura‐Meguro, E., Rivera-Hernández, A. D. J., Garrido-Magaña, E. P., Gutierrez-Gonzalez, A., & Poblano-Alcalá, A. (2017) · Endocrine Practice · doi:10.4158/ep161620.or · Cited by 5
Morohoshi, K., KOMATANI, Y., & Harigaya, T. (2020) · Journal of Reproduction and Development · doi:10.1262/jrd.2020-080 · Cited by 5
Felsted, J. A., Meng, A., Ameroso, D., & Rios, M. (2020) · Endocrinology · doi:10.1210/endocr/bqaa068 · Cited by 6
Role of epigenetics in shaping sex differences in brain development and behavior
Cortes, L. R., & Forger, N. G. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-821785-6.00009-8 · Cited by 4
SRC1 deficiency in hypothalamic arcuate nucleus increases appetite and body weight
Lu, Q., Yang, Y., Jia, S., Zhao, S., Gu, B., Lu, P., He, Y., Liu, R., Wang, J., Ning, G., et al. (2018) · Journal of Molecular Endocrinology · doi:10.1530/jme-18-0075 · Cited by 4
Metadata
- Authors
- Frank, A., Brown, L. M., & Clegg, D. J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- North Carolina Agricultural and Technical State University (US)
- Corresponding author
- Clegg, Deborah J.
- ORCID
- Clegg, Deborah J.
- Venue
- Frontiers in Neuroendocrinology
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 35
- Issue
- 4
- Pages
- 550-557
- ISSN
- 0091-3022 (ISSN-L)
- PMC
- PMC4174989
- OpenAlex
- W2048117553
- Cited by
- 128
- References
- 166
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 10 · 2023: 15 · 2022: 7 · 2021: 11 · 2020: 12 · 2019: 8 · 2018: 9 · 2017: 15 · 2016: 13 · 2015: 9 · 2014: 2
- FWCI
- 1.46
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Frontiers in Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK 073689)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- hypothalamus, estrogen receptor, estrogen receptor alpha, estrogen receptor beta, metabolic regulation, energy homeostasis, dietary intake, energy expenditure, insulin sensitivity, leptin sensitivity, body fat distribution, visceral fat, impaired glucose tolerance, metabolic syndrome, adipose tissue function
- MeSH terms
- Animals, Body Weight, Energy Metabolism, Estrogens, Humans, Hypothalamus, Receptors, Estrogen, Leptin
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