Feature Review
Estrogens and the control of energy homeostasis: a brain perspective

https://doi.org/10.1016/j.tem.2015.06.003Get rights and content

Highlights

  • Estrogens are pleiotropic regulators affecting not only reproduction but also metabolism.

  • Estrogen deprivation induces hyperphagia, low metabolic activity, and obesity.

  • Estrogen actions are conducted via genomic and nongenomic mechanisms, including ERα.

  • Estrogens act in the brain to regulate all aspects of body energy homeostasis and metabolism.

  • Estrogen actions in the ARC regulate food intake and in the VMH energy expenditure.

Despite their prominent roles in the control of reproduction, estrogens pervade many other bodily functions. Key metabolic pathways display marked sexual differences, and estrogens are potent modulators of energy balance, as evidenced in extreme conditions of estrogen deficiency characterized by hyperphagia and decreased energy expenditure, and leading to obesity. Compelling evidence has recently demonstrated that, in addition to their peripheral effects, the actions of estrogens on energy homeostasis are exerted at central levels, to regulate almost every key aspect of metabolic homeostasis, from feeding to energy expenditure, to glucose and lipid metabolism. We review herein the state-of-the-art of the role of estrogens in the regulation of energy balance, with a focus on their central effects and modes of action.

Section snippets

Estrogens and metabolism in the obesity era

Obesity is defined as a state where excess fat accumulation in the adipose tissue causes adverse health problems [1]. While obesity itself results in mechanical and psychological problems, probably the major concern is its association with insulin resistance, type 2 diabetes mellitus, fatty liver, and a range of other disorders generally known as the metabolic syndrome 1, 2, as well as sleep apnea, musculoskeletal and cardiovascular disorders, and several types of cancer 2, 3. Thus, controlling

Estrogens: modes of action, secretory profiles, and regulatory mechanisms

Estrogens are evolutionarily conserved hormones, produced in all vertebrate and some invertebrate species. In mammals, three major forms of estrogens exist: estrone (E1), E2, and estriol (E3) [14]. The major source of estrogens is the ovary, specifically the growing follicles that, during reproductive life, produce predominantly E2, which is endowed with the highest biopotency. Other sources of estrogens are the placenta, responsible to a large extent for the high levels of estrogens during

Estrogens and the control of energy homeostasis: peripheral actions

As mentioned in previous sections, ovarian estrogens have major role in the regulation of energy homeostasis [9]. Decreased levels of E2 after menopause or ovariectomy (OVX) are associated with hyperphagia, reduced energy expenditure, and weight gain 9, 26, 27. E2 replacement therapy in those animal models and human subjects prevents OVX-induced obesity and metabolic dysfunction, by decreasing feeding and increasing energy expenditure 9, 26, 27. A bulk of data has also suggested the presence of

Central effects of estrogens in the control of energy homeostasis

ERs are amply expressed in the central nervous system (CNS) 46, 47, and central administration of E2 induces a profound catabolic effect 26, 27. In addition to morphological and pharmacological evidence (for an extensive review, see [9]), genetic models have unequivocally demonstrated that central ERα is required for optimal body weight control. By crossing loxP-flanked ERα mice with Nestin-Cre transgenic mice, Clegg and colleagues generated mice lacking ERα in most brain regions. Compared with

Estrogens and the interplay between the reproductive and metabolic brain

The relevant role of estrogens, as major gonadal hormones, in the central control of energy homeostasis is illustrative of the tight relation between the regulatory systems controlling reproductive function, metabolism, and body weight 89, 90. Indeed, it is well established that sufficient body energy stores are mandatory for the attainment and maintenance of fertility, especially in the female, due to the considerable metabolic drainage imposed by pregnancy and lactation [91]. However, the

Concluding remarks

Over the past few years, a bulk of data has proposed that estrogens modulate energy balance by acting at central and peripheral levels. In addition, the molecular mechanisms mediating those effects have begun to be revealed. Of note, when acting at a central level, E2 shares the same pathways with other metabolic hormones, such as leptin, ghrelin, insulin, GLP1, and THs 59, 81, 82, 83, 84. Recent strategies have pointed to estrogens as druggable targets for obesity. For example, it has been

Acknowledgments

The research leading to these results received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 281854 – the ObERStress European Research Council project (M.L.), Xunta de Galicia (M.L.: 2012-CP070), Junta de Andalucía (M.T-S.: P08-CVI-03788 and P12-FQM-01943), Instituto de Salud Carlos III (ISCIII) (M.L.: PI12/01814), and MINECO cofunded by the FEDER Program of the European Union (M.T-S.: BFU2011-25021). CIBER de Fisiopatología de la

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      The control of energy homeostasis is a complex process that maintains the balance of energy intake, expenditure, and storage so that each organ has enough energy to function. Both the central, predominantly the hypothalamus, and peripheral organs, predominantly the liver, pancreas, and adipose tissue, are involved in controlling these processes [1,2]. The role of 17β-estradiol (E2) in regulating reproduction by interacting with the population of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and providing feedback on the hypothalamic-pituitary-gonadal (HPG) axis is well documented.

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