Importance of Extranuclear Estrogen Receptor- and Membrane G Protein-Coupled Estrogen Receptor in Pancreatic Islet Survival

Department of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University School of Medicine, Chicago, Illinois, USA.
Diabetes (Impact Factor: 8.1). 08/2009; 58(10):2292-302. DOI: 10.2337/db09-0257
Source: PubMed


We showed that 17beta-estradiol (E(2)) favors pancreatic beta-cell survival via the estrogen receptor-alpha (ERalpha) in mice. E(2) activates nuclear estrogen receptors via an estrogen response element (ERE). E(2) also activates nongenomic signals via an extranuclear form of ERalpha and the G protein-coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival.
We used mice and islets deficient in estrogen receptor-alpha (alphaERKO(-/-)), estrogen receptor-beta (betaERKO(-/-)), estrogen receptor-alpha and estrogen receptor-beta (alphabetaERKO(-/-)), and GPER (GPERKO(-/-)); a mouse lacking ERalpha binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes.
We show that ERalpha protection of islet survival is ERE independent and that E(2) favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERbeta plays a minor cytoprotective role compared to ERalpha. Accordingly, betaERKO(-/-) mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERalpha and ERbeta in mice does not synergize to provoke islet apoptosis. In alphabetaERKO(-/-) mice and their islets, E(2) partially prevents apoptosis suggesting that an alternative pathway compensates for ERalpha/ERbeta deficiency. We find that E(2) protection of islet survival is reproduced by a membrane-impermeant E(2) formulation and a selective GPER agonist. Accordingly, GPERKO(-/-) mice are susceptible to streptozotocin-induced insulin deficiency.
E(2) protects beta-cell survival through ERalpha and ERbeta via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in beta-cells and identifies GPER as a target to protect islet survival.

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    • "E2 acts through at least three estrogen receptor(ER)s in β-cells, ERα ER β and the G-protein coupled ER (GPER). These ERs are expressed in rodent and human β -cells in both sexes, where they exhibit a predominant extranuclear localization [3], [5]. The islet ERα is important for enhancing insulin biosynthesis in vivo via an extranuclear ERα-dependent mechanism that amplifies the effect of glucose in stimulating the insulin gene promoter [6], [7]. "
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    ABSTRACT: The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO(-/-)), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO(-/-) mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO(-/-) mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO(-/-) mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury.
    PLoS ONE 02/2014; 9(2):e87941. DOI:10.1371/journal.pone.0087941 · 3.23 Impact Factor
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    • "ERα has been proposed to play a significant role in the regulation of insulin synthesis by E2 but with no effects on pancreatic β-cell mass (10). Its role in cytoprotection has also been suggested (35). "
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    ABSTRACT: The estrogen receptor beta (ERβ) is emerging as an important player in the physiology of the endocrine pancreas. Here we have evaluated the role of the ERβ selective agonist, WAY200070, as an insulinotropic molecule and its antidiabetic actions. We have demonstrated that it enhances glucose-stimulated insulin secretion both in mouse and human islets. In vivo experiments showed that a single-administration of WAY 200070 leads to an increase in plasma insulin levels with a concomitant improved response to a glucose load. Two-week treatment administration increased glucose-induced insulin release, pancreatic β-cell mass and improved glucose and insulin sensitivity. In addition, streptozotocin-nicotinamide-induced diabetic mice treated with WAY200070 exhibited a significant improvement in plasma insulin levels and glucose tolerance as well as a regeneration of pancreatic β-cell mass. Studies performed in db/db mice demonstrated that this compound restored first-phase insulin secretion and enhanced pancreatic β-cell mass. We conclude that ERβ agonists should be considered as new targets for the treatment of diabetes.
    Diabetes 01/2013; 62(6). DOI:10.2337/db12-1562 · 8.10 Impact Factor
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    • "Louis, MO). The ERα-selective agonist propyl pyrazole triol (PPT) [40] [41] [42]; the PLC agonist m3M3FβS [43]; and the ERβ-selective agonist diarylpropionitrile (DPN) [40–42] were obtained from "
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    ABSTRACT: Both male and female rat growth plate chondrocytes express estrogen receptors (ERs); however 17β-estradiol (E(2)) induces membrane responses leading to activation of phospholipase A(2) (PLA(2)), phospholipase C (PLC), prostaglandin E(2) (PGE(2)) production, protein kinase C (PKC), and ultimately mitogen protein kinase (MAPK) only in female cells. This study investigated if these sex-specific responses are due to differences in the actual ERs or in downstream signaling. Western blots and flow cytometry of costochondral cartilage resting zone chondrocytes (RCs) showed 2-3 times more ERα in plasma membranes (PMs) from female cells than male cells. Tunicamycin blocked E(2)-dependent ER-translocation to the PM, indicating palmitoylation was required. Co-immunoprecipitation showed E(2) induced complex formation between ER isoforms only in female RCs. To examine if the lack of response on PKC and PGE(2) in males is due to differences in signaling, we examined involvement of ERs and the role of PLC and PLA(2). Selective ERα (propylpyrazole triol, PPT) and ERβ (diarylproprionitrile, DPN) agonists activated PKC in female RCs only. The PLC inhibitor, U73122 blocked E(2)'s effect on PKC and the cytosolic PLA(2) inhibitor, AACOCF3 inhibited the effect on PGE(2) in female RCs, confirming involvement of PLC and PLA(2) in the mechanism. The PLC activator, m-3M3FβS activated PKC and PLAA peptide increased PGE(2) levels in male and female RCs, showing the signaling pathways are present. These data indicate that differences in membrane ER amount, localization, translocation and interaction are responsible for the sexual dimorphic response to E(2).
    Biochimica et Biophysica Acta 01/2013; 1833(5). DOI:10.1016/j.bbamcr.2012.12.022 · 4.66 Impact Factor
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