The metabolic syndrome has reached pandemic level worldwide, and evidence is that estradiol plays a key role in its development. The discovery of the second estrogen receptor, ERβ, in tissues previously not considered targets of estradiol was a breakthrough in endocrinology. In the present review, we discuss how the presence of ERβ and the previously described ERα in tissues involved in glucose and lipid homeostasis (brain, skeletal muscle, adipose tissue, pancreas, liver, and heart) may have important implications to risk factors associated with the metabolic syndrome. Imbalance of ERα/ERβ ratio in this "metabolic network" may lead to the metabolic syndrome.

Estrogen receptors (ER) are important regulators of metabolic diseases such as obesity and insulin resistance (IR). While ERα seems to have a protective role in such diseases, the function of ERβ is not clear. To characterize the metabolic function of ERβ, we investigated its molecular interaction with a master regulator of insulin signaling/glucose metabolism, the PPARγ, in vitro and in high-fat diet (HFD)-fed ERβ -/- mice (βERKO) mice. Our in vitro experiments showed that ERβ inhibits ligand-mediated PPARγ-transcriptional activity. That resulted in a blockade of PPARγ-induced adipocytic gene expression and in decreased adipogenesis. Overexpression of nuclear coactivators such as SRC1 and TIF2 prevented the ERβ-mediated inhibition of PPARγ activity. Consistent with the in vitro data, we observed increased PPARγ activity in gonadal fat from HFD-fed βERKO mice. In consonance with enhanced PPARγ activation, HFD-fed βERKO mice showed increased body weight gain and fat mass in the presence of improved insulin sensitivity. To directly demonstrate the role of PPARγ in HFD-fed βERKO mice, PPARγ signaling was disrupted by PPARγ antisense oligonucleotide (ASO). Blockade of adipose PPARγ by ASO reversed the phenotype of βERKO mice with an impairment of insulin sensitization and glucose tolerance. Finally, binding of SRC1 and TIF2 to the PPARγ-regulated adiponectin promoter was enhanced in gonadal fat from βERKO mice indicating that the absence of ERβ in adipose tissue results in exaggerated coactivator binding to a PPARγ target promoter. Collectively, our data provide the first evidence that ERβ-deficiency protects against diet-induced IR and glucose intolerance which involves an augmented PPARγ signaling in adipose tissue. Moreover, our data suggest that the coactivators SRC1 and TIF2 are involved in this interaction. Impairment of insulin and glucose metabolism by ERβ may have significant implications for our understanding of hormone receptor-dependent pathophysiology of metabolic diseases, and may be essential for the development of new ERβ-selective agonists.

Estrogen is known to influence glucose homeostasis with dominant effects in the liver, but the role of estrogen receptors in muscle glucose metabolism is unknown. In the present study, we investigated the expression of the two estrogen receptors, ERα and ERβ, and their influence on regulation of the glucose transporter, GLUT4, and its associated structural protein, caveolin-1, in mouse gastrocnemius muscle. Immunohistochemical analysis revealed that ERα and ERβ are coexpressed in the nuclei of most muscle cells, and that their levels were not affected by absence of estradiol [in aromatase-knockout (ArKO) mice]. GLUT4 expression on the muscle cell membrane was not affected by loss of ERβ but was extremely reduced in ERα -/- mice and elevated in ArKO mice. RT-PCR confirmed a parallel reduction in GLUT4 mRNA levels in ERα -/- mice. Upon treatment of ArKO mice with the ERβ agonist 2,3-bis(4-hydroxyphenyl)propionitrile, GLUT4 expression was reduced. By immunofluorescence and Western blotting, caveolin-1 expression was higher in ArKO mice and lower in ERβ -/- and ERα -/- mice than in WT littermates. GLUT4 and caveolin-1 were colocalized in WT and ArKO mice but not in ERβ -/- and ERα -/- mice. These results reveal that ERα is a positive regulator of GLUT4 expression, whereas ERβ has a suppressive role. Both ERβ and ERα are necessary for optimal caveolin-1 expression. Taken together, these results indicate that colocalization of caveolin-1 and GLUT4 is not an absolute requirement for muscle glucose metabolism but that reduction in GLUT4 could be contributing to the insulin resistance observed in ERα -/- mice.

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Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulinregulated glucose transporter (GLUT)4 is reduced by estrogen receptor (ER)␤ agonists. In the present study, to investigate the relative contributions of ER␣ and ER␤ in glucose homeostasis, we examined the effects of tamoxifen (Tam) on GLUT4 expression in SM and WAT in wild-type (WT) and ERϪ/Ϫ mice. ER␤Ϫ/Ϫ mice were characterized by fasting hypoglycemia, increased levels of SM GLUT4, pancreatic islet hypertrophy, and a belated rise in plasma insulin in response to a glucose challenge. ER␣Ϫ/Ϫ mice, on the contrary, were hyperglycemic and glucose intolerant, and expression of SM GLUT4 was markedly lower than in WT mice. Tam had no effect on glucose tolerance or insulin sensitivity in WT mice. In ER␣Ϫ/Ϫ mice, Tam increased GLUT4 and improved insulin sensitivity. i.e., it behaved as an ER␤ antagonist in SM but had no effect on WAT. In ER␤Ϫ/Ϫ mice, Tam did not affect GLUT4 in SM but acted as an ER␣ antagonist in WAT, decreasing GLUT4. Thus, in the interplay between ER␣ and ER␤, ER␤-mediated repression of GLUT4 predominates in SM but ER␣-mediated induction of GLUT4 predominates in WAT. This tissue-specific difference in dominance of one ER over the other is reflected in the ratio of the expression of the two receptors. ER␣ predominates in WAT and ER␤ in SM.estrogen receptor-␣; estrogen receptor-␤; glucose transporter 4; tamoxifen FOR SEVERAL DECADES the multiple and sometimes contradictory effects of estrogens on human physiology and disease have puzzled endocrinologists. Even today, the modulatory effects of estrogen on glucose homeostasis are not completely understood. The effects of estrogen on gene regulation are mediated by two sometimes opposing forces, estrogen receptor (ER)␣ and ER␤ (20, 28), in both females and males (19,25). Recent experimental evidence has revealed that estradiol (E 2 ) is an important modulator in tissues previously not considered to be classical estrogen targets.In mice, insulin resistance develops when there is no estrogen (in aromatase-knockout mice) and when ER␣ is inactivated (ER␣Ϫ/Ϫ mice) (5,17,19). In women, a clear relationship between E 2 and glycemia has been observed during the menstrual cycle (32), in gestation (7), in gestational diabetes mellitus, and in polycystic ovarian syndrome (11). In normal males, because of the absence of estrogen cyclicity, the effect of estrogen on glycemia is less obvious, but men with hypoestrogenism or with mutations in the aromatase (13) or ER␣ (31) genes do develop insulin resistance.Insulin is the most important hormone for the maintenance of euglycemia. It regulates carbohydrate metabolism in the liver and glucose uptake in insulin-sensitive tissues, i.e., skeletal muscle (SM) and white adipose tissue (WAT) (12). On binding to its receptors on the cell membrane o...

Estrogen and its receptors (ERs) influence many biological processes in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancies, ERb usually is a tumor suppressor and ERa is an oncogene. ERb regulates genes in several key pathways including tumor suppression (p53, PTEN); metabolism (PI3K); survival (Akt); proliferation pathways (p45 Skp2 , cMyc, and cyclin E);cell-cycle arresting factors (p21 WAF1

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Estrogen receptor ␤ (ER␤) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ER␣ is not detectable in the adult lung. Lungs of adult female ER␤ knockout (ER␤ ؊/؊ ) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are large areas of unexpanded alveoli in lungs of both male and female ER␤ ؊/؊ mice. There is increased staining for collagen and, by EM, abnormal clusters of collagen fibers are seen in the alveolar septa of ER␤ ؊/؊ mice. Immunohistochemical analysis and Western blotting with lung membrane fractions of ER␤ ؊/؊ mice revealed down-regulation of caveolin-1, increased expression of membrane type-1 metalloproteinase, matrix metalloproteinase 2 (active form), and tissue inhibitors of metalloproteinases 2. Hypoxia, measured by immunohistochemical analysis for hypoxia-inducible factor 1␣ and chemical adducts (with Hypoxyprobe), was evident in the heart, ventral prostate, periovarian sac, kidney, liver, and brain of ER␤ ؊/؊ mice under resting conditions. Furthermore, both male and female adult ER␤ ؊/؊ mice were reluctant to run on a treadmill and tissue hypoxia became very pronounced after exercise. We conclude that ER␤ is necessary for the maintenance of the extracellular matrix composition in the lung and loss of ER␤ leads to abnormal lung structure and systemic hypoxia. Systemic hypoxia may be responsible for the reported left and right heart ventricular hypertrophy and systemic hypertension in ER␤ ؊/؊ mice. extracellular matrix ͉ caveolin ͉ metalloproteinase ͉ hypertension ͉ lung fibrosis T he importance of estrogens in development, physiology, and pathology of the lung has been known for some time. Estrogen hastens the onset of surfactant production and influences alveolar size and number. In fact, there is sexual dimorphism in late gestational and postnatal maturation of the lung in mammals (1, 2). The lack of detectable estrogen receptor ␣ (ER␣) in the lung led to the belief that effects of estrogen on the lung were indirect. It was not until the discovery of ER␤ in 1995 (3) that it became clear that estrogen, acting through ER␤, has direct actions on the lung. ER␤ knockout (ER␤ Ϫ/Ϫ ) mice (4) are characterized by right and left ventricle hypertrophy (5), systemic hypertension (6), ovarian dysfunction (7), and incompletely differentiated epithelium in ventral prostate (8), mammary gland (9), and colon (10). Compared with their WT littermates, female ER␤ Ϫ/Ϫ mice are reported to have fewer alveoli (11), reduced lung volume at a transpulmonary pressure of 20 cm of H 2 O and reduced elastic recoil (12). Massaro et al. (12) attributed the lung phenotype to some defect of the extracellular matrix (ECM) composition. ECM is essential for normal tissue development, homeostasis, and wound repair. Physiologically, there is a balance between matrix protein accumulation and degradation. The ECM is composed of collagenous and noncollagenous proteins in which turnover is predominantl...