Effects of ERβ and ERα on OVX-induced changes in adiposity and insulin resistance

in Journal of Endocrinology
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  • 1 Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, USA
  • 2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri, USA
  • 3 Department of Biomedical Sciences, Diabetes and Obesity Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
  • 4 Department of Exercise and Health Science, Incheon National University, Incheon, South Korea
  • 5 College of Nursing and Health Professions, Drexel University, Philadelphia, Pennsylvania, USA
  • 6 Department of Biochemistry, University of Missouri, Columbia, Missouri, USA

Correspondence should be addressed to V J Vieira-Potter: vieirapotterv@missouri.edu
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Loss of ovarian hormones leads to increased adiposity and insulin resistance (IR), increasing the risk for cardiovascular and metabolic diseases. The purpose of this study was to investigate whether the molecular mechanism behind the adverse systemic and adipose tissue-specific metabolic effects of ovariectomy requires loss of signaling through estrogen receptor alpha (ERα) or estrogen receptor β (ERβ). We examined ovariectomized (OVX) and ovary-intactwild-type (WT), ERα-null (αKO), and ERβ-null (βKO) female mice (age ~49 weeks; n = 7–12/group). All mice were fed a phytoestrogen-free diet (<15 mg/kg) and either remained ovary-intact (INT) or were OVX and followed for 12 weeks. Body composition, energy expenditure, glucose tolerance, and adipose tissue gene and protein expression were analyzed. INT αKO were ~25% fatter with reduced energy expenditure compared to age-matched INT WT controls and βKO mice (all P < 0.001). Following OVX, αKO mice did not increase adiposity or experience a further increase in IR, unlike WT and βKO, suggesting that loss of signaling through ERα mediates OVX-induced metabolic dysfunction. In fact, OVX in αKO mice (i.e., signaling through ERβ in the absence of ERα) resulted in reduced adiposity, adipocyte size, and IR (P < 0.05 for all). βKO mice responded adversely to OVX in terms of increased adiposity and development of IR. Together, these findings challenge the paradigm that ERα mediates metabolic protection over ERβ in all settings. These findings lead us to suggest that, following ovarian hormone loss, ERβ may mediate protective metabolic benefits.

 

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  • Barros RP & Gustafsson 2011 Estrogen receptors and the metabolic network. Cell Metabolism 14 289299. (https://doi.org/10.1016/j.cmet.2011.08.005)

    • Search Google Scholar
    • Export Citation
  • Bluher M 2009 Adipose tissue dysfunction in obesity. Experimental and Clinical Endocrinology and Diabetes 117 241250. (https://doi.org/10.1055/s-0029-1192044)

    • Search Google Scholar
    • Export Citation
  • Bluher M 2013 Adipose tissue dysfunction contributes to obesity related metabolic diseases. Best Practice and Research: Clinical Endocrinology and Metabolism 27 163177. (https://doi.org/10.1016/j.beem.2013.02.005)

    • Search Google Scholar
    • Export Citation
  • Bryzgalova G, Gao H, Ahren B, Zierath JR, Galuska D, Steiler TL, Dahlman-Wright K, Nilsson S, Gustafsson JA, Efendic S, 2006 Evidence that oestrogen receptor-alpha plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia 49 588597. (https://doi.org/10.1007/s00125-005-0105-3)

    • Search Google Scholar
    • Export Citation
  • Campello RS, Fatima LA, Barreto-Andrade JN, Lucas TF, Mori RC, Porto CS & Machado UF 2017 Estradiol-induced regulation of GLUT4 in 3T3-L1 cells: involvement of ESR1 and AKT activation. Journal of Molecular Endocrinology 59 257268. (https://doi.org/10.1530/JME-17-0041)

    • Search Google Scholar
    • Export Citation
  • Clookey SL, Welly RJ, Zidon TM, Gastecki ML, Woodford ML, Grunewald ZI, Winn NC, Eaton D, Karasseva NG, Sacks HS, 2018 Increased susceptibility to OVX-associated metabolic dysfunction in UCP1-null mice. Journal of Endocrinology 239 107–120. (https://doi.org/10.1530/JOE-18-0139)

    • Search Google Scholar
    • Export Citation
  • Clookey SL, Welly RJ, Shay D, Woodford ML, Fritsche KL, Rector RS, Padilla J, Lubahn DB & Vieira-Potter VJ 2019 Beta 3 adrenergic receptor activation rescues metabolic dysfunction in female estrogen receptor alpha-null mice. Frontiers in Physiology 10 9. (https://doi.org/10.3389/fphys.2019.00009)

    • Search Google Scholar
    • Export Citation
  • Davis KE, D Neinast M, Sun K, M Skiles W, D Bills J, A Zehr J, Zeve D, D Hahner L, W Cox D, M Gent L, 2013 The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Molecular Metabolism 2 227242. (https://doi.org/10.1016/j.molmet.2013.05.006)

    • Search Google Scholar
    • Export Citation
  • Drew BG, Hamidi H, Zhou Z, Villanueva CJ, Krum SA, Calkin AC, Parks BW, Ribas V, Kalajian NY, Phun J, 2015 Estrogen receptor (ER)alpha-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression. Journal of Biological Chemistry 290 55665581. (https://doi.org/10.1074/jbc.M114.606459)

    • Search Google Scholar
    • Export Citation
  • Foryst-Ludwig A, Clemenz M, Hohmann S, Hartge M, Sprang C, Frost N, Krikov M, Bhanot S, Barros R, Morani A, 2008 Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genetics 4 e1000108. (https://doi.org/10.1371/journal.pgen.1000108)

    • Search Google Scholar
    • Export Citation
  • Gao H & Dahlman-Wright K 2013 Implications of estrogen receptor alpha and estrogen receptor beta for adipose tissue functions and cardiometabolic complications. Hormone Molecular Biology and Clinical Investigation 15 8190. (https://doi.org/10.1515/hmbci-2013-0021)

    • Search Google Scholar
    • Export Citation
  • Gonzalez-Granillo M, Savva C, Li X, Fitch M, Pedrelli M, Hellerstein M, Parini P, Korach-Andre M & Gustafsson 2019 ERbeta activation in obesity improves whole body metabolism via adipose tissue function and enhanced mitochondria biogenesis. Molecular and Cellular Endocrinology 479 147158. (https://doi.org/10.1016/j.mce.2018.10.007)

    • Search Google Scholar
    • Export Citation
  • Gorres BK, Bomhoff GL, Morris JK & Geiger PC 2011 In vivo stimulation of oestrogen receptor alpha increases insulin-stimulated skeletal muscle glucose uptake. Journal of Physiology 589 20412054. (https://doi.org/10.1113/jphysiol.2010.199018)

    • Search Google Scholar
    • Export Citation
  • Guillaume M, Handgraaf S, Fabre A, Raymond-Letron I, Riant E, Montagner A, Vinel A, Buscato M, Smirnova N, Fontaine C, 2017 Selective activation of estrogen receptor alpha activation function-1 is sufficient to prevent obesity, steatosis, and insulin resistance in mouse. American Journal of Pathology 187 12731287. (https://doi.org/10.1016/j.ajpath.2017.02.013)

    • Search Google Scholar
    • Export Citation
  • Hamilton DJ, Minze LJ, Kumar T, Cao TN, Lyon CJ, Geiger PC, Hsueh WA & Gupte AA 2016 Estrogen receptor alpha activation enhances mitochondrial function and systemic metabolism in high-fat-fed ovariectomized mice. Physiological Reports 4 e12913. (https://doi.org/10.14814/phy2.12913)

    • Search Google Scholar
    • Export Citation
  • Heine PA, Taylor JA, Iwamoto GA, Lubahn DB & Cooke PS 2000 Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. PNAS 97 1272912734. (https://doi.org/10.1073/pnas.97.23.12729)

    • Search Google Scholar
    • Export Citation
  • Islander U, Erlandsson MC, Hasseus B, Jonsson CA, Ohlsson C, Gustafsson JA, Dahlgren U & Carlsten H 2003 Influence of oestrogen receptor alpha and beta on the immune system in aged female mice. Immunology 110 149157. (https://doi.org/10.1046/j.1365-2567.2003.01704.x)

    • Search Google Scholar
    • Export Citation
  • Iyengar NM, Hudis CA & Dannenberg AJ 2013 Obesity and inflammation: new insights into breast cancer development and progression. American Society of Clinical Oncology Educational Book 33 4651. (https://doi.org/10.14694/EdBook_AM.2013.33.46)

    • Search Google Scholar
    • Export Citation
  • Justenhoven C, Obazee O & Brauch H 2012 The pharmacogenomics of sex hormone metabolism: breast cancer risk in menopausal hormone therapy. Pharmacogenomics 13 659675. (https://doi.org/10.2217/pgs.11.144)

    • Search Google Scholar
    • Export Citation
  • Kern PA, Di Gregorio GB, Lu T, Rassouli N & Ranganathan G 2003 Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-alpha expression. Diabetes 52 17791785. (https://doi.org/10.2337/diabetes.52.7.1779)

    • Search Google Scholar
    • Export Citation
  • Lin KH, Kuo WW, Shibu MA, Day CH, Hsieh YL, Chung LC, Chen RJ, Wen SY, Viswanadha VP & Huang CY 2017 E2/ER beta enhances calcineurin protein degradation and PI3K/Akt/MDM2 signal transduction to inhibit ISO-Induced myocardial cell apoptosis. International Journal of Molecular Sciences 18 892. (https://doi.org/10.3390/ijms18040892)

    • Search Google Scholar
    • Export Citation
  • Lizcano F & Guzman G 2014 Estrogen deficiency and the origin of obesity during menopause. BioMed Research International 2014 757461. (https://doi.org/10.1155/2014/757461)

    • Search Google Scholar
    • Export Citation
  • Lovejoy JC, Champagne CM, de Jonge L, Xie H & Smith SR 2008 Increased visceral fat and decreased energy expenditure during the menopausal transition. International Journal of Obesity 32 949958. (https://doi.org/10.1038/ijo.2008.25)

    • Search Google Scholar
    • Export Citation
  • Lubahn DB, Moyer JS, Golding TS, Couse JF, Korach KS & Smithies O 1993 Alteration of reproductive function but not prenatal sexual development after insertional disruption of the mouse estrogen receptor gene. PNAS 90 1116211166. (https://doi.org/10.1073/pnas.90.23.11162)

    • Search Google Scholar
    • Export Citation
  • Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF & Turner RC 1985 Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28 412419. (https://doi.org/10.1007/bf00280883)

    • Search Google Scholar
    • Export Citation
  • Miao YF, Su W, Dai YB, Wu WF, Huang B, Barros RP, Nguyen H, Maneix L, Guan YF, Warner M, 2016 An ERbeta agonist induces browning of subcutaneous abdominal fat pad in obese female mice. Scientific Reports 6 38579. (https://doi.org/10.1038/srep38579)

    • Search Google Scholar
    • Export Citation
  • Monteiro R, Teixeira D & Calhau C 2014 Estrogen signaling in metabolic inflammation. Mediators of Inflammation 2014 615917. (https://doi.org/10.1155/2014/615917)

    • Search Google Scholar
    • Export Citation
  • Moreno M, Ordonez P, Alonso A, Diaz F, Tolivia J & Gonzalez C 2010 Chronic 17beta-estradiol treatment improves skeletal muscle insulin signaling pathway components in insulin resistance associated with aging. Age 32 113. (https://doi.org/10.1007/s11357-009-9095-2)

    • Search Google Scholar
    • Export Citation
  • Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ, Clegg DJ, Kaplitt MG & Ogawa S 2007 Silencing of estrogen receptor alpha in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. PNAS 104 25012506. (https://doi.org/10.1073/pnas.0610787104)

    • Search Google Scholar
    • Export Citation
  • Naaz A, Zakroczymski M, Heine P, Taylor J, Saunders P, Lubahn D & Cooke PS 2002 Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor alpha (ERalpha): a potential role for estrogen receptor beta (ERbeta). Hormone and Metabolic Research 34 758763. (https://doi.org/10.1055/s-2002-38259)

    • Search Google Scholar
    • Export Citation
  • Nelson HD, Walker M, Zakher B & Mitchell J 2012 Menopausal hormone therapy for the primary prevention of chronic conditions: a systematic review to update the U.S. Preventive Services Task Force recommendations. Annals of Internal Medicine 157 104113. (https://doi.org/10.7326/0003-4819-157-2-201207170-00466)

    • Search Google Scholar
    • Export Citation
  • Nilsson S, Makela S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M & Gustafsson JA 2001 Mechanisms of estrogen action. Physiological Reviews 81 15351565. (https://doi.org/10.1152/physrev.2001.81.4.1535)

    • Search Google Scholar
    • Export Citation
  • Nilsson M, Dahlman I, Jiao H, Gustafsson JA, Arner P & Dahlman-Wright K 2007a Impact of estrogen receptor gene polymorphisms and mRNA levels on obesity and lipolysis--a cohort study. BMC Medical Genetics 8 73. (https://doi.org/10.1186/1471-2350-8-73)

    • Search Google Scholar
    • Export Citation
  • Nilsson M, Dahlman I, Ryden M, Nordstrom EA, Gustafsson JA, Arner P & Dahlman-Wright K 2007b Oestrogen receptor alpha gene expression levels are reduced in obese compared to normal weight females. International Journal of Obesity 31 900907. (https://doi.org/10.1038/sj.ijo.0803528)

    • Search Google Scholar
    • Export Citation
  • Ogawa S, Chan J, Gustafsson JA, Korach KS & Pfaff DW 2003 Estrogen increases locomotor activity in mice through estrogen receptor alpha: specificity for the type of activity. Endocrinology 144 230239. (https://doi.org/10.1210/en.2002-220519)

    • Search Google Scholar
    • Export Citation
  • Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B & Gustafsson JA 2000 Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice. Biochemical and Biophysical Research Communications 278 640645. (https://doi.org/10.1006/bbrc.2000.3827)

    • Search Google Scholar
    • Export Citation
  • Padilla J, Jenkins NT, Vieira-Potter VJ & Laughlin MH 2013 Divergent phenotype of rat thoracic and abdominal perivascular adipose tissues. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 304 R543R552. (https://doi.org/10.1152/ajpregu.00567.2012)

    • Search Google Scholar
    • Export Citation
  • Park YM, Pereira RI, Erickson CB, Swibas TA, Cox-York KA & Van Pelt RE 2017 Estradiol-mediated improvements in adipose tissue insulin sensitivity are related to the balance of adipose tissue estrogen receptor alpha and beta in postmenopausal women. PLoS ONE 12 e0176446. (https://doi.org/10.1371/journal.pone.0176446)

    • Search Google Scholar
    • Export Citation
  • Ponnusamy S, Tran QT, Harvey I, Smallwood HS, Thiyagarajan T, Banerjee S, Johnson DL, Dalton JT, Sullivan RD, Miller DD, 2017a Pharmacologic activation of estrogen receptor beta increases mitochondrial function, energy expenditure, and brown adipose tissue. FASEB Journal 31 266281. (https://doi.org/10.1096/fj.201600787RR)

    • Search Google Scholar
    • Export Citation
  • Ponnusamy S, Tran QT, Thiyagarajan T, Miller DD, Bridges D & Narayanan R 2017b An estrogen receptor beta-selective agonist inhibits non-alcoholic steatohepatitis in preclinical models by regulating bile acid and xenobiotic receptors. Experimental Biology and Medicine 242 606616. (https://doi.org/10.1177/1535370216688569)

    • Search Google Scholar
    • Export Citation
  • Qiu S, Vazquez JT, Boulger E, Liu H, Xue P, Hussain MA & Wolfe A 2017 Hepatic estrogen receptor alpha is critical for regulation of gluconeogenesis and lipid metabolism in males. Scientific Reports 7 1661. (https://doi.org/10.1038/s41598-017-01937-4)

    • Search Google Scholar
    • Export Citation
  • Razmjou S, Bastard JP, Doucet E, Rabasa-Lhoret R, Fellahi S, Lavoie JM & Prud’homme D 2016 Effect of the menopausal transition and physical activity energy expenditure on inflammatory markers: a MONET group study. Menopause 23 13301338. (https://doi.org/10.1097/GME.0000000000000716)

    • Search Google Scholar
    • Export Citation
  • Rector RS, Thyfault JP, Morris RT, Laye MJ, Borengasser SJ, Booth FW & Ibdah JA 2008 Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. American Journal of Physiology: Gastrointestinal and Liver Physiology 294 G619G626. (https://doi.org/10.1152/ajpgi.00428.2007)

    • Search Google Scholar
    • Export Citation
  • Ribas V, Nguyen MT, Henstridge DC, Nguyen AK, Beaven SW, Watt MJ & Hevener AL 2010 Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERalpha-deficient mice. American Journal of Physiology: Endocrinology and Metabolism 298 E304E319. (https://doi.org/10.1152/ajpendo.00504.2009)

    • Search Google Scholar
    • Export Citation
  • Ryan AS, Nicklas BJ & Berman DM 2002 Hormone replacement therapy, insulin sensitivity, and abdominal obesity in postmenopausal women. Diabetes Care 25 127133. (https://doi.org/10.2337/diacare.25.1.127)

    • Search Google Scholar
    • Export Citation
  • Sasayama D, Sugiyama N, Yonekubo S, Pawlak A, Murasawa H, Nakamura M, Hayashi M, Ogawa T, Moro M, Washizuka S, 2017 Novel oestrogen receptor beta-selective ligand reduces obesity and depressive-like behaviour in ovariectomized mice. Scientific Reports 7 4663. (https://doi.org/10.1038/s41598-017-04946-5)

    • Search Google Scholar
    • Export Citation
  • Seidlova-Wuttke D, Nguyen BT & Wuttke W 2012 Long-term effects of ovariectomy on osteoporosis and obesity in estrogen-receptor-beta-deleted mice. Comparative Medicine 62 813.

    • Search Google Scholar
    • Export Citation
  • Shin JH, Hur JY, Seo HS, Jeong YA, Lee JK, Oh MJ, Kim T, Saw HS & Kim SH 2007 The ratio of estrogen receptor alpha to estrogen receptor beta in adipose tissue is associated with leptin production and obesity. Steroids 72 592599. (https://doi.org/10.1016/j.steroids.2007.03.013)

    • Search Google Scholar
    • Export Citation
  • Sondergaard E, Espinosa De Ycaza AE, Morgan-Bathke M & Jensen MD 2017 How to measure adipose tissue insulin sensitivity? Journal of Clinical Endocrinology and Metabolism 102 11931199. (https://doi.org/10.1210/jc.2017-00047)

    • Search Google Scholar
    • Export Citation
  • Sood R, Faubion SS, Kuhle CL, Thielen JM & Shuster LT 2014 Prescribing menopausal hormone therapy: an evidence-based approach. International Journal of Women’s Health 6 4757. (https://doi.org/10.2147/IJWH.S38342)

    • Search Google Scholar
    • Export Citation
  • Stefanska A, Bergmann K & Sypniewska G 2015 Metabolic syndrome and menopause: pathophysiology, clinical and diagnostic significance. Advances in Clinical Chemistry 72 175. (https://doi.org/10.1016/bs.acc.2015.07.001)

    • Search Google Scholar
    • Export Citation
  • Stubbins RE, Holcomb VB, Hong J & Nunez NP 2012a Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. European Journal of Nutrition 51 861870. (https://doi.org/10.1007/s00394-011-0266-4)

    • Search Google Scholar
    • Export Citation
  • Stubbins RE, Najjar K, Holcomb VB, Hong J & Nunez NP 2012b Oestrogen alters adipocyte biology and protects female mice from adipocyte inflammation and insulin resistance. Diabetes, Obesity and Metabolism 14 5866. (https://doi.org/10.1111/j.1463-1326.2011.01488.x)

    • Search Google Scholar
    • Export Citation
  • Thyfault JP, Rector RS, Uptergrove GM, Borengasser SJ, Morris EM, Wei Y, Laye MJ, Burant CF, Qi NR, Ridenhour SE, 2009 Rats selectively bred for low aerobic capacity have reduced hepatic mitochondrial oxidative capacity and susceptibility to hepatic steatosis and injury. Journal of Physiology 587 18051816. (https://doi.org/10.1113/jphysiol.2009.169060)

    • Search Google Scholar
    • Export Citation
  • Tomicek NJ, Lancaster TS & Korzick DH 2011 Increased estrogen receptor beta in adipose tissue is associated with increased intracellular and reduced circulating adiponectin protein levels in aged female rats. Gender Medicine 8 325333. (https://doi.org/10.1016/j.genm.2011.05.010)

    • Search Google Scholar
    • Export Citation
  • Velickovic K, Cvoro A, Srdic B, Stokic E, Markelic M, Golic I, Otasevic V, Stancic A, Jankovic A, Vucetic M, 2014 Expression and subcellular localization of estrogen receptors alpha and beta in human fetal brown adipose tissue. Journal of Clinical Endocrinology and Metabolism 99 151159. (https://doi.org/10.1210/jc.2013-2017)

    • Search Google Scholar
    • Export Citation
  • Vieira Potter VJ, Strissel KJ, Xie C, Chang E, Bennett G, Defuria J, Obin MS & Greenberg AS 2012 Adipose tissue inflammation and reduced insulin sensitivity in ovariectomized mice occurs in the absence of increased adiposity. Endocrinology 153 42664277. (https://doi.org/10.1210/en.2011-2006)

    • Search Google Scholar
    • Export Citation
  • Vieira-Potter VJ, Padilla J, Park YM, Welly RJ, Scroggins RJ, Britton SL, Koch LG, Jenkins NT, Crissey JM, Zidon T, 2015 Female rats selectively bred for high intrinsic aerobic fitness are protected from ovariectomy-associated metabolic dysfunction. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 308 R530R542. (https://doi.org/10.1152/ajpregu.00401.2014)

    • Search Google Scholar
    • Export Citation
  • Wainright KS, Fleming NJ, Rowles JL, Welly RJ, Zidon TM, Park YM, Gaines TL, Scroggins RJ, Anderson-Baucum EK, Hasty AH, 2015 Retention of sedentary obese visceral white adipose tissue phenotype with intermittent physical activity despite reduced adiposity. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 309 R594R602. (https://doi.org/10.1152/ajpregu.00042.2015)

    • Search Google Scholar
    • Export Citation
  • Wang X, Liu J, Long Z, Sun Q, Liu Y, Wang L, Zhang X & Hai C 2015 Effect of diosgenin on metabolic dysfunction: role of ERbeta in the regulation of PPARgamma. Toxicology and Applied Pharmacology 289 286296. (https://doi.org/10.1016/j.taap.2015.09.015)

    • Search Google Scholar
    • Export Citation
  • Winn NC, Jurrissen TJ, Grunewald ZI, Cunningham RP, Woodford ML, Kanaley JA, Lubahn DB, Manrique-Acevedo C, Rector RS, Vieira-Potter VJ, 2019 Estrogen receptor-alpha signaling maintains immunometabolic function in males and is obligatory for exercise-induced amelioration of nonalcoholic fatty liver. American Journal of Physiology: Endocrinology and Metabolism 316 E156E167. (https://doi.org/10.1152/ajpendo.00259.2018)

    • Search Google Scholar
    • Export Citation
  • Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG, Davis KE, Zhang X, Zou F, Gent LM, Hahner LD, 2011 Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metabolism 14 453465. (https://doi.org/10.1016/j.cmet.2011.08.009)

    • Search Google Scholar
    • Export Citation
  • Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nature Medicine 7 941946. (https://doi.org/10.1038/90984)

    • Search Google Scholar
    • Export Citation
  • Yan H, Yang W, Zhou F, Li X, Pan Q, Shen Z, Han G, Newell-Fugate A, Tian Y, Majeti R, 2019 Estrogen improves insulin sensitivity and suppresses gluconeogenesis via the transcription factor FoxO1. Diabetes 68 291304. (https://doi.org/10.2337/db18-0638)

    • Search Google Scholar
    • Export Citation