Central regulation of energy metabolism by estrogens

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Abstract

Background

Estrogenic actions in the brain prevent obesity. Better understanding of the underlying mechanisms may facilitate development of new obesity therapies.

Scope of review

This review focuses on the critical brain regions that mediate effects of estrogens on food intake and/or energy expenditure, the molecular signals that are involved, and the functional interactions between brain estrogens and other signals modulating metabolism. Body weight regulation by estrogens in male brains will also be discussed.

Major conclusions

17β-estradiol acts in the brain to regulate energy homeostasis in both sexes. It can inhibit feeding and stimulate brown adipose tissue thermogenesis. A better understanding of the central actions of 17β-estradiol on energy balance would provide new insight for the development of therapies against obesity in both sexes.

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Most cited references 136

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Anatomy and regulation of the central melanocortin system.

Roger Cone (2005)

The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.

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Sources of estrogen and their importance.

E.R Simpson (2003)

In premenopausal women, the ovaries are the principle source of estradiol, which functions as a circulating hormone to act on distal target tissues. However, in postmenopausal women when the ovaries cease to produce estrogen, and in men, this is no longer the case, because estradiol is no longer solely an endocrine factor. Instead, it is produced in a number of extragonadal sites and acts locally at these sites as a paracrine or even intracrine factor. These sites include the mesenchymal cells of adipose tissue including that of the breast, osteoblasts and chondrocytes of bone, the vascular endothelium and aortic smooth muscle cells, and numerous sites in the brain. Thus, circulating levels of estrogens in postmenopausal women and in men are not the drivers of estrogen action, they are reactive rather than proactive. This is because in these cases circulating estrogen originates in the extragonadal sites where it acts locally, and if it escapes local metabolism then it enters the circulation. Therefore, circulating levels reflect rather than direct estrogen action in postmenopausal women and in men. Tissue-specific regulation of CYP19 expression is achieved through the use of distinct promoters, each of which is regulated by different hormonal factors and second messenger signaling pathways. Thus, in the ovary, CYP19 expression is regulated by FSH which acts through cyclic AMP via the proximal promoter II, whereas in placenta the distal promoter I.1 regulates CYP19 expression in response to retinoids. In adipose tissue and bone by contrast, another distal promoter--promoter I.4--drives CYP19 expression under the control of glucocorticoids, class 1 cytokines and TNFalpha. The importance of this unique aspect of the tissue-specific regulation of aromatase expression lies in the fact that the low circulating levels of estrogens which are observed in postmenopausal women have little bearing on the concentrations of estrogen in, for example, a breast tumor, which can reach levels at least one order of magnitude greater than those present in the circulation, due to local synthesis within the breast. Thus, the estrogen which is responsible for breast cancer development, for the maintenance of bone mineralization and for the maintenance of cognitive function is not circulating estrogen but rather that which is produced locally at these specific sites within the breast, bone and brain. In breast adipose of breast cancer patients, aromatase activity and CYP19 expression are elevated. This occurs in response to tumor-derived factors such as prostaglandin E2 produced by breast tumor fibroblasts and epithelium as well as infiltrating macrophages. This increased CYP19 expression is associated with a switch in promoter usage from the normal adipose-specific promoter I.4 to the cyclic AMP responsive promoter, promoter II. Since these two promoters are regulated by different cohorts of transcription factors and coactivators, it follows that the differential regulation of CYP19 expression via alternative promoters in disease-free and cancerous breast adipose tissue may permit the development of selective aromatase modulators (SAMs) that target the aberrant overexpression of aromatase in cancerous breast, whilst sparing estrogen synthesis in other sites such as normal adipose tissue, bone and brain.

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Central neural regulation of brown adipose tissue thermogenesis and energy expenditure.

Shaun F Morrison, Christopher J Madden, Domenico Tupone (2014)

Thermogenesis, the production of heat energy, is the specific, neurally regulated, metabolic function of brown adipose tissue (BAT) and contributes to the maintenance of body temperature during cold exposure and to the elevated core temperature during several behavioral states, including wakefulness, the acute phase response (fever), and stress. BAT energy expenditure requires metabolic fuel availability and contributes to energy balance. This review summarizes the functional organization and neurochemical influences within the CNS networks governing the level of BAT sympathetic nerve activity to produce the thermoregulatory and metabolically driven alterations in BAT thermogenesis and energy expenditure that contribute to overall energy homeostasis. Copyright © 2014 Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Yong Xu

Miguel López

Journal

Journal ID (nlm-ta): Mol Metab

Journal ID (iso-abbrev): Mol Metab

Title: Molecular Metabolism

Publisher: Elsevier

ISSN (Electronic): 2212-8778

Publication date PMC-release: 23 May 2018

Publication date Collection: September 2018

Publication date (Electronic): 23 May 2018

Volume: 15

Pages: 104-115

Affiliations

[1 ]USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA

[2 ]NeurObesity Group, Department of Physiology, CiMUS, University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain

[3 ]CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela, 15706, Spain

Author notes

[∗ ]Corresponding author. 1100 Bates Street, Rm 8066, Houston, TX 77030, USA. Fax: +1 713 798 7187. yongx@ 123456bcm.edu

[∗∗ ]Corresponding author. Avenida de Barcelona 22, Santiago de Compostela, 15782, Spain. Fax: +34 881 815403. m.lopez@ 123456usc.es

Article

Publisher ID: S2212-8778(18)30257-6

DOI: 10.1016/j.molmet.2018.05.012

PMC ID: 6066788

PubMed ID: 29886181

SO-VID: 99da2146-f031-4187-b72b-6ecb4e881297

License:

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

History

Date received : 10 March 2018

Date revision received : 9 May 2018

Date accepted : 15 May 2018

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Central regulation of energy metabolism by estrogens

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Abstract

Background

Scope of review

Major conclusions

Related collections

Cancer Metabolism

Most cited references 136

Anatomy and regulation of the central melanocortin system.

Sources of estrogen and their importance.

Central neural regulation of brown adipose tissue thermogenesis and energy expenditure.

Author and article information

Contributors

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Affiliations

Author notes

Article

History

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