The role of estrogens in control of energy balance and glucose homeostasis

Endocrine Reviews

Volumn 34, Issue 3, 2013, Pages 309-338

  Mauvais Jarvis, Franck ^a   Clegg, Deborah J ^b   Hevener, Andrea L ^c  

^a NORTHWESTERN UNIVERSITY   (United States)

^b UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANASTROZOLE; CONJUGATED ESTROGEN; ESTRADIOL; ESTROGEN; ESTROGEN RECEPTOR ALPHA; ESTROGEN RECEPTOR BETA; ESTROGEN SULFOTRANSFERASE; EXEMESTANE; GESTAGEN; GLUCOSE TRANSPORTER 4; GSK 232802A; INSULIN; LEPTIN; LETROZOLE; NEUROPEPTIDE Y; PLACEBO; PROGESTERONE; RALOXIFENE; SELECTIVE ESTROGEN RECEPTOR MODULATOR; TAMOXIFEN; UNCLASSIFIED DRUG;

ABDOMINAL SUBCUTANEOUS FAT; ADJUVANT THERAPY; ARCUATE NUCLEUS; BRAIN STEM; BREAST CANCER; CANCER RISK; DISEASE PREDISPOSITION; DRUG EFFECT; DRUG SAFETY; ENERGY BALANCE; ENERGY EXPENDITURE; ESTROGEN ACTIVITY; ESTROGEN DEFICIENCY; ESTROGEN THERAPY; FATTY ACID METABOLISM; FATTY LIVER; FOOD INTAKE; GLUCOSE HOMEOSTASIS; HORMONE RECEPTOR INTERACTION; HORMONE SUBSTITUTION; HUMAN; HYPOTHALAMUS; HYPOTHALAMUS VENTROMEDIAL NUCLEUS; IMMUNOCOMPETENT CELL; INFLAMMATION; INSULIN RELEASE; INSULIN SENSITIVITY; INTRAABDOMINAL FAT; LIPID STORAGE; LIVER; MACROPHAGE FUNCTION; MENOPAUSAL SYNDROME; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; PANCREAS ISLET BETA CELL; POSTMENOPAUSE OSTEOPOROSIS; PRIORITY JOURNAL; REGULATORY MECHANISM; REVIEW; SKELETAL MUSCLE; SUBCUTANEOUS FAT; SURVIVAL; TISSUE DISTRIBUTION; WHITE ADIPOSE TISSUE;

ANIMALS; ENERGY METABOLISM; ESTROGENS; GLUCOSE; GLUCOSE METABOLISM DISORDERS; HOMEOSTASIS; HUMANS; HYPOGLYCEMIC AGENTS; RECEPTORS, ESTROGEN; SELECTIVE ESTROGEN RECEPTOR MODULATORS; SIGNAL TRANSDUCTION;

EID: 84878632677     PISSN: 0163769X     EISSN: None     Source Type: Journal    
DOI: 10.1210/er.2012-1055     Document Type: Review

References (357)

1. Keating NL, Cleary PD, Rossi AS, Zaslavsky AM, Ayanian JZ. Use of hormone replacement therapy by postmenopausal women in the United States. Ann Intern Med. 1999; 130:545-553.
2. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens.NEngl J Med. 1975;293:1167-1170.
3. Smith DC, Prentice R, Thompson DJ, Herrmann WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med. 1975;293:1164-1167.
4. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288: 321-333.
5. Santen RJ, Allred DC, Ardoin SP, et al. Postmenopausal hormone therapy: an Endocrine Society scientific statement. J Clin Endocrinol Metab. 2010;95(7 suppl 1): s1-s66.
6. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab. 2003;88:2404-2411.
7. Mauvais-Jarvis F. Estrogen and androgen receptors: regulators of fuel homeostasis and emerging targets for diabetes and obesity. Trends Endocrinol Metab. 2011;22:24-33.
8. Simpson ER, Misso M, Hewitt KN, et al. Estrogen-the good, the bad, and the unexpected. Endocr Rev. 2005;26: 322-330.
9. Mauvais-Jarvis F. Estrogen sulfotransferase: intracrinology meets metabolic diseases. Diabetes. 2012;61:1353-1354.
10. Strott CA. Steroid sulfotransferases. Endocr Rev. 1996; 17:670-697.
11. O'Malley BW. Mechanisms of action of steroid hormones. N Engl J Med. 1971;284:370-377.
12. Nilsson S, Makela S, Treuter E, et al. Mechanisms of estrogen action. Physiol Rev. 2001;81:1535-1565.
13. Safe S, Kim K. Non-classical genomic estrogen receptor (ER)/specificity protein and ER/activating protein-1 signaling pathways. J Mol Endocrinol. 2008;41:263-275.
14. Paech K, Webb P, Kuiper GG, et al. Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science. 1997;277:1508-1510.
15. Powell E, Xu W. Intermolecular interactions identify ligand-selective activity of estrogen receptor α/β dimers. Proc Natl Acad Sci USA. 2008;105:19012-19017.
16. Charn TH, Liu ET, Chang EC, Lee YK, Katzenellenbogen JA, Katzenellenbogen BS. Genome-wide dynamics of chromatin binding of estrogen receptors α and β: mutual restriction and competitive site selection. Mol Endocrinol. 2010;24:47-59.
17. Shang Y,HuX, DiRenzo J, LazarMA,Brown M. Cofactor dynamics and sufficiency in estrogen receptor-regulated transcription. Cell. 2000;103:843-852.
18. Liu S, Mauvais-Jarvis F. Minireview: estrogenic protection of β-cell failure in metabolic diseases. Endocrinology. 2010;151:859-864.
19. Hammes SR, Levin ER. Extranuclear steroid receptors: nature and actions. Endocr Rev. 2007;28:726-741.
20. Tiano JP, Mauvais-Jarvis F. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes. Nat Rev Endocrinol. 2012;8:342-351.
21. van Londen GJ, Perera S, Vujevich K, et al. The impact of an aromatase inhibitor on body composition and gonadal hormone levels in women with breast cancer. Breast Cancer Res Treat. 2011;125:441-446.
22. Madak-Erdogan Z, Lupien M, Stossi F, Brown M, Katzenellenbogen BS. Genomic collaboration of estrogen receptor α and extracellular signal-regulated kinase 2 in regulating gene and proliferation programs. Mol Cell Biol. 2011;31:226-236.
23. Kang L, Zhang X, Xie Y, et al. Involvement of estrogen receptor variant ER-α36, not GPR30, in nongenomic estrogen signaling. Mol Endocrinol. 2010;24:709-721.
24. Laudet V. Evolution of the nuclear receptor superfamily: early diversification from an ancestral orphan receptor. J Mol Endocrinol. 1997;19:207-226.
25. Thornton JW, Need E, Crews D. Resurrecting the ancestral steroid receptor: ancient origin of estrogen signaling. Science. 2003;301:1714-1717.
26. Eick GN, Thornton JW. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Mol Cell Endocrinol. 2011;334:31-38.
27. Bridgham JT, Carroll SM, Thornton JW. Evolution of hormone-receptor complexity by molecular exploitation. Science. 2006;312:97-101.
28. Carroll SM, Bridgham JT, Thornton JW. Evolution of hormone signaling in elasmobranchs by exploitation of promiscuous receptors. Mol Biol Evol. 2008;25:2643-2652.
29. Markov GV, Tavares R, Dauphin-Villemant C, Demeneix BA, Baker ME, Laudet V. Independent elaboration of steroid hormone signaling pathways in metazoans. Proc Natl Acad Sci USA. 2009;106:11913-11918.
30. Blaustein JD, Wade GN. Ovarian influences on the meal patterns of female rats. Physiol Behav. 1976;17:201-208. 31. Drewett RF. Sexual behaviour and sexual motivation in the female rat. Nature. 1973;242:476-477.
31. Drewett RF. Sexual behaviour and sexual motivation in the female rat. Nature. 1973;242:476-477.
32. Wallen WJ, Belanger MP, Wittnich C. Sex hormones and the selective estrogen receptor modulator tamoxifen modulate weekly body weights and food intakes in adolescent and adult rats. J Nutr. 2001;131:2351-2357.
33. Geary N, Asarian L, Korach KS, Pfaff DW, Ogawa S. Def icits in E2-dependent control of feeding, weight gain, and cholecystokinin satiation in ER-α null mice. Endocrinology. 2001;142:4751-4757.
34. Gao Q, Mezei G, Nie Y, et al. Anorectic estrogen mimics leptin's effect on the rewiring of melanocortin cells and Stat3 signaling in obese animals. Nat Med. 2007; 13:89-94.
35. Ding EL, Song Y, Manson JE, et al. Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N Engl J Med. 2009;361:1152-1163.
36. Jones ME, Thorburn AW, Britt KL, et al. Aromatasedeficient (ArKO) mice have a phenotype of increased adiposity. Proc Natl Acad Sci USA. 2000;97:12735-12740.
37. Heine PA, Taylor JA, IwamotoGA,LubahnDB,Cooke PS. Increased adipose tissue in male and female estrogen receptor-α knockout mice. Proc Natl Acad Sci USA. 2000; 97:12729-12734.
38. Ribas V, Nguyen MT, Henstridge DC, et al. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα deficient mice. Am J Physiol Endocrinol Metab. 2010;298:E304-E319.
39. Rogers NH, Perfield JW II, Strissel KJ, Obin MS, Greenberg AS. Reduced energy expenditure and increased inflammation are early events in the development of ovariectomy-induced obesity. Endocrinology. 2009;150: 2161-2168.
40. Smith GP. The controls of eating: a shift from nutritional homeostasis to behavioral neuroscience. Nutrition. 2000; 16:814-820.
41. Louis-Sylvestre J. Neuroendocrinology of hyperphagias and obesities. Reprod Nutr Dev. 1980;20:1545-1562.
42. Danguir J, Nicolaidis S. Cortical activity and sleep in the rat lateral hypothalamic syndrome. Brain Res. 1980;185: 305-321.
43. Milam KM, Stern JS, Storlien LH, Keesey RE. Effect of lateral hypothalamic lesions on regulation of body weight and adiposity in rats. Am J Physiol. 1980;239:R337-R343.
44. Simerly RB, Chang C, Muramatsu M, Swanson LW. Distribution of androgen and estrogen receptor mRNAcontaining cells in the rat brain: an in situ hybridization study. J Comp Neurol. 1990;294:76-95.
45. Simonian SX, Herbison AE. Differential expression of estrogen receptorα andβ immunoreactivity by oxytocin neurons of rat paraventricular nucleus. J Neuroendocrinol. 1997;9:803-806.
46. Voisin DL, Simonian SX, Herbison AE. Identification of estrogen receptor-containing neurons projecting to the rat supraoptic nucleus. Neuroscience. 1997;78:215-228.
47. Osterlund M, Kuiper GG, Gustafsson JA, Hurd YL. Differential distribution and regulation of estrogen receptor-α and-β mRNA within the female rat brain. Brain Res Mol Brain Res. 1998;54:175-180.
48. Wilkinson HA, Dahllund J, Liu H, et al. Identification and characterization of a functionally distinct form of human estrogen receptor β. Endocrinology. 2002;143:1558-1561.
49. Shima N, Yamaguchi Y, Yuri K. Distribution of estrogen receptor β mRNA-containing cells in ovariectomized and estrogen-treated female rat brain. Anat Sci Int. 2003;78: 85-97.
50. Merchenthaler I, Lane MV, Numan S, Dellovade TL. Distribution of estrogen receptor α and β in the mouse central nervous system: in vivo autoradiographic and immunocytochemical analyses. J Comp Neurol. 2004; 473:270-291.
51. Ohlsson C, Hellberg N, Parini P, et al. Obesity and disturbed lipoprotein profile in estrogen receptor-α-deficient male mice. Biochem Biophys Res Commun. 2000;278: 640-645.
52. Roesch DM. Effects of selective estrogen receptor agonists on food intake and body weight gain in rats. Physiol Behav. 2006;87:39-44.
53. Santollo J, Wiley MD, Eckel LA. Acute activation of ER α decreases food intake, meal size, and body weight in ovariectomized rats. Am J Physiol Regul Integr Comp Physiol. 2007;293:R2194-R2201.
54. Liang YQ, Akishita M, Kim S, et al. Estrogen receptor β is involved in the anorectic action of estrogen. Int J Obes Relat Metab Disord. 2002;26:1103-1109.
55. Yepuru M, Eswaraka J, Kearbey JD, et al. Estrogen receptor-β selective ligands alleviate high-fat diet-and ovariectomy-induced obesity in mice. J Biol Chem. 2010;285: 31292-31303.
56. Langer G, Bader B, Meoli L, et al. A critical review of fundamental controversies in the field of GPR30 research. Steroids. 2010;75:603-610.
57. Dhillon SS, Belsham DD. Estrogen inhibits NPY secretion through membrane-associated estrogen receptor (ER)-α in clonal, immortalized hypothalamic neurons. Int J Obes (Lond). 2011;35:198-207.
58. Qiu J, Bosch MA, Tobias SC, et al. A G-protein-coupled estrogen receptor is involved in hypothalamic control of energy homeostasis. J Neurosci. 2006;26:5649-5655.
59. Roepke TA, Bosch MA, Rick EA, et al. Contribution of a membrane estrogen receptor to the estrogenic regulation of body temperature and energy homeostasis. Endocrinology. 2010;151:4926-4937.
60. Xu Y, Nedungadi TP, Zhu L, et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 2011;14:453-465.
61. Elmquist JK, Maratos-Flier E, Saper CB, Flier JS. Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci. 1998;1:445-450.
62. Elias CF, Aschkenasi C, Lee C, et al. Leptin differentially regulates NPY and POMC neurons projecting to the lateral hypothalamic area. Neuron. 1999;23:775-786.
63. Elmquist JK, Elias CF, Saper CB. From lesions to leptin: hypothalamic control of food intake and body weight. Neuron. 1999;22:221-232.
64. Elias CF, Kelly JF, Lee CE, et al. Chemical characterization of leptin-activated neurons in the rat brain. JCompNeurol. 2000;423:261-281.
65. Wise PM, Scarbrough K, Weiland NG, Larson GH. Diurnal pattern of proopiomelanocortin gene expression in the arcuate nucleus of proestrous, ovariectomized, and steroid-treated rats: a possible role in cyclic luteinizing hormone secretion. Mol Endocrinol. 1990;4:886-892.
66. Bohler HC Jr, Tracer H, Merriam GR, Petersen SL. Changes in proopiomelanocortin messenger ribonucleic acid levels in the rostral periarcuate region of the female rat during the estrous cycle. Endocrinology. 1991;128:1265-1269.
67. Korner J,ChuaSCJr, Williams JA, Leibel RL, Wardlaw SL. Regulation of hypothalamic proopiomelanocortin by leptin in lean and obese rats. Neuroendocrinology. 1999;70: 377-383.
68. Slamberová R, Hnatczuk OC, Vathy I. Expression of proopiomelanocortin and proenkephalin mRNA in sexually dimorphic brain regions are altered in adult male and female rats treated prenatally with morphine. J Pept Res. 2004;63:399-408.
69. Hirosawa M, Minata M, Harada KH, Hitomi T, Krust A, Koizumi A. Ablation of estrogen receptorα (ERα) prevents upregulation ofPOMCby leptin and insulin. Biochem Biophys Res Commun. 2008;371:320-323.
70. Polidori C, Geary N. Estradiol treatment fails to affect the feeding responses to melanocortin-3/4 receptor agonism or antagonism in ovariectomized rats. Peptides. 2002;23: 1697-1700.
71. Malyala A, Zhang C, Bryant DN, Kelly MJ, Ronnekleiv OK. PI3K signaling effects in hypothalamic neurons mediated by estrogen. J Comp Neurol. 2008;506:895-911.
72. King BM. The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight. Physiol Behav. 2006;87:221-244.
73. Gold RM. Hypothalamic obesity: the myth of the ventromedial nucleus. Science. 1973;182:488-490.
74. Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol Endocrinol. 1995;9:478-486.
75. Dellovade TL, Young M, Ross EP, et al. Disruption of the gene encoding SF-1 alters the distribution of hypothalamic neuronal phenotypes. J Comp Neurol. 2000;423:579-589.
76. Majdic G, Young M, Gomez-Sanchez E, et al. Knockout mice lacking steroidogenic factor 1 are a novel genetic model of hypothalamic obesity. Endocrinology. 2002;143: 607-614.
77. Minami T, Oomura Y, Nabekura J, Fukuda A. 17 β-Estradiol depolarization of hypothalamic neurons is mediated by cyclic AMP. Brain Res. 1990;519:301-307.
78. Musatov S, Chen W, Pfaff DW, et al. Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. Proc Natl Acad Sci USA. 2007;104:2501-2506.
79. Schlenker EH, Hansen SN. Sex-specific densities of estrogen receptorsα andβ in the subnuclei of the nucleus tractus solitarius, hypoglossal nucleus and dorsal vagal motor nucleus weanling rats. Brain Res. 2006;1123:89-100.
80. Asarian L, Geary N. Estradiol enhances cholecystokinindependent lipid-induced satiation and activates estrogen receptor-α-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology. 2007;148:5656-5666.
81. Geary N. Estradiol, CCK and satiation. Peptides. 2001; 22:1251-1263.
82. Moran TH. Gut peptides in the control of food intake. Int J Obes (Lond). 2009;33(suppl 1):S7-S10.
83. Degen L, Matzinger D, Drewe J, Beglinger C. The effect of cholecystokinin in controlling appetite and food intake in humans. Peptides. 2001;22:1265-1269.
84. Geary N, Smith GP, Corp ES. The increased satiating potency of CCK-8 by estradiol is not mediated by upregulation of NTS CCK receptors. Brain Res. 1996;719: 179-186.
85. Linden A, Uvnas-Moberg K, Forsberg G, Bednar I, Sodersten P. Involvement of cholecystokinin in food intake. III. Oestradiol potentiates the inhibitory effect of cholecystokinin octapeptide on food intake in ovariectomized rats. J Neuroendocrinol. 1990;2:797-801.
86. Butera PC, Bradway DM, Cataldo NJ. Modulation of the satiety effect of cholecystokinin by estradiol. Physiol Behav. 1993;53:1235-1238.
87. Asarian L, Geary N. Cyclic estradiol treatment phasically potentiates endogenous cholecystokinin's satiating action in ovariectomized rats. Peptides. 1999;20:445-450.
88. Thammacharoen S, Lutz TA, Geary N, Asarian L. Hindbrain administration of estradiol inhibits feeding and activates estrogen receptor-α-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology. 2008;149:1609-1617.
89. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM. Positional cloning of the mouse obese gene and its human homologue. Nature. 1994;372:425-432.
90. SchwartzMW,WoodsSC, Porte DJ, Seeley RJ, BaskinDG. Central nervous system control of food intake. Nature. 2000;404:661-671.
91. MyersMGJr, Leibel RL, Seeley RJ, SchwartzMW.Obesity and leptin resistance: distinguishing cause from effect. Trends Endocrinol Metab. 2010;21:643-651.
92. van Dijk G, Thiele TE, Donahey JC, et al. Central infusion of leptin and GLP-1 (7-36) amide differentially stimulate c-Fos-like immunoreactivity in the rat brain.AmJ Physiol. 1996;271:R1096-R1100.
93. Elmquist JK, Ahima RS, Elias CF, Flier JS, Saper CB. Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei. Proc Natl Acad Sci USA. 1998;95:741-746.
94. Elmquist JK, Bjorbaek C, Ahima RS, Flier JS, Saper CB. Distributions of leptin receptor mRNA isoforms in the rat brain. J Comp Neurol. 1998;395:535-547.
95. Diano S, Kalra SP, Sakamoto H, Horvath TL. Leptin receptors in estrogen receptor-containing neurons of the female rat hypothalamus. Brain Res. 1998;812:256-259.
96. Bennett PA, Lindell K, Wilson C, CarlssonLM,Carlsson B, Robinson IC. Cyclical variations in the abundance of leptin receptors, but not in circulating leptin, correlate with NPY expression during the oestrous cycle. Neuroendocrinology. 1999;69:417-423.
97. Lindell K, Bennett PA, Itoh Y, Robinson IC, Carlsson LM, Carlsson B. Leptin receptor 5βuntranslated regions in the rat: relative abundance, genomic organization and relation to putative response elements. Mol Cell Endocrinol. 2001; 172:37-45.
98. Ainslie DA, Morris MJ, Wittert G, Turnbull H, Proietto J, Thorburn AW. Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y. Int J Obes Relat Metab Disord. 2001;25:1680-1688. 99. Clegg DJ, Riedy CA, Smith KA, Benoit SC, Woods SC. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes. 2003;52:682-687.
99. Clegg DJ, Riedy CA, Smith KA, Benoit SC, Woods SC. Differential sensitivity to central leptin and insulin in male and female rats. Diabetes. 2003;52:682-687.
100. Clegg DJ, Brown LM, Woods SC, Benoit SC. Gonadal hormones determine sensitivity to central leptin and insulin. Diabetes. 2006;55:978-987.
101. Chavez M, van Dijk G, Arkies BJ, Woods SC. 1995 ventricular insulin infusion attenuates NPY-induced feeding at the level of the paraventricular nucleus. Obes Res. 1995; 3:335s
102. Levin BE. ArcuateNPYneurons and energy homeostasis in diet-induced obese and resistant rats. Am J Physiol. 1999; 276:R382-R387.
103. Cone RD, CowleyMA,Butler AA, FanW,Marks DL,Low MJ. The arcuate nucleus as a conduit for diverse signals relevant to energy homeostasis. Int J Obes Relat Metab Disord. 2001;25(suppl 5):S63-S67.
104. Herzog H. Neuropeptide Y and energy homeostasis: insights fromYreceptor knockout models. Eur J Pharmacol. 2003;480:21-29.
105. Baskin DG, SchwartzMW,Seeley RJ, et al. Leptin receptor long-form splice-variant protein expression in neuron cell bodies of the brain and colocalization with neuropeptideY mRNA in the arcuate nucleus. J Histochem Cytochem. 1999;47:353-362.
106. Hill JW, Urban JH, Xu M, Levine JE. Estrogen induces neuropeptide Y (NPY) Y1 receptor gene expression and responsiveness to NPY in gonadotrope-enriched pituitary cell cultures. Endocrinology. 2004;145:2283-2290.
107. Bonavera JJ, Dube MG, Kalra PS, Kalra SP. Anorectic effects of estrogen may be mediated by decreased neuropeptide-Y release in the hypothalamic paraventricular nucleus. Endocrinology. 1994;134:2367-2370.
108. Titolo D, Cai F, Belsham DD. Coordinate regulation of neuropeptideYand agouti-related peptide gene expression by estrogen depends on the ratio of estrogen receptor (ER) α toERβ in clonal hypothalamic neurons.MolEndocrinol. 2006;20:2080-2092.
109. Olofsson LE, Pierce AA, Xu AW. Functional requirement of AgRP andNPYneurons in ovarian cycle-dependent regulation of food intake. Proc Natl Acad Sci USA. 2009;106: 15932-15937.
110. Bouchard C, Despres JP, Mauriege P. Genetic and nongenetic determinants of regional fat distribution. Endocr Rev. 1993;14:72-93.
111. Enzi G, Gasparo M, Biondetti PR, Fiore D, Semisa M, Zurlo F. Subcutaneous and visceral fat distribution according to sex, age, and overweight, evaluated by computed tomography. Am J Clin Nutr. 1986;44:739-746.
112. Bjorntorp P. Abdominal fat distribution and disease: an overview of epidemiological data. Ann Med. 1992;24: 15-18. 113. Bjorntorp P. Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol. 1992;20(suppl 8): S26-S28.
113. Bjorntorp P. Abdominal fat distribution and the metabolic syndrome. J Cardiovasc Pharmacol. 1992;20(suppl 8): S26-S28.
114. Bjørntorp P. 1992 Hormonal effects on fat distribution and its relationship to health risk factors. Acta Paediatr Suppl 383:59-60; discussion 61.
115. Guthrie JR, Dennerstein L, Taffe JR, Lehert P, Burger HG. The menopausal transition a 9-year prospective population-based study The MelbourneWomen'sMidlife Health Project. Climacteric. 2004;7:375-389.
116. Lovejoy JC, ChampagneCM,de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes (Lond). 2008;32:949-958.
117. Gambacciani M, Ciaponi M, Cappagli B, et al. Body weight, body fat distribution, and hormonal replacement therapy in early postmenopausal women. J Clin Endocrinol Metab. 1997;82:414-417.
118. Haarbo J, Hansen BF, Christiansen C. Hormone replacement therapy prevents coronary artery disease in ovariectomized cholesterol-fed rabbits. APMIS. 1991;99:721-727.
119. Haarbo J, Marslew U, Gotfredsen A, Christiansen C. Postmenopausal hormone replacement therapy prevents central distribution of body fat after menopause. Metabolism. 1991;40:1323-1326.
120. Elbers JM, Asscheman H, Seidell JC, Gooren LJ. Effects of sex steroid hormones on regional fat depots as assessed by magnetic resonance imaging in transsexuals.AmJ Physiol. 1999;276:E317-E325.
121. Wajchenberg BL. Subcutaneous and visceral adipose tissue: their relation to the metabolic syndrome. Endocr Rev. 2000;21:697-738.
122. Thorne A, Lonnqvist F, Apelman J, Hellers G, Arner P. A pilot study of long-term effects of a novel obesity treatment: omentectomy in connection with adjustable gastric banding. Int J Obes Relat Metab Disord. 2002;26:193-199.
123. Herrera MF, Pantoja JP, Velazquez-Fernandez D, et al. Potential additional effect of omentectomy on metabolic syndrome, acute-phase reactants, and inflammatory mediators in grade III obese patients undergoing laparoscopic Roux-en-Y gastric bypass: a randomized trial. Diabetes Care. 2010;33:1413-1418.
124. Fabbrini E, Tamboli RA, Magkos F, et al. Surgical removal of omental fat does not improve insulin sensitivity and cardiovascular risk factors in obese adults. Gastroenterology. 2010;139:448-455.
125. Gabriely I, Ma XH, Yang XM, et al. Removal of visceral fat prevents insulin resistance and glucose intolerance of aging: an adipokine-mediated process? Diabetes. 2002;51: 2951-2958.
126. Lapidus L, Bengtsson C, Larsson B, Pennert K, Rybo E, Sjostrom L. Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. Br Med J (Clin Res Ed). 1984;289:1257-1261.
127. Donahue RP, Orchard TJ, Becker DJ, Kuller LH, Drash AL. Sex differences in the coronary heart disease risk profile: a possible role for insulin. The Beaver County Study. Am J Epidemiol. 1987;125:650-657.
128. Donahue RP, Abbott RD. Central obesity and coronary heart disease in men. Lancet. 1987;2:1215.
129. Ohlson LO, Larsson B, Svardsudd K, et al. The influence of body fat distribution on the incidence of diabetes mellitus: 13.5 years of follow-up of the participants in the study of men born in 1913. Diabetes. 1985;34:1055-1058.
130. Bjorntorp P. The android woman-a risky condition. J Intern Med. 1996;239:105-110.
131. Tran TT, Yamamoto Y, Gesta S, Kahn CR. Beneficial ef-fects of subcutaneous fat transplantation on metabolism. Cell Metab. 2008;7:410-420.
132. Schneider G, Kirschner MA, Berkowitz R, Ertel NH. Increased estrogen production in obese men. J Clin Endocrinol Metab. 1979;48:633-638.
133. Tchernof A, Despres JP, Dupont A, et al. Relation of steroid hormones to glucose tolerance and plasma insulin levels in men. Importance of visceral adipose tissue. Diabetes Care. 1995;18:292-299.
134. Mizutani T, Nishikawa Y, Adachi H, et al. Identification of estrogen receptor in human adipose tissue and adipocytes. J Clin Endocrinol Metab. 1994;78:950-954.
135. PriceTM,O'Brien SN. Determination of estrogen receptor messenger ribonucleic acid (mRNA) and cytochrome P450 aromatasemRNAlevels in adipocytes and adipose stromal cells by competitive polymerase chain reaction amplification. J Clin Endocrinol Metab. 1993;77:1041-1045.
136. Ogawa S, Chan J, Chester AE, Gustafsson JA, Korach KS, Pfaff DW. Survival of reproductive behaviors in estrogen receptor β gene-deficient (βERKO) male and female mice. Proc Natl Acad Sci USA. 1999;96:12887-12892.
137. Smith EP, Boyd J, Frank GR, et al. Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man. N Engl J Med. 1994;331:1056-1061.
138. Okura T, Koda M, Ando F, Niino N, Ohta S, Shimokata H. Association of polymorphisms in the estrogen receptor α gene with body fat distribution. Int J Obes Relat Metab Disord. 2003;27:1020-1027.
139. Nilsson M, Dahlman I, Ryden M, et al. Oestrogen receptor α gene expression levels are reduced in obese compared to normal weight females. Int J Obes (Lond). 2007;31:900-907.
140. Deng HW, Li J, Li JL, et al. Association of estrogen receptor-α genotypes with body mass index in normal healthy postmenopausal Caucasian women. J Clin Endocrinol Metab. 2000;85:2748-2751.
141. Casazza K, Page GP, Fernandez JR. The association between the rs2234693 and rs9340799 estrogen receptor α gene polymorphisms and risk factors for cardiovascular disease: a review. Biol Res Nurs. 2010;12:84-97.
142. Yamada Y, Ando F, Niino N, Ohta S, Shimokata H. Association of polymorphisms of the estrogen receptorα gene with bone mineral density of the femoral neck in elderly Japanese women. J Mol Med. 2002;80:452-460.
143. Okura T, Koda M, Ando F, Niino N, Shimokata H. Relationships of resting energy expenditure with body fat distribution and abdominal fatness in Japanese population. J Physiol Anthropol Appl Human Sci. 2003;22: 47-52.
144. Okura T, Koda M, Ando F, Niino N, Tanaka M, Shimokata H. Association of the mitochondrial DNA 15497G/A polymorphism with obesity in a middle-aged and elderly Japanese population. Hum Genet. 2003;113: 432-436.
145. D'Eon TM, Souza SC, Aronovitz M, Obin MS, Fried SK, Greenberg AS. Estrogen regulation of adiposity and fuel partitioning. Evidence of genomic and non-genomic regulation of lipogenic and oxidative pathways. J Biol Chem. 2005;280:35983-35991.
146. Lundholm L, Zang H, Hirschberg AL, Gustafsson JA, Arner P, Dahlman-Wright K. Key lipogenic gene expression can be decreased by estrogen in human adipose tissue. Fertil Steril. 2008;90:44-48.
147. PriceTM,O'Brien SN, WelterBH,George R, Anandjiwala J, Kilgore M. Estrogen regulation of adipose tissue lipoprotein lipase-possible mechanism of body fat distribution. Am J Obstet Gynecol. 1998;178:101-107.
148. Bryzgalova G, Lundholm L, Portwood N, et al. Mechanisms of antidiabetogenic and body weight-lowering effects of estrogen in high-fat diet-fed mice. Am J Physiol Endocrinol Metab. 2008;295:E904-E912.
149. Gao H, Bryzgalova G, Hedman E, et al. Long-term administration of estradiol decreases expression of hepatic lipogenic genes and improves insulin sensitivity in ob/ob mice: a possible mechanism is through direct regulation of signal transducer and activator of transcription 3. Mol Endocrinol. 2006;20:1287-1299.
150. Lundholm L, Bryzgalova G, Gao H, et al. The estrogen receptor α-selective agonist propyl pyrazole triol improves glucose tolerance in ob/ob mice; potential molecular mechanisms. J Endocrinol. 2008;199:275-286.
151. Semenkovich CF, Wims M, Noe L, Etienne J, Chan L. Insulin regulation of lipoprotein lipase activity in 3T3-L1 adipocytes is mediated at posttranscriptional and posttranslational levels. J Biol Chem. 1989;264:9030-9038.
152. Iverius PH, Brunzell JD. Relationship between lipoprotein lipase activity and plasma sex steroid level in obese women. J Clin Invest. 1988;82:1106-1112.
153. Urabe M, Yamamoto T, Kashiwagi T, et al. Effect of estrogen replacement therapy on hepatic triglyceride lipase, lipoprotein lipase and lipids including apolipoprotein E in climacteric and elderly women. Endocr J. 1996;43:737-742.
154. HommaH, Kurachi H, Nishio Y, et al. Estrogen suppresses transcription of lipoprotein lipase gene. Existence of a unique estrogen response element on the lipoprotein lipase promoter. J Biol Chem. 2000;275:11404-11411.
155. Reue K, Dwyer JR. Lipin proteins and metabolic homeostasis. J Lipid Res. 2009;50 suppl:S109-S114.
156. Miranda M, Chacon MR, Gomez J, et al. Human subcutaneous adipose tissue LPIN1 expression in obesity, type 2 diabetes mellitus, and human immunodeficiency virus-associated lipodystrophy syndrome. Metabolism. 2007; 56:1518-1526.
157. van Harmelen V, Ryden M, Sjolin E, Hoffstedt J. A role of lipin in human obesity and insulin resistance: relation to adipocyte glucose transport andGLUT4expression. J Lipid Res. 2007;48:201-206.
158. Gonzalez CR, Novelle MG, Caminos JE, et al. Regulation of lipin1 by nutritional status, adiponectin, sex and pituitary function in rat white adipose tissue. Physiol Behav. 2012;105:777-783.
159. Cooke PS, Naaz A. Role of estrogens in adipocyte development and function. Exp Biol Med (Maywood). 2004; 229:1127-1135.
160. Foryst-Ludwig A, Clemenz M, Hohmann S, et al. Metabolic actions of estrogen receptor β (ERβ) are mediated by a negative cross-talk with PPARγ. PLoS Genet. 2008;4: e1000108.
161. Park YW, Zhu S, Palaniappan L, Heshka S, Carnethon MR, Heymsfield SB. The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med. 2003;163: 427-436.
162. Yki-Jarvinen H. Sex and insulin sensitivity. Metabolism. 1984;33:1011-1015.
163. Hevener AL, Olefsky JM, Reichart D, et al. Macrophage PPAR γ is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest. 2007;117:1658-1669.
164. Choi CS, Fillmore JJ, Kim JK, et al. Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance. J Clin Invest. 2007;117: 1995-2003.
165. Frias JP, Macaraeg GB, Ofrecio J, Yu JG, Olefsky JM, Kruszynska YT. Decreased susceptibility to fatty acidinduced peripheral tissue insulin resistance in women. Diabetes. 2001;50:1344-1350.
166. Hevener A, Reichart D, Janez A, Olefsky J. Female rats do not exhibit free fatty acid-induced insulin resistance. Diabetes. 2002;51:1907-1912.
167. Djouadi F, Weinheimer CJ, Saffitz JE, et al. A genderrelated defect in lipid metabolism and glucose homeostasis in peroxisome proliferator-activated receptor α-deficient mice. J Clin Invest. 1998;102:1083-1091.
168. Hong J, Stubbins RE, Smith RR, Harvey AE, Nunez NP. Differential susceptibility to obesity between male, female and ovariectomized female mice. Nutr J. 2009;8:11.
169. Pfeilschifter J, Koditz R, Pfohl M, Schatz H. Changes in proinflammatory cytokine activity after menopause. Endocr Rev. 2002;23:90-119.
170. Sites CK, Toth MJ, Cushman M, et al. Menopause-related differences in inflammation markers and their relationship to body fat distribution and insulin-stimulated glucose disposal. Fertil Steril. 2002;77:128-135.
171. Campbell SE, Febbraio MA. Effect of the ovarian hormones on GLUT4 expression and contraction-stimulated glucose uptake. Am J Physiol Endocrinol Metab. 2002; 282:E1139-E1146.
172. Stubbins RE, Holcomb VB, Hong J, Nunez NP. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr. 2012;51:861-870.
173. Rogers NH, Witczak CA, Hirshman MF, Goodyear LJ, Greenberg AS. Estradiol stimulates Akt, AMP-activated protein kinase (AMPK) and TBC1D1/4, but not glucose uptake in rat soleus. Biochem Biophys Res Commun. 2009;382:646-650.
174. Gorres BK, Bomhoff GL, Morris JK, Geiger PC. In vivo stimulation of oestrogen receptor α increases insulin-stimulated skeletal muscle glucose uptake. J Physiol. 2011;589: 2041-2054.
175. Van Pelt RE, Gozansky WS, Schwartz RS, Kohrt WM. Intravenous estrogens increase insulin clearance and action in postmenopausal women. Am J Physiol Endocrinol Metab. 2003;285:E311-E317.
176. Alonso A, Gonzalez-Pardo H, Garrido P, et al. Acute effects of 17 β-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats. Age (Dordr). 2010;32:421-434.
177. Salehzadeh F, Rune A, Osler M, Al-Khalili L. Testosterone or 17β-estradiol exposure reveals sex-specific effects on glucose and lipid metabolism in human myotubes. J Endocrinol. 2011;210:219-229.
178. Rochira V, Madeo B, Zirilli L, Caffagni G, Maffei L, Carani C. Oestradiol replacement treatment and glucose homeostasis in two men with congenital aromatase deficiency: evidence for a role of oestradiol and sex steroids imbalance on insulin sensitivity in men. DiabetMed. 2007; 24:1491-1495.
179. Guercio G, Di Palma MI, Pepe C, et al. Metformin, estrogen replacement therapy and gonadotropin inhibition fail to improve insulin sensitivity in a girl with aromatase deficiency. Horm Res. 2009;72:370-376.
180. Takeda K, Toda K, Saibara T, et al. Progressive development of insulin resistance phenotype in male mice with complete aromatase (CYP19) deficiency. J Endocrinol. 2003;176:237-246.
181. Maffei L, Murata Y, Rochira V, et al. Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment. J Clin Endocrinol Metab. 2004;89:61-70.
182. Maffei L, Rochira V, Zirilli L, et al. A novel compound heterozygous mutation of the aromatase gene in an adult man: reinforced evidence on the relationship between congenital oestrogen deficiency, adiposity and the metabolic syndrome. Clin Endocrinol (Oxf). 2007;67:218-224.
183. Jones ME, McInnes KJ, Boon WC, Simpson ER. Estrogen and adiposity-utilizing models of aromatase deficiency to explore the relationship. J Steroid Biochem Mol Biol. 2007;106:3-7.
184. Morishima A, GrumbachMM,Simpson ER, Fisher C, Qin K. Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens. J Clin Endocrinol Metab. 1995;80:3689-3698.
185. Nadal A, Alonso-Magdalena P, Soriano S, Quesada I, Ropero AB. The pancreatic β-cell as a target of estrogens and xenoestrogens: implications for blood glucose homeostasis and diabetes. Mol Cell Endocrinol. 2009;304: 63-68.
186. Barros RP, Morani A, Moriscot A, Machado UF. Insulin resistance of pregnancy involves estrogen-induced repression of muscle GLUT4. Mol Cell Endocrinol. 2008;295: 24-31.
187. Ding EL, Song Y, Manson JE, Rifai N, Buring JE, Liu S. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia. 2007;50:2076-2084.
188. Kalyani RR, Franco M, Dobs AS, et al. The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. J Clin Endocrinol Metab. 2009;94:4127-4135.
189. Wiik A, Gustafsson T, Esbjornsson M, et al. Expression of oestrogen receptor α and β is higher in skeletal muscle of highly endurance-trained than of moderately active men. Acta Physiol Scand. 2005;184:105-112.
190. Baltgalvis KA, Greising SM, Warren GL, Lowe DA. Estrogen regulates estrogen receptors and antioxidant gene expression in mouse skeletal muscle. PLoS One. 2010;5: e10164.
191. Perry JR, Weedon MN, Langenberg C, et al. Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes. Hum Mol Genet. 2010;19:535-544.
192. Ribas V, Nguyen MT, Henstridge DC, et al. Impaired oxidative metabolism and inflammation are associated with insulin resistance in ERα-deficient mice. Am J Physiol Endocrinol Metab. 2010;298:E304-E319.
193. Riant E, Waget A, Cogo H, Arnal JF, Burcelin R, Gourdy P. Estrogens protect against high-fat diet-induced insulin resistance and glucose intolerance in mice. Endocrinology. 2009;150:2109-2117.
194. Bryzgalova G, Gao H, Ahren B, et al. Evidence that oestrogen receptor-α plays an important role in the regulation of glucose homeostasis in mice: insulin sensitivity in the liver. Diabetologia. 2006;49:588-597.
195. Ribas V, Drew BG, Soleymani T, Daraei P, Hevener A. Skeletal muscle specific ERα deletion is causal for the metabolic syndrome. Endocr Rev. 2010;31:S5.
196. Barros RP, Machado UF, Warner M, Gustafsson J-Å. Muscle GLUT4 regulation by estrogen receptors ERβ and ERα. Proc Natl Acad Sci USA. 2006;103:1605-1608.
197. Campbell SE, Mehan KA, Tunstall RJ, Febbraio MA, Cameron-Smith D. 17β-Estradiol upregulates the expression of peroxisome proliferator-activated receptor α and lipid oxidative genes in skeletal muscle. J Mol Endocrinol. 2003;31:37-45.
198. Alonso A, Ordonez P, Fernandez R, et al. 17β-Estradiol treatment is unable to reproduce p85 α redistribution associated with gestational insulin resistance in rats. J Steroid Biochem Mol Biol. 2009;116:160-170.
199. Hansen PA, McCarthy TJ, Pasia EN, Spina RJ, Gulve EA. Effects of ovariectomy and exercise training on muscle GLUT-4 content and glucose metabolism in rats. J Appl Physiol. 1996;80:1605-1611.
200. Barros RP, Gustafsson JA. Estrogen receptors and the metabolic network. Cell Metab. 2011;14:289-299.
201. Murgia M, Jensen TE, Cusinato M, Garcia M, Richter EA, Schiaffino S. Multiple signalling pathways redundantly control glucose transporter GLUT4 gene transcription in skeletal muscle. J Physiol. 2009;587:4319-4327.
202. Zorzano A, Palacin M, Guma A. Mechanisms regulating GLUT4 glucose transporter expression and glucose transport in skeletal muscle. Acta Physiol Scand. 2005;183: 43-58.
203. Fu MH, Maher AC, Hamadeh MJ, Ye C, Tarnopolsky MA. Exercise, sex, menstrual cycle phase, and 17β-estradiol influence metabolism-related genes in human skeletal muscle. Physiol Genomics. 2009;40:34-47.
204. Hoeg L, Roepstorff C, Thiele M, Richter EA, Wojtaszewski JF, Kiens B. Higher intramuscular triacylglycerol in women does not impair insulin sensitivity and proximal insulin signaling. J Appl Physiol. 2009;107:824-831.
205. Garvey WT, Maianu L, Zhu JH, Brechtel-Hook G, Wallace P, Baron AD. Evidence for defects in the trafficking and translocation of GLUT4 glucose transporters in skeletal muscle as a cause of human insulin resistance. J Clin Invest. 1998;101:2377-2386.
206. Garvey WT, Maianu L, Hancock JA, Golichowski AM, Baron A. Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM. Diabetes. 1992;41:465-475.
207. Banks EA, Brozinick JT Jr, Yaspelkis BB III, Kang HY, Ivy JL. Muscle glucose transport, GLUT-4 content, and degree of exercise training in obese Zucker rats. Am J Physiol. 1992;263:E1010-E1015.
208. Brozinick JT Jr, Etgen GJ Jr, Yaspelkis BB III, Kang HY, Ivy JL. Effects of exercise training on muscle GLUT-4 protein content and translocation in obese Zucker rats. Am J Physiol. 1993;265:E419-E427.
209. Brozinick JT Jr, Etgen GJ Jr, Yaspelkis BB III, Ivy JL. Glucose uptake and GLUT-4 protein distribution in skeletal muscle of the obese Zucker rat. Am J Physiol. 1994;267: R236-R243.
210. Hevener AL, Reichart D, Olefsky J. Exercise and thiazolidinedione therapy normalize insulin action in the obese Zucker fatty rat. Diabetes. 2000;49:2154-2159.
211. Dela F, Ploug T, Handberg A, et al. Physical training increases muscleGLUT4protein andmRNAin patients with NIDDM. Diabetes. 1994;43:862-865.
212. Rodnick KJ, Holloszy JO, Mondon CE, James DE. Effects of exercise training on insulin-regulatable glucose-transporter protein levels in rat skeletal muscle. Diabetes. 1990; 39:1425-1429.
213. Lemoine S, Granier P, Tiffoche C, et al. Effect of endurance training on oestrogen receptorα expression in different rat skeletal muscle type. Acta Physiol Scand. 2002;175:211-217.
214. Lemoine S, Granier P, Tiffoche C, et al. Effect of endurance training on oestrogen receptor α transcripts in rat skeletal muscle. Acta Physiol Scand. 2002;174:283-289.
215. Mora S, Pessin JE. The MEF2A isoform is required for striated muscle-specific expression of the insulin-responsive GLUT4 glucose transporter. J Biol Chem. 2000;275: 16323-16328.
216. van Rooij E, Fielitz J, Sutherland LB, et al. Myocyte enhancer factor 2 and class II histone deacetylases control a gender-specific pathway of cardioprotection mediated by the estrogen receptor. Circ Res. 2010;106:155-165.
217. Moreno H, Serrano AL, Santalucia T, et al. Differential regulation of the muscle-specific GLUT4 enhancer in regenerating and adult skeletal muscle. J Biol Chem. 2003; 278:40557-40564.
218. Gan Z, Burkart-Hartman EM, Han DH, et al. The nuclear receptor PPARβ/δ programs muscle glucose metabolism in cooperation with AMPK and MEF2. Genes Dev. 2011; 25:2619-2630.
219. Oshel KM, Knight JB, Cao KT, Thai MV, Olson AL. Identification of a 30-base pair regulatory element and novel DNA binding protein that regulates the human GLUT4 promoter in transgenic mice. J Biol Chem. 2000;275: 23666-23673.
220. Smith JA, Kohn TA, Chetty AK, Ojuka EO. CaMK activation during exercise is required for histone hyperacetylation and MEF2A binding at the MEF2 site on the Glut4 gene. Am J Physiol Endocrinol Metab. 2008;295:E698-E704.
221. Gong H, Xie J, Zhang N, Yao L, Zhang Y.MEF2Abinding to the Glut4 promoter occurs via an AMPKα2-dependent mechanism. Med Sci Sports Exerc. 2011;43:1441-1450.
222. Ordonez P, Moreno M, Alonso A, Llaneza P, Diaz F, Gonzalez C. 17β-Estradiol and/or progesterone protect from insulin resistance in STZ-induced diabetic rats. J Steroid Biochem Mol Biol. 2008;111:287-294.
223. Galluzzo P, Rastelli C, Bulzomi P, Acconcia F, Pallottini V, Marino M. 17β-Estradiol regulates the first steps of skeletal muscle cell differentiation via ER-α-mediated signals. Am J Physiol Cell Physiol. 2009;297:C1249-C1262.
224. Stitt TN, Drujan D, Clarke BA, et al. The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibitingFOXOtranscription factors. Mol Cell. 2004;14:395-403.
225. Enns DL, Iqbal S, Tiidus PM. Oestrogen receptors mediate oestrogen-induced increases in post-exercise rat skeletal muscle satellite cells. Acta Physiol (Oxf). 2008;194:81-93.
226. Enns DL, Tiidus PM. Estrogen influences satellite cell activation and proliferation following downhill running in rats. J Appl Physiol. 2008;104:347-353.
227. Thomas A, Bunyan K, Tiidus PM. Oestrogen receptor-α activation augments post-exercise myoblast proliferation. Acta Physiol (Oxf). 2010;198:81-89.
228. Kamanga-Sollo E, White ME, Hathaway MR, Weber WJ, Dayton WR. Effect of estradiol-17β on protein synthesis and degradation rates in fused bovine satellite cell cultures. Domest Anim Endocrinol. 2010;39:54-62.
229. Lee YR, Park J, Yu HN, Kim JS, Youn HJ, Jung SH. Upregulation of PI3K/Akt signaling by 17β-estradiol through activation of estrogen receptor-α, but not estrogen receptor-β, and stimulates cell growth in breast cancer cells. Biochem Biophys Res Commun. 2005;336:1221-1226.
230. Noh EM, Lee YR, Chay KO, et al. Estrogen receptor α induces down-regulation of PTEN through PI3-kinase activation in breast cancer cells. Mol Med Report. 2011;4: 215-219.
231. Simoncini T, Hafezi-Moghadam A, Brazil DP, Ley K, Chin WW, Liao JK. Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature. 2000;407:538-541.
232. Simoncini T, Fornari L, Mannella P, et al. Novel non-transcriptional mechanisms for estrogen receptor signaling in the cardiovascular system. Interaction of estrogen receptor α with phosphatidylinositol 3-OH kinase. Steroids. 2002; 67:935-939.
233. Mannella P, Brinton RD. Estrogen receptor protein interaction with phosphatidylinositol 3-kinase leads to activation of phosphorylated Akt and extracellular signal-regulated kinase 1/2 in the same population of cortical neurons: a unified mechanism of estrogen action. J Neurosci. 2006; 26:9439-9447.
234. Ronda AC, Vasconsuelo A, Boland R. Extracellularregulated kinase and p38 mitogen-activated protein kinases are involved in the antiapoptotic action of 17β-estradiol in skeletal muscle cells. J Endocrinol. 2010;206: 235-246.
235. Ronda AC, Buitrago C, Boland R. Role of estrogen receptors, PKC and Src in ERK2 and p38 MAPK signaling triggered by 17β-estradiol in skeletal muscle cells. J Steroid Biochem Mol Biol. 2010;122:287-294.
236. Niu W, Huang C, Nawaz Z, et al. Maturation of the regulation of GLUT4 activity by p38 MAPK during L6 cell myogenesis. J Biol Chem. 2003;278:17953-17962.
237. Furtado LM, Somwar R, Sweeney G, Niu W, Klip A. Activation of the glucose transporter GLUT4 by insulin. Biochem Cell Biol. 2002;80:569-578.
238. Sweeney G, Somwar R, Ramlal T, Volchuk A, Ueyama A, Klip A. An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. J Biol Chem. 1999;274:10071-10078.
239. Sorensen MB, Rosenfalck AM, Hojgaard L, Ottesen B. Obesity and sarcopenia after menopause are reversed by sex hormone replacement therapy. Obes Res. 2001;9:622-626.
240. Leger B, Derave W, De Bock K, Hespel P, Russell AP. Humansarcopenia reveals an increase inSOCS-3and myostatin and a reduced efficiency of Akt phosphorylation. Rejuvenation Res. 2008;11:163-175B.
241. Tiidus PM. Estrogen and gender effects on muscle damage, inflammation, and oxidative stress. Can J Appl Physiol. 2000;25:274-287.
242. Messier V, Rabasa-Lhoret R, Barbat-Artigas S, Elisha B, Karelis AD, Aubertin-Leheudre M. Menopause and sarcopenia: a potential role for sex hormones. Maturitas. 2011;68:331-336.
243. Chen Z, Bassford T, Green SB, et al. Postmenopausal hormone therapy and body composition-a substudy of the estrogen plus progestin trial of the Women's Health Initiative. Am J Clin Nutr. 2005;82:651-656.
244. Sipila S, Taaffe DR, Cheng S, Puolakka J, Toivanen J, Suominen H. Effects of hormone replacement therapy and high-impact physical exercise on skeletal muscle in postmenopausal women: a randomized placebo-controlled study. Clin Sci (Lond). 2001;101:147-157.
245. Teixeira PJ, Going SB, Houtkooper LB, et al. Resistance training in postmenopausal women with and without hormone therapy. Med Sci Sports Exerc. 2003;35:555-562.
246. Dieli-Conwright CM, Spektor TM, Rice JC, Sattler FR, Schroeder ET. Hormone therapy attenuates exerciseinduced skeletal muscle damage in postmenopausal women. J Appl Physiol. 2009;107:853-858.
247. Sotiriadou S, Kyparos A, Albani M, et al. Soleus muscle force following downhill running in ovariectomized rats treated with estrogen. Appl Physiol Nutr Metab. 2006;31: 449-459.
248. Boland R, Vasconsuelo A, Milanesi L, Ronda AC, de Boland AR. 17β-Estradiol signaling in skeletal muscle cells and its relationship to apoptosis. Steroids. 2008;73:859-863.
249. Vasconsuelo A, Milanesi L, Boland R. 17β-Estradiol abrogates apoptosis in murine skeletal muscle cells through estrogen receptors: role of the phosphatidylinositol 3-kinase/Akt pathway. J Endocrinol. 2008;196:385-397.
250. Wang F, He Q, Sun Y, Dai X, Yang XP. Female adult mouse cardiomyocytes are protected against oxidative stress. Hypertension. 2010;55:1172-1178.
251. McLoughlin TJ, Smith SM, DeLong AD, Wang H, Unterman TG, Esser KA. FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner. Am J Physiol Cell Physiol. 2009;297:C548-C555.
252. Naaz A, Zakroczymski M, Heine P, et al. Effect of ovariectomy on adipose tissue of mice in the absence of estrogen receptor α (ERα): a potential role for estrogen receptor β (ERβ). Horm Metab Res. 2002;34:758-763.
253. Barros RP, Gabbi C, Morani A, Warner M, Gustafsson JA. Participation of ERα and ERβ in glucose homeostasis in skeletal muscle and white adipose tissue. Am J Physiol Endocrinol Metab. 2009;297:E124-E133.
254. Hoeg LD, Sjoberg KA, Jeppesen J, et al. Lipid-induced insulin resistance affects women less than men and is not accompanied by inflammation or impaired proximal insulin signaling. Diabetes. 2011;60:64-73.
255. Cortright RN, Koves TR. Sex differences in substrate metabolism and energy homeostasis. Can J Appl Physiol. 2000;25:288-311.
256. Amati F, Dube JJ, Alvarez-Carnero E, et al. Skeletal muscle triglycerides, diacylglycerols, and ceramides in insulin resistance: another paradox in endurance-trained athletes? Diabetes. 2011;60:2588-2597.
257. Maher AC, Akhtar M, Vockley J, Tarnopolsky MA. Women have higher protein content of β-oxidation enzymes in skeletal muscle than men. PLoS One. 2010;5: e12025.
258. Turcotte LP, Richter EA, Kiens B. Increased plasma FFA uptake and oxidation during prolonged exercise in trained vs. untrained humans. Am J Physiol. 1992;262:E791-E799.
259. Hamadeh MJ, Devries MC, Tarnopolsky MA. Estrogen supplementation reduces whole body leucine and carbohydrate oxidation and increases lipid oxidation in men during endurance exercise. J Clin Endocrinol Metab. 2005; 90:3592-3599.
260. Maher AC, Akhtar M, Tarnopolsky MA. Men supplemented with 17β-estradiol have increased β-oxidation capacity in skeletal muscle. Physiol Genomics. 2010;42:342-347.
261. D'Eon TM, Rogers NH, Stancheva ZS, Greenberg AS. Estradiol and the estradiol metabolite, 2-hydroxyestradiol, activate AMP-activated protein kinase in C2C12 myotubes. Obesity (Silver Spring). 2008;16:1284-1288.
262. Mihaylova MM, Shaw RJ. The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol. 2011;13:1016-1023.
263. Hardie DG. AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev. 2011;25:1895-1908.
264. Kim JY, Jo KJ, Kim OS, et al. Parenteral 17β-estradiol decreases fasting blood glucose levels in non-obese mice with short-term ovariectomy. Life Sci. 2010;87:358-366. 265. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111-1119.
265. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111-1119.
266. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipidinduced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IκB-α. Diabetes. 2002;51:2005-2011.
267. Adams JM II, Pratipanawatr T, Berria R, et al. Ceramide content is increased in skeletal muscle from obese insulinresistant humans. Diabetes. 2004;53:25-31.
268. Yang G, Badeanlou L, Bielawski J, Roberts AJ, Hannun YA, Samad F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2009; 297:E211-E224.
269. Summers SA. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res. 2006;45:42-72.
270. Holland WL, Brozinick JT, Wang LP, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturatedfat-, and obesity-induced insulin resistance. Cell Metab. 2007;5:167-179.
271. HollandWL,Knotts TA, Chavez JA,WangLP, Hoehn KL, Summers SA. Lipid mediators of insulin resistance. Nutr Rev. 2007;65:S39-S46.
272. Hotamisligil GS. Inflammation and endoplasmic reticulum stress in obesity and diabetes. Int J Obes (Lond). 2008; 32(suppl 7):S52-S54.
273. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98-107.
274. Borras C, Sastre J, Garcia-Sala D, Lloret A, Pallardo FV, Vina J. Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males. Free Radic Biol Med. 2003;34:546-552.
275. Chung SS, Kim M, Youn BS, et al. Glutathione peroxidase 3 mediates the antioxidant effect of peroxisome proliferator-activated receptor γ in human skeletal muscle cells. Mol Cell Biol. 2009;29:20-30.
276. Yang X, Deignan JL, Qi H, et al. Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks. Nat Genet. 2009;41:415-423.
277. Patti ME, Butte AJ, Crunkhorn S, et al. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: potential role of PGC1 and NRF1. Proc Natl Acad Sci USA. 2003;100:8466-8471.
278. Befroy DE, Petersen KF, Dufour S, et al. Impaired mitochondrial substrate oxidation in muscle of insulin-resistant offspring of type 2 diabetic patients. Diabetes. 2007;56: 1376-1381.
279. Morino K, Petersen KF, Dufour S, et al. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. J Clin Invest. 2005;115:3587-3593.
280. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes. N Engl J Med. 2004;350:664-671.
281. Gomez-Perez Y, Amengual-Cladera E, Catala-Niell A, et al. Gender dimorphism in high-fat-diet-induced insulin resistance in skeletal muscle of aged rats. Cell Physiol Biochem. 2008;22:539-548.
282. Mauvais-Jarvis F, Kulkarni RN, Kahn CR. Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Clin Endocrinol (Oxf). 2002; 57:1-9.
283. Tiwari-Woodruff S, Voskuhl RR. Neuroprotective and anti-inflammatory effects of estrogen receptor ligand treatment in mice. J Neurol Sci. 2009;286:81-85.
284. Spence RD, Voskuhl RR. 2011 Neuroprotective effects of estrogens and androgens in CNS inflammation and neurodegeneration. Front Neuroendocrinol. 2012;33:105-115.
285. Gold SM, Sasidhar MV, Morales LB, et al. Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor α (ERα). Lab Invest. 2009;89:1076-1083.
286. Atwater I, Gondos B, DiBartolomeo R, Bazaes R, Jovanovic L. Pregnancy hormones prevent diabetes and reduce lymphocytic infiltration of islets in the NOD mouse. Ann Clin Lab Sci. 2002;32:87-92.
287. Dulos J, Vijn P, van Doorn C, et al. Suppression of the inflammatory response in experimental arthritis is mediated via estrogen receptor α but not estrogen receptor β. Arthritis Res Ther. 2010;12:R101.
288. Yang YH, Ngo D, Jones M, Simpson E, Fritzemeier KH, Morand EF. Endogenous estrogen regulation of inflammatory arthritis and cytokine expression in male mice, predominantly via estrogen receptor α. Arthritis Rheum. 2010;62:1017-1025.
289. Klein PW, Easterbrook JD, Lalime EN, Klein SL. Estrogen and progesterone affect responses to malaria infection in female C57BL/6 mice. Gend Med. 2008;5:423-433.
290. Vegeto E, Cuzzocrea S, Crisafulli C, et al. Estrogen receptor-α as a drug target candidate for preventing lung inflammation. Endocrinology. 2010;151:174-184.
291. Calippe B, Douin-Echinard V, Delpy L, et al.17β-Estradiol promotes TLR4-triggered proinflammatory mediator production through direct estrogen receptor α signaling in macrophages in vivo. J Immunol. 2010;185:1169-1176.
292. Hepworth MR, Hardman MJ, Grencis RK. The role of sex hormones in the development of Th2 immunity in a gender-biased model of Trichuris muris infection. Eur J Immunol. 2010;40:406-416.
293. Lezama-Davila CM, Isaac-Marquez AP, Barbi J, Cummings HE, Lu B, Satoskar AR. Role of phosphatidylinositol-3-kinase-γ (PI3Kγ)-mediated pathway in 17β-estradiol-induced killing of L. mexicana in macrophages from C57BL/6 mice. Immunol Cell Biol. 2008;86:539-543.
294. Douin-Echinard V, Calippe B, Billon-Gales A, et al. Estradiol administration controls eosinophilia through estrogen receptor-α activation during acute peritoneal inflammation. J Leukoc Biol. 2011;90:145-154.
295. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol. 2010;72:219-246.
296. Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nat Rev Immunol. 2011;11:738-749.
297. Ribas V, Drew BG, Le JA, et al. Myeloid-specific estrogen receptor α deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci USA. 2011;108:16457-16462.
298. Wong WP, Tiano JP, Liu S, et al. Extranuclear estrogen receptor-α stimulates NeuroD1 binding to the insulin promoter and favors insulin synthesis. Proc Natl Acad Sci USA. 2010;107:13057-13062.
299. Tiano JP, Delghingaro-Augusto V, Le May C, et al. Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes. J Clin Invest. 2011;121:3331-3342.
300. Tiano J, Mauvais-Jarvis F. Selective estrogen receptor modulation in pancreaticβ-cells and the prevention of type 2 diabetes. Islets. 2012;4:173-176.
301. Tiano JP, Mauvais-Jarvis F. Molecular mechanisms of estrogen receptors' suppression of lipogenesis in pancreatic β-cells. Endocrinology. 2012;153:2997-3005.
302. Alonso-Magdalena P, Ropero AB, Carrera MP, et al. Pancreatic insulin content regulation by the estrogen receptor ER α. PLoS One. 2008;3:e2069.
303. The 2012 hormone therapy position statement of: The North American Menopause Society. Menopause. 2012; 19:257-271.
304. Choe SS, Choi AH, Lee JW, et al. Chronic activation of liver X receptor induces β-cell apoptosis through hyperactivation of lipogenesis: liver X receptor-mediated lipotoxicity in pancreatic β-cells. Diabetes. 2007;56:1534-1543.
305. Le May C, Chu K, Hu M, et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice. Proc Natl Acad Sci USA. 2006; 103:9232-9237.
306. Liu S, LeMayC,WongWP,et al. Importance of extranuclear estrogen receptor-α and membraneGprotein-coupled estrogen receptor in pancreatic islet survival. Diabetes. 2009;58: 2292-2302.
307. Liu S, Mauvais-Jarvis F. Rapid, nongenomic estrogen actions protect pancreatic islet survival. Islets. 2009;1:273-275.
308. BaquieM,St-Onge L, Kerr-Conte J, et al. The liver receptor homolog-1 (LRH-1) is expressed in human islets and protects β-cells against stress-induced apoptosis. Hum Mol Genet. 2011;20:2823-2833.
309. Soriano S, Ropero AB, Alonso-Magdalena P, et al. Rapid regulation of K(ATP) channel activity by 17β-estradiol in pancreatic β-cells involves the estrogen receptor β and the atrial natriuretic peptide receptor. Mol Endocrinol. 2009; 23:1973-1982.
310. Soriano S, Alonso-Magdalena P, Garcia-Arevalo M, et al. Rapid insulinotropic action of low doses of bisphenol-A on mouse and human islets of Langerhans: role of estrogen receptor β. PLoS One. 2012;7:e31109.
311. Tiano J, Mauvais-Jarvis F. Selective estrogen receptor modulation in pancreaticβ-cells and the prevention of type 2 diabetes. Islets. 2012;4:173-176.
312. Balhuizen A, Kumar R, Amisten S, Lundquist I, Salehi A. Activation of G protein-coupled receptor 30 modulates hormone secretion and counteracts cytokine-induced apoptosis in pancreatic islets of female mice. Mol Cell Endocrinol. 2010;320:16-24.
313. Kumar R, Balhuizen A, Amisten S, Lundquist I, Salehi A. Insulinotropic and antidiabetic effects of 17β-estradiol and the GPR30 agonist G-1 on human pancreatic islets. Endocrinology. 2011;152:2568-2579.
314. Sharma G, Prossnitz ER. Mechanisms of estradiol-induced insulin secretion by the G protein-coupled estrogen receptor GPR30/GPER in pancreatic β-cells. Endocrinology. 2011;152:3030-3039.
315. Contreras JL, Smyth CA, Bilbao G, Young CJ, Thompson JA, Eckhoff DE. 17β-Estradiol protects isolated human pancreatic islets against proinflammatory cytokineinduced cell death: molecular mechanisms and islet functionality. Transplantation. 2002;74:1252-1259.
316. Salonia A, Lanzi R, Scavini M, et al. Sexual function and endocrine profile in fertile women with type 1 diabetes. Diabetes Care. 2006;29:312-316.
317. Liu S, Kilic G, Meyers MS, et al. Oestrogens improve human pancreatic islet transplantation in a mouse model of insulin deficient diabetes. Diabetologia. 2013;56:370-381.
318. Finan B, Yang B, Ottaway N, et al. Targeted estrogen delivery reverses the metabolic syndrome. Nat Med. 2012; 18:1847-1856.
319. Tiano J, Finan B, DiMarchi R, Mauvais-Jarvis F. A glucagon-like peptide-1-estrogen fusion peptide shows en-hanced efficacy in preventing insulin-deficient diabetes in mice. Endocr Rev. 2012;33:OR21-OR26.
320. Khor VK, Tong MH, Qian Y, Song WC. Gender-specific expression and mechanism of regulation of estrogen sulfotransferase in adipose tissues of the mouse. Endocrinology. 2008;149:5440-5448.
321. Khor VK, Dhir R, Yin X, Ahima RS, Song WC. Estrogen sulfotransferase regulates body fat and glucose homeostasis in female mice. Am J Physiol Endocrinol Metab. 2010; 299:E657-E664.
322. Ahima RS, Stanley TL, Khor VK, Zanni MV, Grinspoon SK. Estrogen sulfotransferase is expressed in subcutaneous adipose tissue of obese humans in association with TNF-α and SOCS3. J Clin Endocrinol Metab. 2011;96:E1153-E1158.
323. Leiter EH, Chapman HD. Obesity-induced diabetes (diabesity) in C57BL/KsJ mice produces aberrant transregulation of sex steroid sulfotransferase genes. J Clin Invest. 1994;93:2007-2013.
324. Gao J, He J, Shi X, et al. Sex-specific effect of estrogen sulfotransferase on mouse models of type 2 diabetes. Diabetes. 2012;61:1543-1551.
325. Mauvais-Jarvis P, Wepierre J, Vickers CF. 1990 Percutaneous absorption of steroids. New York: Academic Press Inc.
326. 326. Good WR, John VA, Ramirez M, Higgins JE. Comparison of Alora estradiol matrix transdermal delivery system with oral conjugated equine estrogen therapy in relieving menopausal symptoms. Alora Study Group. Climacteric. 1999; 2:29-36.
327. Sitruk-Ware R, de Lignieres B, Basdevant A, Mauvais-Jarvis P. Absorption of percutaneous oestradiol in postmenopausal women. Maturitas. 1980;2:207-211.
328. Elkik F, Gompel A, Mercier-Bodard C, et al. Effects of percutaneous estradiol and conjugated estrogens on the level of plasma proteins and triglycerides in postmenopausal women. Am J Obstet Gynecol. 1982;143:888-892.
329. ChuMC,Cosper P, Nakhuda GS, Lobo RA.Acomparison of oral and transdermal short-term estrogen therapy in postmenopausal women with metabolic syndrome. Fertil Steril. 2006;86:1669-1675.
330. Chu MC, Cushman M, Solomon R, Lobo RA. Metabolic syndrome in postmenopausal women: the influence of oral or transdermal estradiol on inflammation and coagulation markers.AmJ Obstet Gynecol. 2008;199:526.e1-526.e7.
331. Salpeter SR, Walsh JM, OrmistonTM,Greyber E, Buckley NS, Salpeter EE. Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women. Diabetes Obes Metab. 2006;8: 538-554.
332. Grodstein F, Manson JE, Colditz GA, Willett WC, Speizer FE, Stampfer MJ. A prospective, observational study of postmenopausal hormone therapy and primary prevention of cardiovascular disease. Ann Intern Med. 2000;133: 933-941.
333. Salpeter SR, Cheng J, Thabane L, Buckley NS, Salpeter EE. Bayesian meta-analysis of hormone therapy and mortality in younger postmenopausal women.AmJ Med. 2009;122: 1016-1022.e1.
334. Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605-613.
335. Grodstein F, Manson JE, Stampfer MJ. Postmenopausal hormone use and secondary prevention of coronary events in the Nurses' Health Study. A prospective, observational study. Ann Intern Med. 2001;135:1-8.
336. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial. JAMA. 2004;291:1701-1712.
337. Ogawa Y, Murata Y, Nishioka A, Inomata T, Yoshida S. Tamoxifen-induced fatty liver in patients with breast cancer. Lancet. 1998;351:725.
338. Coskun U, Toruner FB, Gunel N. Tamoxifen therapy and hepatic steatosis. Neoplasma. 2002;49:61-64.
339. NishinoM,HayakawaK,NakamuraY,MorimotoT,Mukaihara S. Effects of tamoxifen on hepatic fat content and the development of hepatic steatosis in patients with breast cancer: high frequency of involvement and rapid reversal after completion of tamoxifen therapy. AJR Am J Roentgenol. 2003;180:129-134.
340. Lelliott CJ, Lopez M, Curtis RK, et al. Transcript and metabolite analysis of the effects of tamoxifen in rat liver reveals inhibition of fatty acid synthesis in the presence of hepatic steatosis. FASEB J. 2005;19:1108-1119.
341. Gudbrandsen OA, Rost TH, Berge RK. Causes and prevention of tamoxifen-induced accumulation of triacylglycerol in rat liver. J Lipid Res. 2006;47:2223-2232.
342. Cole LK, Jacobs RL, Vance DE. Tamoxifen induces triacylglycerol accumulation in the mouse liver by activation of fatty acid synthesis. Hepatology. 2010;52:1258-1265.
343. Lopez M, Lelliott CJ, Tovar S, et al. Tamoxifen-induced anorexia is associated with fatty acid synthase inhibition in the ventromedial nucleus of the hypothalamus and accumulation of malonyl-CoA. Diabetes. 2006;55:1327-1336.
344. Lipscombe LL, Fischer HD, Yun L, et al. Association between tamoxifen treatment and diabetes: a populationbased study. Cancer. 2012;118:2615-2622.
345. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999;282: 637-645.
346. Meli R, Pacilio M, RasoGM,et al. Estrogen and raloxifene modulate leptin and its receptor in hypothalamus and adipose tissue from ovariectomized rats. Endocrinology. 2004;145:3115-3121.
347. Tommaselli GA, Di Carlo C, Di Spiezio Sardo A, et al. Serum leptin levels and body composition in postmenopausal women treated with tibolone and raloxifene. Menopause. 2006;13:660-668.
348. Francucci CM, Daniele P, Iori N, Camilletti A, Massi F, Boscaro M. Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal women. J Endocrinol Invest. 2005;28:623-631.
349. Barrett-Connor E, Ensrud KE, Harper K, et al. Post hoc analysis of data from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial on the effects of three years of raloxifene treatment on glycemic control and cardiovascular disease risk factors in women with and without type 2 diabetes. Clin Ther. 2003;25:919-930.
350. Jacobsen DE, Samson MM, Emmelot-Vonk MH, Verhaar HJ. Raloxifene and body composition and muscle strength in postmenopausal women: a randomized, double-blind, placebo-controlled trial. Eur J Endocrinol. 2010;162:371-376. 351. Andersson B, Johannsson G, Holm G, et al. Raloxifene does not affect insulin sensitivity or glycemic control in postmenopausal women with type 2 diabetes mellitus: a randomized clinical trial. J Clin Endocrinol Metab. 2002; 87:122-128.
351. Andersson B, Johannsson G, Holm G, et al. Raloxifene does not affect insulin sensitivity or glycemic control in postmenopausal women with type 2 diabetes mellitus: a randomized clinical trial. J Clin Endocrinol Metab. 2002; 87:122-128.
352. Nagamani M, Szymajda A, Sepilian V, Urban RJ, Gilkison C. Effects of raloxifene on insulin sensitivity, β-cell function, and hepatic insulin extraction in normal postmenopausal women. Fertil Steril. 2008;89:614-619.
353. Carr MC, Knopp RH, Brunzell JD, et al. Effect of raloxifene on serum triglycerides in women with a history of hypertriglyceridemia while on oral estrogen therapy. Diabetes Care. 2005;28:1555-1561.
354. Kharode Y, Bodine PV, Miller CP, Lyttle CR, Komm BS. The pairing of a selective estrogen receptor modulator, bazedoxifene, with conjugated estrogens as a new paradigm for the treatment of menopausal symptoms and osteoporosis prevention. Endocrinology. 2008;149:6084-6091.
355. Komm BS. A new approach to menopausal therapy: the tissue selective estrogen complex. Reprod Sci. 2008;15: 984-992.
356. Sullivan EL, Shearin J, Koegler FH, Cameron JL. Selective estrogen receptor modulator promotes weight loss in ovariectomized female rhesus monkeys (Macaca mulatta) by decreasing food intake and increasing activity. Am J Physiol Endocrinol Metab. 2012;302:E759-E767.
357. Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med. 2003;348:2431-2442.