Trends in Endocrinology & Metabolism
Feature ReviewEstrogens and the control of energy homeostasis: a brain perspective
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
References (120)
- et al.
The hunger genes: pathways to obesity
Cell
(2015) Neural control of energy balance: translating circuits to therapies
Cell
(2015)Regulation of energy homeostasis by the NPY system
Trends Endocrinol. Metab.
(2015)Gut hormones and obesity: physiology and therapies
Vitam. Horm.
(2013)The role of estrogen receptors in the control of energy and glucose homeostasis
Steroids
(2008)The role of hypothalamic estrogen receptors in metabolic regulation
Front. Neuroendocrinol.
(2014)Mechanisms in tissue-specific regulation of estrogen biosynthesis in humans
Trends Endocrinol. Metab.
(2002)Follicular oestrogen synthesis: the ‘two-cell, two-gonadotrophin’ model revisited
Mol. Cell. Endocrinol.
(1994)Estrogen receptors alpha (ERalpha) and beta (ERbeta): subtype-selective ligands and clinical potential
Steroids
(2014)- et al.
Estrogen biology: new insights into GPER function and clinical opportunities
Mol. Cell. Endocrinol.
(2014)