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Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis Via Central Activation of Protein Phosphatase 2A

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Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis Via Central Activation of Protein Phosphatase 2A 1524 Diabetes Volume 67, August 2018 Membrane-Initiated Estrogen Receptor Signaling Mediates Metabolic Homeostasis via Central Activation of Protein Phosphatase 2A Kazutaka Ueda,1,2 Eiki Takimoto,2 Qing Lu,1 Pangyen Liu,2 Nobuaki Fukuma,2 Yusuke Adachi,2 Ryo Suzuki,3 Shengpu Chou,3 Wendy Baur,1 Mark J. Aronovitz,1 Andrew S. Greenberg,4 Issei Komuro,2 and Richard H. Karas1 Diabetes 2018;67:1524–1537 | https://doi.org/10.2337/db17-1342 Women gain weight and their diabetes risk increases as estrogen withdrawal (3–6). Ovariectomized rodents con- they transition through menopause; these changes can sistently exhibit increased body weight and glucose in- be partly reversed by hormone therapy. However, the un- tolerance, which are reversed with estrogen treatment derlying molecular mechanisms mediating these effects are (7,8). However, estrogen replacement as a clinical ap- unknown. A novel knock-in mouse line with the selective proach is limited owing to its gynecological and tumor- blockade of the membrane-initiated estrogen receptor promoting actions revealed by randomized controlled (ER) pathway was used, and we found that the lack trials (9). Altogether, these findings underscore the com- of this pathway precipitated excessive weight gain and plexity of estrogen’s physiological functions, highlight its glucose intolerance independent of food intake and that ability to exert both harmful and beneficial effects, and this was accompanied by impaired adaptive thermogen- strongly support the need for better understanding of esis and reduced physical activity. Notably, the central ac- ’ tivation of protein phosphatase (PP) 2A improved metabolic molecular mechanisms underlying estrogen s effects on metabolism. OBESITY STUDIES disorders induced by the lack of membrane-initiated ER fi signaling. Furthermore, the antiobesity effect of estrogen Studies using genetically modi ed mice provide valu- replacement in a murine menopause model was abol- able mechanistic insights. Transgenic mice with inacti- ished by central PP2A inactivation. These findings define vated aromatase enzyme that is essential for estrogen a critical role for membrane-initiated ER signaling in synthesis exhibit increased adiposity and insulin levels metabolic homeostasis via the central action of PP2A. (10). Complete ablation of the estrogen receptor (ER) isoform ERa in mice results in metabolic syndrome-like phenotypes, including increased body weight, adiposity, Obesity is strongly associated with the development of altered glucose homeostasis, decreased energy expendi- metabolic disorders, including type 2 diabetes, dyslipide- ture, hyperinsulinemia, and hyperleptinemia (11,12). mia, and hypertension, as well as an increased risk of Meanwhile, contribution of the ER isoform ERb to met- cardiovascular diseases (1). Increased prevalence of obesity abolic homeostasis is still debatable (13–15). and associated metabolic disorders in postmenopausal ERs are ligand-activated transcription factors that, women suggests that the female steroid hormone estrogen upon binding to specific ligands, form dimers to interact mediates metabolic homeostasis (2). Observational studies with canonical ER response elements (EREs) in the pro- have shown that certain metabolic conditions, such as motor regions of estrogen-regulated genes. This canoni- obesity and insulin resistance, are strongly related to cal ER pathway is involved in several estrogen-mediated 1Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA Received 8 November 2017 and accepted 5 May 2018. 2 Department of Cardiovascular Medicine, Graduate School of Medicine, The This article contains Supplementary Data online at http://diabetes University of Tokyo, Tokyo, Japan .diabetesjournals.org/lookup/suppl/doi:10.2337/db17-1342/-/DC1. 3Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, © 2018 by the American Diabetes Association. Readers may use this article as The University of Tokyo, Tokyo, Japan long as the work is properly cited, the use is educational and not for profit, and the 4Obesity and Metabolism Laboratory, U.S. Department of Agriculture Human work is not altered. More information is available at http://www.diabetesjournals Nutrition Research Center on Aging at Tufts University, Boston, MA .org/content/license. Corresponding author: Issei Komuro, [email protected], or Richard H. Karas, [email protected]. diabetes.diabetesjournals.org Ueda and Associates 1525 adverse effects such as tumorigenesis. In contrast, nonca- ERa gene was expressed under the control of the endog- nonical pathways involve ER interplay with other transcrip- enous ERa promoter. Mutant mouse strains were gener- tional mediators that operate in non-ERE regions. Moreover, ated using C57BL/6 embryonic stem cells. Specifically, ERs localized to caveolae, cell membrane microdomains, embryonic stem cells containing the mutated ERa allele can signal without nuclear translocation, which is referred were injected into C57BL/6 blastocytes, and pups were to as the rapid nonnuclear ER pathway (16). To determine genotyped using PCR with primers as follows: forward, 59- which of these multiple ER-mediated signaling pathways ACATGAGAAATCCCATAAAACTCAGACCAAAC-39;reverse, specifically mediates these effects, we tested the hypothesis 59-AAAGCCTCTCCCCATCACATGACCT-39.Expectedsizes that membrane-initiated ERa signaling plays an important of the PCR products in the mutant allele were 246 base role in the biological regulation of metabolic homeostasis. pairs for WT and 344 base pairs for KRRki/ki mice, and WT We have previously reported that the nonnuclear ER littermates were used as controls. pathway activation by estrogen requires ER binding to the scaffolding protein striatin, which is disrupted by a peptide Glucose and Insulin Tolerance Tests derived from amino acids 176–253 of ERa,resultingin Mice were fasted for 16 h and 2 h before intraperitoneal (i.p.) nonnuclear signaling pathway inhibition while sparing the injections of 1 g/kg glucose and 0.5 units/kg insulin, respec- classic genomic signaling pathway (17,18). Moreover, to tively. Blood samples were collected from the tail veins at distinguish the unique role of nonnuclear ERa signaling indicated time points after glucose or insulin administration, from those of other signaling pathways, we recently eluci- and blood glucose levels were measured using a blood glucose dated specificERa domains critical for binding with striatin monitoring system (OneTouch Ultra; Johnson & Johnson). and determined that mutations of amino acids 231, 233, and Measurement of Food Intake and Body Temperature 234 of ERa from KRR to AAA (KRR mutant ERa)disrupted Food intake was measured daily at specified ages, and ERa-striatin binding and blocked rapid nonnuclear ERa average daily food intake was calculated using data from at signaling with no effect on genomic ERa signaling (19). least 5 consecutive days. For body temperature measure- 2 2 In the current study, we established the novel KRR ment, WT, ERa / , and KRRki/ki mice were housed in- knock-in (KRRKI) mouse line, in which endogenous ERa was ki/ki dividually. Mice had free access to water, but food was replaced by KRR mutant ERa in homozygous (KRR )mice, restricted to avoid the influence of diet-induced thermo- leading to exclusive disruption of the membrane-initiated genesis. Core body temperature was measured using a rec- ERa signaling in the presence of an intact ERE-mediated tal temperature probe. Before cold exposure, mice were genomic ERa signaling pathway. Using this mouse line, we housed individually at ambient temperature (22°C) for at tested the role of membrane-initiated ERa signaling in least 1 h, and basal body temperature was recorded. Mice metabolic homeostasis and its molecular mechanisms. were then transferred to a cold room (4°C), and body temperature was recorded every hour for a total of 4 h. RESEARCH DESIGN AND METHODS Physiological Analyses Animals Adiposity in mice was examined using computed tomog- The Tufts Medical Center Institutional Animal Care and Use raphy (CT) (LaTheta; ALOKA) according to the manufac- Committee and the University of Tokyo Ethics Committee for turer’s protocol. Scanning was performed at 1-mm intervals Animal Experiments approved all animal procedures. In the from the diaphragm to the floor of the abdominal cavity. current study, C57BL/6 female mice were used unless other- VO2 and locomotor activity were measured using an O2/CO2 wise indicated. Mice were fed a normal chow diet (4.4% fat, 3.4 metabolic measurement system (MK-5000; Muromachi), as kcal/g) or a high-fat diet (32% fat, 5.1 kcal/g; CLEA Japan, 2/2 previously described (21), and VO2 was normalized to body Tokyo, Japan). ERa mice were provided by P. Chambon weight. (University of Strasbourg Institute for Advanced Study, Strasbourg, France). Heterozygous males and females were Central and Peripheral Administration of Chemicals bred to produce wild-type (WT) (ERa+/+) and homozygous null Intracerebroventricular injection was performed as pre- 2 2 ERa / offspring. Mice were genotyped by PCR as previously viously described (22). Briefly, mice were anesthetized described (20). Littermate WT mice were used as controls. with isoflurane, a small incision was made in the scalp, and All experiments were performed on mice at 12 weeks of an injection was achieved at a point 1 mm lateral and 1 mm age unless otherwise indicated. caudal to bregma, at a depth of 2 mm. The volume for all The KRRki/ki mouse model was generated by GenOway. intracerebroventricular
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