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Extranuclear Estrogen Receptor-Α Stimulates Neurod1 Binding to the Insulin Promoter and Favors Insulin Synthesis

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Extranuclear Estrogen Receptor-Α Stimulates Neurod1 Binding to the Insulin Promoter and Favors Insulin Synthesis Extranuclear estrogen receptor-α stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis Winifred P. S. Wonga, Joseph P. Tianoa, Suhuan Liua,b, Sylvia C. Hewittc, Cedric Le Maya, Stéphane Dalled, John A. Katzenellenbogene, Benita S. Katzenellenbogenf, Kenneth S. Korachc, and Franck Mauvais-Jarvisa,b,1 aDivision of Endocrinology, Metabolism and Molecular Medicine and bComprehensive Center on Obesity, Department of Medicine, Northwestern University School of Medicine, Chicago, IL 60611; cNational Institute of Environmental Health Sciences, Research Triangle Park, NC 27709; dInstitut National de la Santé et de la Recherche Médicale U661, Institut de Génomique Fonctionnelle, Montpellier 34094, France; and Departments of eChemistry and fMolecular and Integrative Physiology, University of Illinois, Urbana, IL 61801 Edited* by Donald F. Steiner, The University of Chicago, Chicago, IL, and approved June 3, 2010 (received for review December 16, 2009) Estrogen receptors (ERs) protect pancreatic islet survival in mice dress these issues, we generated a pancreas-specificERα knockout − − through rapid extranuclear actions. ERα also enhances insulin syn- mouse (PERαKO / ) using the Cre-loxP strategy and used a com- thesis in cultured islets. Whether ERα stimulates insulin synthesis in bination of genetic and pharmacologic tools in cultured islets and vivo and, if so, through which mechanism(s) remain largely un- MIN6 β cells. known. To address these issues, we generated a pancreas-specific ERα knockout mouse (PERαKO−/−) using the Cre-loxP strategy and Results used a combination of genetic and pharmacologic tools in cultured E2 Increases Insulin Synthesis Through ERα. To investigate the roles islets and β cells. Whereas 17β-estradiol (E2) treatment up-regulates of ERα,ERβ, and GPER in insulin synthesis, we treated cultured pancreatic insulin gene and protein content in control ERαlox/lox ERα-, ERβ-, and GPER-deficient islets with E2 and studied insulin − − mice, these E2 effects are abolished in PERαKO / mice. We find that gene transcription. Whereas E2 stimulated preproinsulin expression − − E2-activated ERα increases insulin synthesis by enhancing glucose by 3-fold in WT islets, this effect was abolished in αERKO / mice stimulation of the insulin promoter activity. Using a knock-in mouse A preproinsulin (Fig. 1 ). Conversely, E2 stimulated expression in MEDICAL SCIENCES − − − − with a mutated ERα eliminating binding to the estrogen response βERKO / and GPERKO / islets to a similar extent as that of WT elements (EREs), we show that E2 stimulation of insulin synthesis is islets (Fig. S1 A and B). To confirm the role of ERα in insulin syn- independent of the ERE. We find that the extranuclear ERα interacts thesis in vivo, we treated WT mice with E2 and the selective ERα with the tyrosine kinase Src, which activates extracellular signal- agonist propyl-pyrazole-triol (PPT) (15). These E2 and PPT treat- regulated kinases1/2, to increase nuclear localization and binding ments produced a 1.3-fold and 1.4-fold increase in pancreas to the insulin promoter of the transcription factor NeuroD1. This insulin concentration, respectively (Fig. 1B). Taken together, these study supports the importance of ERα in β cells as a regulator of findings confirm the importance of ERα in mediating E2-induced insulin synthesis in vivo. insulin synthesis. diabetes | islet Generation of PERαKO−/− Mice. To investigate whether ERα is in- volved in insulin synthesis through a direct effect on islets in vivo, we − − everal lines of evidence suggest that the female hormone 17β- generated PERαKO / mice using the Cre-loxP strategy. We Sestradiol (E2) improves insulin production. First, a sex di- confirmed recombination of the ERα gene in the pancreas and the morphism in diabetic syndromes associated with insulin defi- presence of normal ERα transcript in all other organs of the − − ciency has been reported (1). Second, during pregnancy, when PERαKO / mice (Fig. 1C). We observed the absence of ERα − − circulating E2 concentrations are elevated, an increase in insulin protein in PERαKO / compared with control ERαlox/lox islets, biosynthesis in isolated rat islets of Langerhans has been ob- confirming the efficiency of recombination (Fig. 1D). No significant served (2, 3). Third, during the estrous cycle in rats, insulin gene differences in fasting and fed blood glucose concentrations and i.p. − − expression has been found to positively correlate with serum E2 glucose tolerance were observed between PERαKO / and level (4). ERαlox/lox mice at age 8 wk (Fig. S2 A–D), 16 wk (Fig. 1 E–H), and In physiological conditions, short-term glucose stimulation of 24 wk (Fig. S2 E–H). Fasting and fed plasma insulin concentrations − − insulin biosynthesis is regulated predominantly through increased were also similar in the PERαKO / and ERαlox/lox mice (Fig. 1 I − − translation of preproinsulin mRNA (5, 6). During prolonged ex- and J). Female PERαKO / and ERαlox/lox mice had similar body posure to glucose, increased insulin gene transcription (7–9) and weight (Fig. 1K) and food intake (Fig. 1L) up to age 24 wk. increased preRNA splicing (10) also contribute to maintenance of insulin biosynthesis. ERα in Islets Stimulates Insulin Synthesis in Vivo. To determine E2 classically exerts its genomic effects by activating nuclear es- whether E2-induced insulin synthesis was mediated through ERα −/− trogen receptors (ERs) that bind to estrogen response elements in the islets in vivo, we treated ERαlox/lox and PERαKO mice (EREs) on the promoter of target genes or through a non-ERE tethering mechanism involving AP1 or SP1 sites (11). E2 also reg- ulates the activity of target genes through activation of extranuclear Author contributions: F.M.-J. designed research; W.P.S.W., J.P.T., S.L., C.L.M., and S.D. – performed research; S.C.H., J.A.K., B.S.K., and K.S.K. contributed new reagents/analytic ERs or the membrane-bound G protein coupled ER (GPER). ERs tools; W.P.S.W., J.P.T., C.L.M., S.D., and F.M.-J. analyzed data; and W.P.W. and F.M.-J. are present in the islet β cells (12–14), and we have previously shown wrote the paper. α β β that E2 acting through ER and GPER in cells favors cell sur- The authors declare no conflict of interest. vival in mice of both sexes (13, 14). Alonso-Magdalena et al. (12) *This Direct Submission article had a prearranged editor. recently reported that E2 also increases pancreatic insulin content 1To whom correspondence should be addressed. E-mail: f-mauvais-jarvis@northwestern. through ERα in cultured islets. Whether E2 stimulates insulin syn- edu. α β thesis in vivo through a direct effect on ER in cells and, if so, This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. through which mechanism(s) remain unknown, however. To ad- 1073/pnas.0914501107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0914501107 PNAS Early Edition | 1of6 Downloaded by guest on September 23, 2021 A B C * 889bp * 160 4 ERa t r a t i o n i o n * 140 359bp s e s r n 120 -actin 3 c e x p e n ) s u l i n c o r o i n s u l i n 100 g / m 2 g 80 n( n r e a s i p 60 p r e 1 40 pancreas liver brain spleen kidney heart e c vital P a n 20 889bp e R ERa 0 0 VE2 V E2 359bp WT ERKO-/- b-actin D ERa Insulin DAPI Merge l o x / l o x a lung skeletal uterus ovary hypo- WAT ER muscle thalamus - / - KO a PER G H 80 Fasting blood glucose(m g/dl) 150 E F Fed blood glucose(m g/dl) 16 weeks ) n 400 i 16000 d l * m 60 m g / d l ) / g 100 300 ER lox/lox 12000 m ( ( -/- PER KO l 40 s e s a o 200 b a 8000 d g l u c e 50 v 20 fi α o Fig. 1. Characterization of the pancreas-speci cER knockout 100 b 4000 o U C a −/− ol mice. (A) Relative preproinsulin expression in WT and αERKO B −8 0 A 0 0 0 – 0 20 40 60 80 100 120 islets (n =4 10) after treatment with E2 (10 M) for 48 h. (B) Time (min) Pancreatic insulin concentration in female WT mice treated with either E2 (4 μg/d) or PPT (100 g/d) for 7 d (n =6–7/group). (C) − − I J K L ERα mRNA expression in various tissues from PERαKO / female n g / m l ) 0.4 35 1.2 5 mice. (D) Coimmunolocalization of ERα and insulin in islets from )y Fed plas m ainsulin(ng/ml) − − 30 a α / α 1.0 d/g female PER KO and ER lox/lox mice. (E and F) Glucose tol- ( )g 4 0.3 ( Fasting plas m ainsulin ( 25 e erance (E) and corresponding (F) area under the curve (AUC) for k 0.8 th atni −/− gie 20 3 glucose in 16-wk-old female PERαKO and ERαlox/lox mice 0.2 0.6 o d y w 15 (n =6–12/group). (G–J) Fasting blood glucose (G), fed blood e f o B o d ER lox/lox 2 0.4 -/- 10 PER KO vi glucose (H), fasting plasma insulin concentration (I), and 0.1 t al − − 0.2 1 α / 5 u fed plasma insulin concentration (J) in female PER KO mice m u – 0.0 0.0 0 C 0 (n =6 20/group). (K and L) Body weight (K) and cumulative food − − 0 5 10 15 20 25 intake (L) in female PERαKO / and ERαlox/lox mice. V, vehicle.
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