Distinct Hypothalamic Neurons Mediate Estrogenic Effects on Energy Homeostasis and Reproduction
Open accessAbstract
Estrogens regulate body weight and reproduction primarily through actions on estrogen receptor-α (ERα). However, ERα-expressing cells mediating these effects are not identified. We demonstrate that brain-specific deletion of ERα in female mice causes abdominal obesity stemming from both hyperphagia and hypometabolism. Hypometabolism and abdominal obesity, but not hyperphagia, are recapitulated in female mice lacking ERα in hypothalamic steroidogenic factor-1 (SF1) neurons. In contrast, deletion of ERα in hypothalamic pro-opiomelanocortin (POMC) neurons leads to hyperphagia, without directly influencing energy expenditure or fat distribution. Further, simultaneous deletion of ERα from both SF1 and POMC neurons causes hypometabolism, hyperphagia, and increased visceral adiposity. Additionally, female mice lacking ERα in SF1 neurons develop anovulation and infertility, while POMC-specific deletion of ERα inhibits negative feedback regulation of estrogens and impairs fertility in females. These results indicate that estrogens act on distinct hypothalamic ERα neurons to regulate different aspects of energy homeostasis and reproduction.
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Estrogens directly act on POMC neurons and regulate their cellular activity.
“Estrogens directly act on POMC neurons and regulate their cellular activity.”
From Estrogen deficiency and the origin of obesity during menopause (2014) · cites this paper as [88]
ERα is abundantly expressed in the rodent brain in VMN, ARC, PVN, and the medial preoptic area; ERβ is found in the same hypothalamic nuclei but at significantly lower expression relative to ERα.
“While ERα is abundantly expressed in the rodent brain in VMN and ARC, PVN, and the medial preoptic area, ERβ is found in the same hypothalamic nuclei, but ERβ expression is significantly lower relative to ERα [88, 91].”
From Estrogen deficiency and the origin of obesity during menopause (2014) · cites this paper as [88]
Deletion of ER in POMC neurons in mice leads to hyperphagia without directly influencing energy expenditure or adipose tissue distribution.
“Indeed, deletion of ER in POMC neurons in mice leads to hyperphagia without directly influencing energy expenditure or adipose tissue distribution [88].”
From Estrogen deficiency and the origin of obesity during menopause (2014) · cites this paper as [88]
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Self-citationMembrane Estrogen Receptor Regulation of Hypothalamic Function
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Self-citationThe hypothalamus for whole-body physiology: from metabolism to aging
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- Authors
- Xu, Y., Nedungadi, T. P., Zhu, L., Sobhani, N., Irani, B. G., Davis, K. E., Zhang, X., Zou, F., Gent, L. M., Hahner, L. D., Khan, S. A., Elias, C. F., Elmquist, J. K., & Clegg, D. J.
- Affiliations
- Baylor College of Medicine (US)
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Clegg, Deborah J.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 14
- Issue
- 4
- Pages
- 453-465
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC3235745
- OpenAlex
- W2013865699
- Cited by
- 597
- References
- 43
- Citations by year
- 2026: 19 · 2025: 34 · 2024: 35 · 2023: 36 · 2022: 38 · 2021: 48 · 2020: 42 · 2019: 56 · 2018: 45 · 2017: 54 · 2016: 48 · 2015: 39 · 2014: 36 · 2013: 36 · 2012: 27
- FWCI
- 14.74
- Type
- journal article
- Language
- en
- Update notices
- erratum (2019-05-07)
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 655 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (DK073689, DK088220, HD061539, P30 DK079638-03, PL1 DK081182, PO1DK088761, R00DK085330, R01DK071320, R01DK088423, R01DK093587, R37DK53301, RL1 DK081185, UL1 RR024923)
- American Diabetes Association
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- estrogen receptor alpha, hypothalamic neurons, energy homeostasis, reproduction, abdominal obesity, hyperphagia, hypometabolism, proopiomelanocortin neurons, anovulation, infertility, estrogen negative feedback, visceral fat, female fertility
- MeSH terms
- Animals, Energy Metabolism, Estradiol, Female, Hyperphagia, Hypothalamus, Infertility, Female, Male, Neurons, Obesity, Pro-Opiomelanocortin, Mice, Knockout, Estrogen Receptor alpha, Mice, Steroidogenic Factor 1
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