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)
Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK
Cell Metab.
Effects of selective estrogen receptor agonists on food intake and body weight gain in rats
Physiol. Behav.
Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice
Biochem. Biophys. Res. Commun.
Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus
Biochem. Biophys. Res. Commun.
Regulation of lipin1 by nutritional status, adiponectin, sex and pituitary function in rat white adipose tissue
Physiol. Behav.
The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis
Mol. Metab.
ERalpha upregulates Phd3 to ameliorate HIF-1 induced fibrosis and inflammation in adipose tissue
Mol. Metab.
The sexual dimorphism of obesity
Mol. Cell. Endocrinol.
Differential distribution and regulation of estrogen receptor-alpha and -beta mRNA within the female rat brain
Brain Res. Mol. Brain Res.
Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction
Cell Metab.
Behavioral phenotyping of Nestin-Cre mice: implications for genetic mouse models of psychiatric disorders
J. Psychiatr. Res.
Ablation of estrogen receptor alpha (ERalpha) prevents upregulation of POMC by leptin and insulin
Biochem. Biophys. Res. Commun.
Leptin receptors in estrogen receptor-containing neurons of the female rat hypothalamus
Brain Res.
Cross-talk between endocrine-disrupting chemicals and cytokine signaling through estrogen receptors
Biochem. Biophys. Res. Commun.
Rapid effects of 17beta-estradiol on cell signaling and function of Mytilus hemocytes
Gen. Comp. Endocrinol.
Estrogen receptor alpha, a molecular switch converting transforming growth factor-alpha-mediated proliferation into differentiation in neuroblastoma cells
J. Biol. Chem.
Hypothalamic fatty acid metabolism mediates the orexigenic action of ghrelin
Cell Metab.
Central neural regulation of brown adipose tissue thermogenesis and energy expenditure
Cell Metab.
17 beta-estradiol depolarization of hypothalamic neurons is mediated by cyclic AMP
Brain Res.
Bmp8b increases brown adipose tissue thermogenesis through both central and peripheral actions
Cell
An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females
Cell Rep.
Estrogen receptor-{beta}-selective ligands alleviate high-fat diet- and ovariectomy-induced obesity in mice
J. Biol. Chem.
Connecting metabolism and reproduction: roles of central energy sensors and key molecular mediators
Mol. Cell. Endocrinol.
Roles of leptin in reproduction, pregnancy and polycystic ovary syndrome: consensus knowledge and recent developments
Metabolism
Kisspeptins: bridging energy homeostasis and reproduction
Brain Res.
Modulation of body temperature and LH secretion by hypothalamic KNDy (kisspeptin, neurokinin B and dynorphin) neurons: a novel hypothesis on the mechanism of hot flushes
Front. Neuroendocrinol.
‘Mens sana in corpore sano’: exercise and hypothalamic ER stress
PLoS Biol.
Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms
Nat. Rev. Cancer
Central regulation of food intake, body weight, energy expenditure, and glucose homeostasis
Front. Neurosci.
20 years of leptin: connecting leptin signaling to biological function
J. Endocrinol.
The role of estrogens in control of energy balance and glucose homeostasis
Endocr. Rev.
Sex steroids and the control of the Kiss1 system: developmental roles and major regulatory actions
J. Neuroendocrinol.
The neuroprotective actions of oestradiol and oestrogen receptors
Nat. Rev. Neurosci.
The role of estrogen in adipose tissue metabolism: insights into glucose homeostasis regulation
Endocr. J.
The estrogen trinity: membrane, cytosolic, and nuclear effects
News Physiol. Sci.
Cloning of a novel receptor expressed in rat prostate and ovary
Proc. Natl. Acad. Sci. U.S.A.
An estrogen receptor (ER)alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo
Mol. Endocrinol.
Nonclassical estrogen receptor alpha signaling mediates negative feedback in the female mouse reproductive axis
Proc. Natl. Acad. Sci. U.S.A.
Genetic rescue of nonclassical ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice
J. Clin. Invest.
GPER deficiency in male mice results in insulin resistance, dyslipidemia, and a proinflammatory state
Endocrinology
Cited by (95)
Genistein early in life modifies the arcuate nucleus of the hypothalamus morphology differentially in male and female rats
2023, Molecular and Cellular EndocrinologyTLR4 in POMC neurons regulates thermogenesis in a sex-dependent manner
2023, Journal of Lipid ResearchEstrogen as a key regulator of energy homeostasis and metabolic health
2022, Biomedicine and PharmacotherapyCitation Excerpt :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.