Open Journal Systems

REVIEW ARTICLES

Received: June 2^nd 2015

Accepted: July 23^rd 2015

Estrogen receptor alpha in obesity and diabetes

José Ángel Cahua-Pablo,^a Eugenia Flores-Alfaro,^a Miguel Cruz^b

^aLaboratorio de Investigación en Epidemiología Clínica y Molecular, Unidad Académica de Ciencias Químico-Biológicas, Universidad Autónoma de Guerrero, Chilpancingo, Guerrero, México

^bUnidad de Investigación Médica en Bioquímica, Hospital de Especialidades Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México

Communication with: Miguel Cruz

Telephone: (55) 5761 2358

Email: mcruzl@yahoo.com

Estradiol (E2) is an important hormone in reproductive physiology, cardiovascular, skeletal and in the central nervous system (CNS). In human and rodents, E2 and its receptors are involved in the control of energy and glucose metabolism in health and metabolic diseases. The estrogen receptor (ER) belongs to the superfamily of nuclear receptors (NR), which are transcription factors that regulate gene expression. Three ER, ER-alpha, ER-beta and the G protein-coupled ER (GPER; also called GPR30) in tissues are involved in glucose and lipid homeostasis. Also, it may have important implications for risk factors associated with metabolic syndrome (MS), insulin resistance (IR), obesity and type 2 diabetes (T2D).

Keywords: Estrogens; Estradiol; Diabetes mellitus; Obesity

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An important mechanism for maintaining glucose homeostasis is the rapid action of insulin to stimulate its uptake and metabolism in peripheral tissue such as skeletal muscle, liver, and adipose tissue.¹ The action of insulin to transport glucose into cells of the skeletal muscle, adipose tissue, and liver, is by activation of the insulin receptor substrate (IRS-1), phosphatidylinositol 3-kinase (PI3K), and protein kinase B (Akt), which contribute to the translocation of glucose transporter 4 (GLUT4), the main glucose transporter regulated by insulin. On the other hand, insulin resistance (IR) in the skeletal muscle is one of the main factors of diabetes mellitus type 2 (DM2). Alteration in signaling mechanisms contributes to metabolic imbalance and morbidity from obesity, defined as excess fat in the body that can progressively affect health.² 

Estradiol (E2) participates in regulating the processes of many tissues, as a member of the steroid hormone family, including progesterone and testosterone, among others; these hormones primarily control physiological aspects in mammals.³ Steroid hormones are sintered in the ovaries, testes, and adrenal glands. They also participate in regulating the development, growth, and homeostasis of many tissues,⁴ regulate skeletal physiology,⁵ cardiovascular function,⁶ the central nervous system (CNS),⁷ and participate in the immune control system.⁸ In postmenopausal women, the development of visceral obesity and IR represent a high risk of DM2. Also, in diabetic postmenopausal women it has been reported that estrogen use may be associated with increased apoA, as well as a decrease in fasting glucose and total cholesterol in this group women.⁹

Studies have been conducted in knockout mouse models for ER-alpha gene (ERαKO), which have demonstrated the role of estrogen and its receptors in obesity and glucose tolerance.¹⁰ Thus, in a study in mice lacking ER-alpha, but not in mice lacking ER-beta, a large increase in white adipose tissue occurs in both female and male mice, accompanied by IR and glucose intolerance, and the increase in adipose tissue appears to result from a reduction in energy expenditure.¹¹

Origin of circulating estrogen in women and men

In women of reproductive age, E2 is the major circulating estrogen produced by the ovaries after the aromatization of androstenedione to estrone (E1), followed by the conversion of E1 to E2.³ In women with normal menstrual cycles, E2 usually acts on distant organs. On the other hand, naturally low circulating values are observed in men. E2 is synthesized in extragonadal sites such as the breasts, brain, bone, and adipose tissue, where they act locally as a paracrine and intracrine factor.¹² Estrogens, to perform their function, act with their receptors, of which at least three ERs, two ligand-activated transcription factors, ER-alpha, and ER-beta have been reported,^12,13 with 95% homology of identical amino acids between these (Figure 1), and a G-protein coupled receptor (GPRE) known as GPR30. The latter acts independently of the alpha and beta receptors, but affects the activation of epidermal growth factor (EGF) and can participate in the biology of the cancer.⁴ Another receiver described but not fully defined is ER-X, whose existence is evidenced in the brain.⁷

Estrogen receptors and ER-alpha structure

The ERs belong to the nuclear receptor (NR) superfamily, which are transcription factors that regulate gene expression dependently of its binding to the ligand and in response to specific physiological and pathological signals.^13,14

ER-alpha and ER-beta are encoded by different genes located on chromosome 6q25.1 and 14q23-24.1, respectively, and their expression varies depending on the type of tissue.¹⁵ ER-alpha is expressed predominantly in organs of the reproductive system (uterus, breast, and ovaries), however there are reports of expression in liver and CNS; while ER-beta is mainly expressed in other tissues such as bone, endothelium, lungs, urogenital tract, ovaries, CNS, and prostate.¹⁶

ER-alpha consists of 595 amino acids, consisting of six domains designated A to F.¹⁷ The N-terminal domain (region AB) has a ligand-independent transcriptional activation (TAF-1), and it is involved in both intra- and inter-molecular interactions, and in gene transcription. The DNA-binding domains (DBD or region C) contain two zinc fingers that are highly conserved in all hormone steroid receptors.¹⁸ The hinge domain (region D) has an important role in the dimerization of these receptors and the binding of heat shock proteins (HSP). Meanwhile, the hormone-binding domain (HBD, regions E/F and C-terminal) has the hormone-dependent transcriptional activation function (TAF-2).¹⁹ The domain F is a variable region that includes the sequence for helix 12 of the molecule, which is probably important for the difference in response of ERs to E2 and the selective estrogen receptor modulators (SERMs).^7,19-21

ERs contain two regions called activation functions (AFs), which are important for ligand-dependent transcriptional activity.²² AF-1 and AF-2 regions interact with transcriptional coactivators.¹⁹ AF-1 could be activated ligand-independently, depending on the phosphorylation status of the ER, particularly of the Ser118 residues in the AF1 region of the ER-alpha, and the Ser106 and Ser124 residues in the AF1 region of ER-beta, essential phosphorylation sites for ligand-independent activation of the ER through the signaling cascade of mitogen-activated protein kinase (MAPK).²³

ER mechanism of action

The ligand-independent mechanism of action of ER is defined as a member of the superfamily of class I RN, of which ER-alpha and ER-beta are members. The classical genomic mechanism of action of ER usually occurs in hours, resulting in the activation or repression of target genes. In the classic signaling pathway, the ligand binding to the ER causes a conformational change and dissociation of HSP, promoting homodimerization and high-affinity binding to estrogen response elements (ERE), which are palindromic sequences in a gene promoter (Figure 2).^17,24

After ligand binding, ER act on the ERE, these ERs interact with cofactors (coactivators or co-repressors) to regulate gene expression,¹⁶ and, depending on the co-regulators present in the cell, the estrogen-ER complex may have different effects.²⁵ The recruitment of co-regulators depends on the ligand binding probably attributable to different arrangements with different ligands, e.g. tamoxifen is an agonist in the endometrium because it recruits coactivators, but is an antagonist in the breasts because it recruits co-repressors.^26,27

ERs can also act ligand-independently to alter gene transcription, they can be phosphorylated directly enabling ERE binding or DNA binding indirectly via transcription factors, thus modulating transcription in the absence of ligand binding (Figure 2). Thus, it has been reported that EGF activation requires ER, and this growth factor can stimulate proliferation.²⁸ Furthermore, phosphorylation in specific sites of serine such as Ser104 and Ser106 is important for the activation of ligand-independent transcription.^29-31 It has also been shown that the cAMP or MAPK-dependent kinase pathways are activated by phosphorylation in the ER-alpha, and it is reported that ER-alpha can be phosphorylated in tyrosine 537.^32,33

An important component of ER actions related to energy metabolism are the extranuclear ER that directly modulate gene expression or act indirectly with nuclear events.³⁴ E2 can directly activate rapid signaling pathways producing effects in minutes or seconds via membrane-associated ER.³⁵ ER-alpha and ER-beta are located in caveolae where they associate with other molecules such as G-proteins, growth factor receptors, tyrosine kinases (Src), and G-protein coupled receptors, facilitating interaction and rapid signaling.³⁶ Estrogens also bind to G-protein coupled receptors, GPR30 can activate a rapid signaling pathway through kinases like PI3K, MAPK, and intracellular calcium mobilization.^37,38

Role of estrogen in the regulation of body weight and insulin resistance

In women, estrogen favors fat deposition in the gluteal area; after menopause, fat distribution in women switches to a phenotype similar to that of men.^39,40 Part of the function of estrogen is to regulate body composition, energy balance, and to regulate glucose homeostasis and insulin sensitivity in women and men (Table I).⁴¹ Body weight increases with several conditions associated with estrogen deficiency such as ovariectomy, polycystic ovary syndrome, or lack of aromatase functionality due to gene alterations, and all can be corrected by treatment with E2.^42-44

In men, testosterone decrease contributes to the development of MS; there is also a relationship between testosterone and the amount of visceral adipose tissue and MS.⁴⁵ The aromatization of testosterone to E2 has been proven important for energy homeostasis in males, suggesting that testosterone serves as a prohormone, providing E2 for energy homeostasis. In addition, male mice castrated and treated with either testosterone or E2 remain thin, while those treated with pure androgen 5-alpha-dihydrotestosterone (DHT) (which cannot be aromatized by E2) develop obesity.⁴⁶ 

The central regulation of energy balance is mediated by a complex signaling pathway in the CNS, integrating multiple endocrine signals from the periphery. Hypothalamic neurocircuits are essential for the regulation of energy balance, involving the arcuate nucleus (AN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN), paraventricular nucleus (PVN), and the lateral hypothalamic region.⁴⁷

Both ER-alpha and ER-beta are expressed in the hypothalamic nucleus; it has been observed that ER-alpha is the main isoform involved in the control of body weight by estrogen.⁴⁸ A deletion directed against ER-alpha in mice results in an obese phenotype with increased fat accumulation, but with no significant differences between wild-type mice (WT) and knockout.¹¹ Also, ER-alpha is expressed in the brainstem, including the nucleus tractus solitarius (NTS), medial dorsal vagal.⁴⁹ It has been shown that replacement by E2 in WT mice suppresses food intake, satiety induced by cholecystokinin (CCK), and is accompanied by an increase in NTS activity. CCK is synthesized and released from upper intestinal cells and acts with the abdominal CCK-A receptor; CCK is involved in the digestive process such as delaying the emptying process and intestinal mobility.⁵⁰ E2 increases the power of CCK by increasing the sensitivity of the CCK-A receptor, but it does not increase CCK secretion or the number of receptors.^51,52

The absence of ER-alpha has been shown to produce adipocyte hyperplasia and hypertrophy in white adipose tissue but not brown adipose tissue, and it is accompanied by IR and glucose intolerance.^53,54 Moreover, animals and humans that lack of endogenous estrogen synthesis, show IR that can be treated by estrogen supplementation.⁵⁵ In particular, estrogen increases the activity of hepatic insulin by decreasing gluconeogenesis and glycolysis, and reversing aspects of IR, increasing insulin release from the Langerhans pancreatic islets.^56,57 Estrogen prevents beta-cell apoptosis, reduces proinflammatory signaling, and enhances insulin action.⁵⁸ As demonstrated by Vogel et al. in a study in obese mice in New Zealand (NZO), estrogen protects against beta cell loss and obesity associated with DM2, due to the reduction in IR and a possibly decreased sensitivity of beta cells to glucolipotoxicity.⁵⁹ Less endogenous estrogen has been found with a greater amount of visceral adipose tissue in men, which may be related to a higher IR compared with women without menopause, which may contribute to gender differences observed in cardiovascular disease (CVD).^42,60

ER-alpha and adipose tissue distribution

The excessive accumulation of adipose tissue in the central region of the body has been linked to an increased risk of mortality from metabolic disorders such as DM2, hypercholesterolemia, hypertriglyceridemia, and atherosclerosis.⁶¹ Estrogens are produced in adipocytes via aromatization of androgen precursors; an increase in blood levels of estrogen and decreased testosterone have been seen in morbidly obese men, however these increases are not observed in women with obesity.^62,63

The subcutaneous and intra-abdominal adipose tissue expresses ER-alpha and ER-beta, ER-alpha being predominantly expressed in intra-abdominal adipose tissue.^64,65 Male and female mice that are knockout for ER-alpha (ERαKO) develop central obesity with increased body weight, white adipose tissue, adipocyte size and number, and decreased energy expenditure.^11,66 Moreover, inguinal deposits also increase in ERβKO mice; this suggests that ER-alpha elimination may not only focus on intra-abdominal deposits.⁶⁷ Thus, reduction in expression and damage to ER-alpha function have been linked to an increased prevalence of various MS factors in both human and rodent males and females.^68,69 ER-alpha gene polymorphisms are also associated with abnormal adiposity.^15,69,70

Animals that are knockout to ER-alpha show an increase in serum cholesterol levels,⁷¹ indicating an important physiological role for ER-alpha in the effect of estrogen on weight control. Expression of the ER-alpha gene in adipose tissue and adipocytes is reduced in obese premenopausal women.¹⁵ However, several single nucleotide polymorphisms (SNPs) in ER-alpha have been associated with an obese phenotype in men and women.^69,72

ER-alpha in glucose homeostasis and insulin sensitivity

Circulating glucose levels are mainly regulated by the hormones insulin and glucagon. In response to high glucose levels, proinsulin is released from pancreatic beta cells, composed of chains A, B, and C, which is converted to insulin and peptide C by endopeptidase action.⁷³ Insulin stimulates glucose expenditure and storage as glycogen in the skeletal muscle, adipose tissue, and liver. Two main transduction pathways are activated by insulin action: the PI3K pathway and the MAPK pathway.⁷⁴ The two pathways regulate most of the insulin actions associated with the regulation of energy metabolism, gene expression, and mitogenic effects; the PI3K pathway is the main mechanism by which insulin exerts its functions in glucose and lipid metabolism.⁷⁵ When insulin binds to its receptor, it activates a signaling cascade involving several proteins including IRS, PI3K, Akt, and AMPK, which ultimately results in translocation to the plasma membrane of GLUT4, allowing the entry of glucose into the cell.⁷³

Glucose intolerance and hyperinsulinemia was observed in men who lack ER-alpha. A metabolic function of ER-alpha, based on animal studies, is its participation in glucose homeostasis through ER-alpha and ER-beta.¹¹ On the other hand, premenopausal women are more sensitive to insulin with better glucose tolerance, and are more resistant to IR development compared to men; they also show increased GLUT4 expression.⁷⁶ It has been shown that ER-alpha is involved in the regulation of glucose metabolism in several tissues including liver, skeletal muscle, adipose tissue, pancreatic beta cells, and CNS.⁶⁹

Estrogen also regulates the function of pancreatic beta cells through a mechanism dependent on ER-alpha.⁵⁶ Estrogen-dependent insulin release in cultures of pancreatic islets was found reduced in ER-alpha-deficient mice, as compared to islets derived from ER-beta-deficient mice. It has been found that the two ER subtypes have opposite effects on muscle: ER-alpha induces GLUT4 expression and ER- beta inhibits it.⁷⁴

ER-alpha action in regulating glucose metabolism in muscle

The molecular mechanism by which E2 regulates metabolism in muscle is still unknown, but there is evidence suggesting that in physiological ranges, E2 is beneficial for insulin sensitivity, while hypo- or hyper-estrogenism is related to IR.⁷⁷

The ER-E2 complex modulates glucose processing through its actions on several proteins of the insulin signaling pathway and GLUT4 expression and translocation. In rat studies, it was observed that E2 increases phosphorylation of AMPK, Akt, and its substrate TBC1D1/4 in muscle.⁷⁸ In a rat study, treatment with E2 improves glucose homeostasis, mainly through its ability to increase GLUT4 content in the membrane of muscle cells.⁷⁹ Furthermore, in 2009 Alexanderson reported that in young female rats a single dose of E2 during the postnatal period results in increased regulation of genes involved in glucose metabolism, lipid oxidation, peroxisome proliferator-activated receptor delta (PPARδ), and uncoupling protein 3 (UCP3) in muscle.⁸⁰ Meanwhile for ER-beta -/- mice, glucose tolerance and IR are normal, or even better than in WT mice; ER-alpha -/- mice are glucose-intolerant and insulin-resistant.^11,81 When ArKO E2-deficient male mice are treated with diarylpropionitrile (DPN), an ER-beta-selective agonist, there is an increase in GLUT4 expression in muscle.⁸² This suggests that ER-beta has a suppressive role for GLUT4. The opposite holds for ER-alpha, which shows is a reduction in glucose uptake in muscle. These data suggest that ER-beta could have the effect of causing diabetes.⁸¹

Furthermore, when dealing with a selective agonist for ER-alpha, propylpyrazoletriol (PPT) increases the translocation of GLUT4 to the cell membrane in myeloblasts L6, and when ER-alpha is silenced there is a decrease in transfer. In ovariectomized rats treated with PPT, glucose uptake and GLUT4 expression increases in skeletal muscle.⁸²

Conclusions

In this review we focused on describing the functions of ER-alpha and ER-beta in metabolic pathways composed of tissues involved in glucose and lipid metabolism. It is clear that ERs are involved in many complex mechanisms, however, these mechanisms are not known exactly, rather they are considered in context as a complete system.

Each organ has an important role in metabolism, and these tissues are dependent on each other for the regulation of body homeostasis. Therefore it is reasonable to think that homeostasis depends on the balance between ER-alpha and ER-beta in the metabolic pathways. Estrogens and ERs have been linked with energy balance and glucose metabolism, however, the mechanisms involved in their actions are still unknown. With regard to obesity, future research should focus on identifying important sites in the brain where ERs regulate body weight homeostasis and signaling pathways that are necessary for the action of estrogen.

Acknowledgments

Recognition of the support given by CONACYT with agreement number: I010 / 455/2013 C-677/2013 of the Programa de Fortalecimiento Académico del Posgrado de Alta Calidad-CONACYT.

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