1932

Abstract

The role of central estrogen in cognitive, metabolic, and reproductive health has long fascinated the lay public and scientists alike. In the last two decades, insight into estrogen signaling in the brain and its impact on female physiology is beginning to catch up with the vast information already established for its actions on peripheral tissues. Using newer methods to manipulate estrogen signaling in hormone-sensitive brain regions, neuroscientists are now identifying the molecular pathways and neuronal subtypes required for controlling sex-dependent energy allocation. However, the immense cellular complexity of these hormone-sensitive brain regions makes it clear that more research is needed to fully appreciate how estrogen modulates neural circuits to regulate physiological and behavioral end points. Such insight is essential for understanding how natural or drug-induced hormone fluctuations across lifespan affect women's health.

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2022-02-10
2024-06-14
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Literature Cited

  1. 1. 
    Colditz GA, Hankinson SE, Hunter DJ, Willett WC, Manson JE et al. 1995. The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N. Engl. J. Med. 332:1589–93
    [Google Scholar]
  2. 2. 
    Arnold AP. 2004. Sex chromosomes and brain gender. Nat. Rev. Neurosci. 5:701–8
    [Google Scholar]
  3. 3. 
    Cooke PS, Nanjappa MK, Ko C, Prins GS, Hess RA. 2017. Estrogens in male physiology. Physiol. Rev. 97:995–1043
    [Google Scholar]
  4. 4. 
    Wu MV, Manoli DS, Fraser EJ, Coats JK, Tollkuhn J et al. 2009. Estrogen masculinizes neural pathways and sex-specific behaviors. Cell 139:61–72
    [Google Scholar]
  5. 5. 
    Brooks DC, Coon VJ, Ercan CM, Xu X, Dong H et al. 2020. Brain aromatase and the regulation of sexual activity in male mice. Endocrinology 161:bqaa137
    [Google Scholar]
  6. 6. 
    Unger EK, Burke KJ Jr., Yang CF, Bender KJ, Fuller PM, Shah NM. 2015. Medial amygdalar aromatase neurons regulate aggression in both sexes. Cell Rep. 10:453–62
    [Google Scholar]
  7. 7. 
    Sato T, Matsumoto T, Kawano H, Watanabe T, Uematsu Y et al. 2004. Brain masculinization requires androgen receptor function. PNAS 101:1673–78
    [Google Scholar]
  8. 8. 
    Ogawa S, Chester AE, Hewitt SC, Walker VR, Gustafsson JA et al. 2000. Abolition of male sexual behaviors in mice lacking estrogen receptors α and β (αβERKO). PNAS 97:14737–41
    [Google Scholar]
  9. 9. 
    Cheong RY, Czieselsky K, Porteous R, Herbison AE 2015. Expression of ESR1 in glutamatergic and GABAergic neurons is essential for normal puberty onset, estrogen feedback, and fertility in female mice. J. Neurosci. 35:14533–43
    [Google Scholar]
  10. 10. 
    Wu MV, Tollkuhn J. 2017. Estrogen receptor alpha is required in GABAergic, but not glutamatergic, neurons to masculinize behavior. Horm. Behav. 95:3–12
    [Google Scholar]
  11. 11. 
    Navarro G, Allard C, Morford JJ, Xu W, Liu S et al. 2018. Androgen excess in pancreatic β cells and neurons predisposes female mice to type 2 diabetes. JCI Insight 3:e98607
    [Google Scholar]
  12. 12. 
    Hines M, Ahmed SF, Hughes IA 2003. Psychological outcomes and gender-related development in complete androgen insensitivity syndrome. Arch. Sex. Behav. 32:93–101
    [Google Scholar]
  13. 13. 
    Li Y, Hamilton KJ, Perera L, Wang T, Gruzdev A et al. 2020. ESR1 mutations associated with estrogen insensitivity syndrome change conformation of ligand-receptor complex and altered transcriptome profile. Endocrinology 161:bqaa050
    [Google Scholar]
  14. 14. 
    Bernard V, Kherra S, Francou B, Fagart J, Viengchareun S et al. 2017. Familial multiplicity of estrogen insensitivity associated with a loss-of-function ESR1 mutation. J. Clin. Endocrinol. Metab. 102:93–99
    [Google Scholar]
  15. 15. 
    Juntti SA, Coats JK, Shah NM. 2008. A genetic approach to dissect sexually dimorphic behaviors. Horm. Behav. 53:627–37
    [Google Scholar]
  16. 16. 
    Bell MR. 2018. Comparing postnatal development of gonadal hormones and associated social behaviors in rats, mice, and humans. Endocrinology 159:2596–613
    [Google Scholar]
  17. 17. 
    Bakker J, De Mees C, Douhard Q, Balthazart J, Gabant P et al. 2006. Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens. Nat. Neurosci. 9:220–26
    [Google Scholar]
  18. 18. 
    Shen WH, Moore CC, Ikeda Y, Parker KL, Ingraham HA 1994. Nuclear receptor steroidogenic factor 1 regulates the Müllerian inhibiting substance gene: a link to the sex determination cascade. Cell 77:651–61
    [Google Scholar]
  19. 19. 
    Hara Y, Waters EM, McEwen BS, Morrison JH. 2015. Estrogen effects on cognitive and synaptic health over the lifecourse. Physiol. Rev. 95:785–807
    [Google Scholar]
  20. 20. 
    Inoue S, Yang R, Tantry A, Davis CH, Yang T et al. 2019. Periodic remodeling in a neural circuit governs timing of female sexual behavior. Cell 179:1393–408.e16
    [Google Scholar]
  21. 21. 
    Hao J, Rapp PR, Janssen WG, Lou W, Lasley BL et al. 2007. Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. PNAS 104:11465–70
    [Google Scholar]
  22. 22. 
    Ingalhalikar M, Smith A, Parker D, Satterthwaite TD, Elliott MA et al. 2014. Sex differences in the structural connectome of the human brain. PNAS 111:823–28
    [Google Scholar]
  23. 23. 
    Ritchie SJ, Cox SR, Shen X, Lombardo MV, Reus LM et al. 2018. Sex differences in the adult human brain: evidence from 5216 UK Biobank participants. Cereb. Cortex 28:2959–75
    [Google Scholar]
  24. 24. 
    Ikeda Y, Shen WH, Ingraham HA, Parker KL. 1994. Developmental expression of mouse steroidogenic factor-1, an essential regulator of the steroid hydroxylases. Mol. Endocrinol. 8:654–62
    [Google Scholar]
  25. 25. 
    Ingraham HA, Lala DS, Ikeda Y, Luo X, Shen WH et al. 1994. The nuclear receptor steroidogenic factor 1 acts at multiple levels of the reproductive axis. Genes Dev. 8:2302–12
    [Google Scholar]
  26. 26. 
    Ikeda Y, Luo X, Abbud R, Nilson JH, Parker KL 1995. The nuclear receptor steroidogenic factor 1 is essential for the formation of the ventromedial hypothalamic nucleus. Mol. Endocrinol. 9:478–86
    [Google Scholar]
  27. 27. 
    Buonocore F, Achermann JC. 2020. Primary adrenal insufficiency: New genetic causes and their long-term consequences. Clin. Endocrinol. 92:11–20
    [Google Scholar]
  28. 28. 
    Meinsohn MC, Smith OE, Bertolin K, Murphy BD. 2019. The orphan nuclear receptors steroidogenic factor-1 and liver receptor homolog-1: structure, regulation, and essential roles in mammalian reproduction. Physiol. Rev. 99:1249–79
    [Google Scholar]
  29. 29. 
    Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM et al. 2005. Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120:343–55
    [Google Scholar]
  30. 30. 
    Li Y, Choi M, Cavey G, Daugherty J, Suino K et al. 2005. Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol. Cell 17:491–502
    [Google Scholar]
  31. 31. 
    Blind RD, Sablin EP, Kuchenbecker KM, Chiu HJ, Deacon AM et al. 2014. The signaling phospholipid PIP3 creates a new interaction surface on the nuclear receptor SF-1. PNAS 111:15054–59
    [Google Scholar]
  32. 32. 
    Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F et al. 2009. Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Mol. Endocrinol. 23:25–34
    [Google Scholar]
  33. 33. 
    Hammer GD, Krylova I, Zhang Y, Darimont BD, Simpson K et al. 1999. Phosphorylation of the nuclear receptor SF-1 modulates cofactor recruitment: integration of hormone signaling in reproduction and stress. Mol. Cell 3:521–26
    [Google Scholar]
  34. 34. 
    Lee FY, Faivre EJ, Suzawa M, Lontok E, Ebert Det al 2011. Eliminating SF-1 (NR5A1) sumoylation in vivo results in ectopic hedgehog signaling and disruption of endocrine development. Dev. Cell 21:315–27
    [Google Scholar]
  35. 35. 
    Sekido R, Lovell-Badge R. 2008. Sex determination involves synergistic action of SRY and SF1 on a specific Sox9 enhancer. Nature 453:930–34
    [Google Scholar]
  36. 36. 
    Suntharalingham JP, Buonocore F, Duncan AJ, Achermann JC. 2015. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease. Best Pract. Res. Clin. Endocrinol. Metab. 29:607–19
    [Google Scholar]
  37. 37. 
    Luo X, Ikeda Y, Parker KL. 1994. A cell-specific nuclear receptor is essential for adrenal and gonadal development and sexual differentiation. Cell 77:481–90
    [Google Scholar]
  38. 38. 
    Bland ML, Jamieson C, Akana S, Dallman M, Ingraham HA 2000. Gene dosage effects of steroidogenic factor 1 (SF-1) in adrenal development and the stress. Endocr. Res. 26:515–16
    [Google Scholar]
  39. 39. 
    Dellovade TL, Young M, Ross EP, Henderson R, Caron K et al. 2000. Disruption of the gene encoding SF-1 alters the distribution of hypothalamic neuronal phenotypes. J. Comp. Neurol. 423:579–89
    [Google Scholar]
  40. 40. 
    Tran PV, Lee MB, Marin O, Xu B, Jones KR et al. 2003. Requirement of the orphan nuclear receptor SF-1 in terminal differentiation of ventromedial hypothalamic neurons. Mol. Cell. Neurosci. 22:441–53
    [Google Scholar]
  41. 41. 
    Cheung CC, Kurrasch DM, Liang JK, Ingraham HA. 2013. Genetic labeling of steroidogenic factor-1 (SF-1) neurons in mice reveals ventromedial nucleus of the hypothalamus (VMH) circuitry beginning at neurogenesis and development of a separate non-SF-1 neuronal cluster in the ventrolateral VMH. J. Comp. Neurol. 521:1268–88
    [Google Scholar]
  42. 42. 
    Dhillon H, Zigman JM, Ye C, Lee CE, McGovern RA et al. 2006. Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis. Neuron 49:191–203
    [Google Scholar]
  43. 43. 
    Xu Y, Nedungadi TP, Zhu L, Sobhani N, Irani BG et al. 2011. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14:453–65
    [Google Scholar]
  44. 44. 
    Correa SM, Newstrom DW, Warne JP, Flandin P, Cheung CC et al. 2015. An estrogen-responsive module in the ventromedial hypothalamus selectively drives sex-specific activity in females. Cell Rep. 10:62–74
    [Google Scholar]
  45. 45. 
    Gervais NJ, Remage-Healey L, Starrett JR, Pollak DJ, Mong JA, Lacreuse A. 2019. Adverse effects of aromatase inhibition on the brain and behavior in a nonhuman primate. J. Neurosci. 39:918–28
    [Google Scholar]
  46. 46. 
    Biegon A, Alia-Klein N, Alexoff DL, Fowler JS, Kim SW et al. 2020. Relationship of estrogen synthesis capacity in the brain with obesity and self-control in men and women. PNAS 117:22962–66
    [Google Scholar]
  47. 47. 
    Eick GN, Colucci JK, Harms MJ, Ortlund EA, Thornton JW 2012. Evolution of minimal specificity and promiscuity in steroid hormone receptors. PLOS Genet. 8:e1003072
    [Google Scholar]
  48. 48. 
    Sagoshi S, Maejima S, Morishita M, Takenawa S, Otubo A et al. 2020. Detection and characterization of estrogen receptor beta expression in the brain with newly developed transgenic mice. Neuroscience 438:182–97
    [Google Scholar]
  49. 49. 
    Shughrue PJ, Lane MV, Merchenthaler I. 1999. Biologically active estrogen receptor-β: evidence from in vivo autoradiographic studies with estrogen receptor α-knockout mice. Endocrinology 140:2613–20
    [Google Scholar]
  50. 50. 
    Heine PA, Taylor JA, Iwamoto GA, Lubahn DB, Cooke PS. 2000. Increased adipose tissue in male and female estrogen receptor-α knockout mice. PNAS 97:12729–34
    [Google Scholar]
  51. 51. 
    Ogawa S, Chan J, Gustafsson JA, Korach KS, Pfaff DW. 2003. Estrogen increases locomotor activity in mice through estrogen receptor α: specificity for the type of activity. Endocrinology 144:230–39
    [Google Scholar]
  52. 52. 
    Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly YM et al. 2000. Obesity and disturbed lipoprotein profile in estrogen receptor-α-deficient male mice. Biochem. Biophys. Res. Commun. 278:640–45
    [Google Scholar]
  53. 53. 
    Park CJ, Zhao Z, Glidewell-Kenney C, Lazic M, Chambon P et al. 2011. Genetic rescue of nonclassical ERα signaling normalizes energy balance in obese Erα-null mutant mice. J. Clin. Investig. 121:604–12
    [Google Scholar]
  54. 54. 
    Hazell GG, Yao ST, Roper JA, Prossnitz ER, O'Carroll AM, Lolait SJ. 2009. Localisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues. J. Endocrinol. 202:223–36
    [Google Scholar]
  55. 55. 
    Sharma G, Hu C, Staquicini DI, Brigman JL, Liu M et al. 2020. Preclinical efficacy of the GPER-selective agonist G-1 in mouse models of obesity and diabetes. Sci. Transl. Med. 12:eaau5956
    [Google Scholar]
  56. 56. 
    Fanning SW, Greene GL. 2019. Next-generation ERα inhibitors for endocrine-resistant ER+ breast cancer. Endocrinology 160:759–69
    [Google Scholar]
  57. 57. 
    Krause WC, Rodriguez R, Gegenhuber B, Matharu N, Rodriguez AN et al. 2021. Oestrogen engages brain MC4R signalling to increase physical activity in female mice. Nature 599:131–35
    [Google Scholar]
  58. 58. 
    Yang JA, Stires H, Belden WJ, Roepke TA. 2017. The arcuate estrogen-regulated transcriptome: estrogen response element-dependent and -independent signaling of ERα in female mice. Endocrinology 158:612–26
    [Google Scholar]
  59. 59. 
    Herber CB, Krause WC, Wang L, Bayrer JR, Li A et al. 2019. Estrogen signaling in arcuate Kiss1 neurons suppresses a sex-dependent female circuit promoting dense strong bones. Nat. Commun. 10:163
    [Google Scholar]
  60. 60. 
    Gegenhuber B, Wu MV, Bronstein R, Tollkuhn J. 2021. Regulation of neural gene expression by estrogen receptor alpha. BioRxiv 349290. https://doi.org/10.1101/2020.10.21.349290
    [Crossref]
  61. 61. 
    Skene PJ, Henikoff JG, Henikoff S. 2018. Targeted in situ genome-wide profiling with high efficiency for low cell numbers. Nat. Protoc. 13:1006–19
    [Google Scholar]
  62. 62. 
    Kininis M, Chen BS, Diehl AG, Isaacs GD, Zhang T et al. 2007. Genomic analyses of transcription factor binding, histone acetylation, and gene expression reveal mechanistically distinct classes of estrogen-regulated promoters. Mol. Cell. Biol. 27:5090–104
    [Google Scholar]
  63. 63. 
    Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA et al. 2005. Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122:33–43
    [Google Scholar]
  64. 64. 
    Della Torre S, Benedusi V, Fontana R, Maggi A. 2014. Energy metabolism and fertility: a balance preserved for female health. Nat. Rev. Endocrinol. 10:13–23
    [Google Scholar]
  65. 65. 
    Slonaker JR. 1924. The effect of pubescence, oestruatlon and menopause on the voluntary activity in the albino rat. Am. J. Physiol. 68:294–315
    [Google Scholar]
  66. 66. 
    Andermann ML, Lowell BB. 2017. Toward a wiring diagram understanding of appetite control. Neuron 95:757–78
    [Google Scholar]
  67. 67. 
    Toda C, Santoro A, Kim JD, Diano S. 2017. POMC neurons: from birth to death. Annu. Rev. Physiol. 79:209–36
    [Google Scholar]
  68. 68. 
    Huisman C, Cho H, Brock O, Lim SJ, Youn SM et al. 2019. Single cell transcriptome analysis of developing arcuate nucleus neurons uncovers their key developmental regulators. Nat. Commun. 10:3696
    [Google Scholar]
  69. 69. 
    Lam BYH, Cimino I, Polex-Wolf J, Nicole Kohnke S, Rimmington D et al. 2017. Heterogeneity of hypothalamic pro-opiomelanocortin-expressing neurons revealed by single-cell RNA sequencing. Mol. Metab. 6:383–92
    [Google Scholar]
  70. 70. 
    Campbell JN, Macosko EZ, Fenselau H, Pers TH, Lyubetskaya A et al. 2017. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20:484–96
    [Google Scholar]
  71. 71. 
    Padilla SL, Carmody JS, Zeltser LM. 2010. Pomc-expressing progenitors give rise to antagonistic neuronal populations in hypothalamic feeding circuits. Nat. Med. 16:403–5
    [Google Scholar]
  72. 72. 
    Kumar D, Freese M, Drexler D, Hermans-Borgmeyer I, Marquardt A, Boehm U. 2014. Murine arcuate nucleus kisspeptin neurons communicate with GnRH neurons in utero. J. Neurosci. 34:3756–66
    [Google Scholar]
  73. 73. 
    Haddad-Tovolli R, Dragano NRV, Ramalho AFS, Velloso LA. 2017. Development and function of the blood-brain barrier in the context of metabolic control. Front. Neurosci. 11:224
    [Google Scholar]
  74. 74. 
    Yulyaningsih E, Rudenko IA, Valdearcos M, Dahlen E, Vagena E et al. 2017. Acute lesioning and rapid repair of hypothalamic neurons outside the blood-brain barrier. Cell Rep. 19:2257–71
    [Google Scholar]
  75. 75. 
    Robins SC, Stewart I, McNay DE, Taylor V, Giachino C et al. 2013. α-Tanycytes of the adult hypothalamic third ventricle include distinct populations of FGF-responsive neural progenitors. Nat. Commun 4:2049
    [Google Scholar]
  76. 76. 
    Lee DA, Bedont JL, Pak T, Wang H, Song J et al. 2012. Tanycytes of the hypothalamic median eminence form a diet-responsive neurogenic niche. Nat. Neurosci. 15:700–2
    [Google Scholar]
  77. 77. 
    Bolborea M, Pollatzek E, Benford H, Sotelo-Hitschfeld T, Dale N. 2020. Hypothalamic tanycytes generate acute hyperphagia through activation of the arcuate neuronal network. PNAS 117:14473–81
    [Google Scholar]
  78. 78. 
    Prevot V, Dehouck B, Sharif A, Ciofi P, Giacobini P, Clasadonte J 2018. The versatile tanycyte: a hypothalamic integrator of reproduction and energy metabolism. Endocr. Rev. 39:333–68
    [Google Scholar]
  79. 79. 
    Yoo S, Cha D, Kim S, Jiang L, Cooke Pet al 2020. Tanycyte ablation in the arcuate nucleus and median eminence increases obesity susceptibility by increasing body fat content in male mice. Glia 68:1987–2000
    [Google Scholar]
  80. 80. 
    Beyer C, Green SJ, Barker PJ, Huskisson NS, Hutchison JB. 1994. Aromatase-immunoreactivity is localised specifically in neurones in the developing mouse hypothalamus and cortex. Brain Res. 638:203–10
    [Google Scholar]
  81. 81. 
    Hill RA, Pompolo S, Jones ME, Simpson ER, Boon WC. 2004. Estrogen deficiency leads to apoptosis in dopaminergic neurons in the medial preoptic area and arcuate nucleus of male mice. Mol. Cell. Neurosci. 27:466–76
    [Google Scholar]
  82. 82. 
    Gonzalez-Mariscal G, Melo AI, Jimenez P, Beyer C, Rosenblatt JS. 1996. Estradiol, progesterone, and prolactin regulate maternal nest-building in rabbits. J. Neuroendocrinol. 8:901–7
    [Google Scholar]
  83. 83. 
    Stincic TL, Grachev P, Bosch MA, Ronnekleiv OK, Kelly MJ. 2018. Estradiol drives the anorexigenic activity of proopiomelanocortin neurons in female mice. eNeuro 5:ENEURO.0103-18.2018
    [Google Scholar]
  84. 84. 
    Stincic TL, Ronnekleiv OK, Kelly MJ. 2018. Diverse actions of estradiol on anorexigenic and orexigenic hypothalamic arcuate neurons. Horm. Behav. 104:146–55
    [Google Scholar]
  85. 85. 
    Goodman RL, Knobil E. 1981. The sites of action of ovarian steroids in the regulation of LH secretion. Neuroendocrinology 32:57–63
    [Google Scholar]
  86. 86. 
    Wang D, He X, Zhao Z, Feng Q, Lin R et al. 2015. Whole-brain mapping of the direct inputs and axonal projections of POMC and AgRP neurons. Front. Neuroanat. 9:40
    [Google Scholar]
  87. 87. 
    Santollo J, Eckel LA. 2008. Estradiol decreases the orexigenic effect of neuropeptide Y, but not agouti-related protein, in ovariectomized rats. Behav. Brain Res. 191:173–77
    [Google Scholar]
  88. 88. 
    Benedusi V, Della Torre S, Mitro N, Caruso D, Oberto A et al. 2017. Liver ERα regulates AgRP neuronal activity in the arcuate nucleus of female mice. Sci Rep 7:1194
    [Google Scholar]
  89. 89. 
    Corrigan JK, Ramachandran D, He Y, Palmer CJ, Jurczak MJ et al. 2020. A big-data approach to understanding metabolic rate and response to obesity in laboratory mice. eLife 9:e53560
    [Google Scholar]
  90. 90. 
    Asarian L, Geary N. 2007. Estradiol enhances cholecystokinin-dependent lipid-induced satiation and activates estrogen receptor-α-expressing cells in the nucleus tractus solitarius of ovariectomized rats. Endocrinology 148:5656–66
    [Google Scholar]
  91. 91. 
    Cao X, Xu P, Oyola MG, Xia Y, Yan X et al. 2014. Estrogens stimulate serotonin neurons to inhibit binge-like eating in mice. J. Clin. Investig. 124:4351–62
    [Google Scholar]
  92. 92. 
    Fu LY, van den Pol AN. 2008. Agouti-related peptide and MC3/4 receptor agonists both inhibit excitatory hypothalamic ventromedial nucleus neurons. J. Neurosci. 28:5433–49
    [Google Scholar]
  93. 93. 
    Qiu J, Rivera HM, Bosch MA, Padilla SL, Stincic TL et al. 2018. Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females. eLife 7:e35656
    [Google Scholar]
  94. 94. 
    Frazao R, Dungan Lemko HM, da Silva RP, Ratra DV, Lee CE et al. 2014. Estradiol modulates Kiss1 neuronal response to ghrelin. Am. J. Physiol. Endocrinol. Metab. 306:E606–14
    [Google Scholar]
  95. 95. 
    Fenselau H, Campbell JN, Verstegen AM, Madara JC, Xu J et al. 2017. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20:42–51
    [Google Scholar]
  96. 96. 
    Padilla SL, Perez JG, Ben-Hamo M, Johnson CW, Sanchez REA et al. 2019. Kisspeptin neurons in the arcuate nucleus of the hypothalamus orchestrate circadian rhythms and metabolism. Curr. Biol. 29:592–604.e4
    [Google Scholar]
  97. 97. 
    Stafford LJ, Xia C, Ma W, Cai Y, Liu M. 2002. Identification and characterization of mouse metastasis-suppressor KiSS1 and its G-protein-coupled receptor. Cancer Res. 62:5399–404
    [Google Scholar]
  98. 98. 
    Mayer C, Acosta-Martinez M, Dubois SL, Wolfe A, Radovick S et al. 2010. Timing and completion of puberty in female mice depend on estrogen receptor α-signaling in kisspeptin neurons. PNAS 107:22693–98
    [Google Scholar]
  99. 99. 
    Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA 2009. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J. Neurosci. 29:11859–66
    [Google Scholar]
  100. 100. 
    Stephens SB, Chahal N, Munaganuru N, Parra RA, Kauffman AS. 2016. Estrogen stimulation of Kiss1 expression in the medial amygdala involves estrogen receptor-α but not estrogen receptor-β. Endocrinology 157:4021–31
    [Google Scholar]
  101. 101. 
    Frazao R, Cravo RM, Donato J Jr., Ratra DV, Clegg DJ et al. 2013. Shift in Kiss1 cell activity requires estrogen receptor α. J. Neurosci. 33:2807–20
    [Google Scholar]
  102. 102. 
    Lindzey J, Jayes FL, Yates MM, Couse JF, Korach KS. 2006. The bi-modal effects of estradiol on gonadotropin synthesis and secretion in female mice are dependent on estrogen receptor-α. J. Endocrinol. 191:309–17
    [Google Scholar]
  103. 103. 
    Moenter SM, Chu Z, Christian CA 2009. Neurobiological mechanisms underlying oestradiol negative and positive feedback regulation of gonadotrophin-releasing hormone neurones. J. Neuroendocrinol. 21:327–33
    [Google Scholar]
  104. 104. 
    Rønnekleiv OK, Zhang C, Bosch MA, Kelly MJ 2015. Kisspeptin and gonadotropin-releasing hormone neuronal excitability: molecular mechanisms driven by 17β-estradiol. Neuroendocrinology 102:184–93
    [Google Scholar]
  105. 105. 
    Dubois SL, Acosta-Martinez M, DeJoseph MR, Wolfe A, Radovick S et al. 2015. Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor α in kisspeptin neurons. Endocrinology 156:1111–20
    [Google Scholar]
  106. 106. 
    Wang L, Vanacker C, Burger LL, Barnes T, Shah YM et al. 2019. Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction. eLife 8:e43999
    [Google Scholar]
  107. 107. 
    Dorling AA, Todman MG, Korach KS, Herbison AE. 2003. Critical role for estrogen receptor alpha in negative feedback regulation of gonadotropin-releasing hormone mRNA expression in the female mouse. Neuroendocrinology 78:204–9
    [Google Scholar]
  108. 108. 
    Greenwald-Yarnell ML, Marsh C, Allison MB, Patterson CM, Kasper C et al. 2016. ERα in Tac2 neurons regulates puberty onset in female mice. Endocrinology 157:1555–65
    [Google Scholar]
  109. 109. 
    Gieske MC, Kim HJ, Legan SJ, Koo Y, Krust A et al. 2008. Pituitary gonadotroph estrogen receptor-α is necessary for fertility in females. Endocrinology 149:20–27
    [Google Scholar]
  110. 110. 
    Fergani C, Leon S, Padilla SL, Verstegen AM, Palmiter RD, Navarro VM 2018. NKB signaling in the posterodorsal medial amygdala stimulates gonadotropin release in a kisspeptin-independent manner in female mice. eLife 7:e40476
    [Google Scholar]
  111. 111. 
    Dudek M, Ziarniak K, Sliwowska JH. 2018. Kisspeptin and metabolism: the brain and beyond. Front. Endocrinol. 9:145
    [Google Scholar]
  112. 112. 
    Padilla SL, Qiu J, Nestor CC, Zhang C, Smith AW et al. 2017. AgRP to Kiss1 neuron signaling links nutritional state and fertility. PNAS 114:2413–18
    [Google Scholar]
  113. 113. 
    Kim JG, Sun BH, Dietrich MO, Koch M, Yao GQ et al. 2015. AgRP neurons regulate bone mass. Cell Rep 13:8–14
    [Google Scholar]
  114. 114. 
    Farman HH, Windahl SH, Westberg L, Isaksson H, Egecioglu E et al. 2016. Female mice lacking estrogen receptor-α in hypothalamic proopiomelanocortin (POMC) neurons display enhanced estrogenic response on cortical bone mass. Endocrinology 157:3242–52
    [Google Scholar]
  115. 115. 
    Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z et al. 2006. FSH directly regulates bone mass. Cell 125:247–60
    [Google Scholar]
  116. 116. 
    Szawka RE, Ribeiro AB, Leite CM, Helena CV, Franci CR et al. 2010. Kisspeptin regulates prolactin release through hypothalamic dopaminergic neurons. Endocrinology 151:3247–57
    [Google Scholar]
  117. 117. 
    Doan KV, Kinyua AW, Yang DJ, Ko CM, Moh SH et al. 2016. FoxO1 in dopaminergic neurons regulates energy homeostasis and targets tyrosine hydroxylase. Nat. Commun. 7:12733
    [Google Scholar]
  118. 118. 
    Herber CB, Ingraham HA. 2019. Should we make more bone or not, as told by Kisspeptin neurons in the arcuate nucleus. Semin. Reprod. Med. 37:147–50
    [Google Scholar]
  119. 119. 
    Coutinho EA, Okamoto S, Ishikawa AW, Yokota S, Wada N et al. 2017. Activation of SF1 neurons in the ventromedial hypothalamus by DREADD technology increases insulin sensitivity in peripheral tissues. Diabetes 66:2372–86
    [Google Scholar]
  120. 120. 
    Garfield AS, Shah BP, Madara JC, Burke LK, Patterson CM et al. 2014. A parabrachial-hypothalamic cholecystokinin neurocircuit controls counterregulatory responses to hypoglycemia. Cell Metab. 20:1030–37
    [Google Scholar]
  121. 121. 
    Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B et al. 2007. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab. 5:383–93
    [Google Scholar]
  122. 122. 
    Borg WP, Sherwin RS, During MJ, Borg MA, Shulman GI. 1995. Local ventromedial hypothalamus glucopenia triggers counterregulatory hormone release. Diabetes 44:180–84
    [Google Scholar]
  123. 123. 
    Cheung CC, Krause WC, Edwards RH, Yang CF, Shah NM et al. 2015. Sex-dependent changes in metabolism and behavior, as well as reduced anxiety after eliminating ventromedial hypothalamus excitatory output. Mol. Metab. 4:857–66
    [Google Scholar]
  124. 124. 
    Kunwar PS, Zelikowsky M, Remedios R, Cai H, Yilmaz M et al. 2015. Ventromedial hypothalamic neurons control a defensive emotion state. eLife 4:e06633
    [Google Scholar]
  125. 125. 
    Silva BA, Mattucci C, Krzywkowski P, Murana E, Illarionova A et al. 2013. Independent hypothalamic circuits for social and predator fear. Nat. Neurosci. 16:1731–33
    [Google Scholar]
  126. 126. 
    Viskaitis P, Irvine EE, Smith MA, Choudhury AI, Alvarez-Curto E et al. 2017. Modulation of SF1 neuron activity coordinately regulates both feeding behavior and associated emotional states. Cell Rep. 21:3559–72
    [Google Scholar]
  127. 127. 
    Saito K, He Y, Yang Y, Zhu L, Wang C et al. 2016. PI3K in the ventromedial hypothalamic nucleus mediates estrogenic actions on energy expenditure in female mice. Sci. Rep. 6:23459
    [Google Scholar]
  128. 128. 
    Flanagan-Cato LM. 2011. Sex differences in the neural circuit that mediates female sexual receptivity. Front. Neuroendocrinol. 32:124–36
    [Google Scholar]
  129. 129. 
    Brock O, De Mees C, Bakker J. 2015. Hypothalamic expression of oestrogen receptor α and androgen receptor is sex-, age- and region-dependent in mice. J. Neuroendocrinol. 27:264–76
    [Google Scholar]
  130. 130. 
    Yokosuka M, Okamura H, Hayashi S. 1997. Postnatal development and sex difference in neurons containing estrogen receptor-α immunoreactivity in the preoptic brain, the diencephalon, and the amygdala in the rat. J. Comp. Neurol. 389:81–93
    [Google Scholar]
  131. 131. 
    Cao J, Patisaul HB. 2011. Sexually dimorphic expression of hypothalamic estrogen receptors α and β and Kiss1 in neonatal male and female rats. J. Comp. Neurol. 519:2954–77
    [Google Scholar]
  132. 132. 
    Cisternas CD, Cortes LR, Golynker I, Castillo-Ruiz A, Forger NG. 2020. Neonatal inhibition of DNA methylation disrupts testosterone-dependent masculinization of neurochemical phenotype. Endocrinology 161:bqz022
    [Google Scholar]
  133. 133. 
    Yang CF, Chiang MC, Gray DC, Prabhakaran M, Alvarado M et al. 2013. Sexually dimorphic neurons in the ventromedial hypothalamus govern mating in both sexes and aggression in males. Cell 153:896–909
    [Google Scholar]
  134. 134. 
    Lo L, Yao S, Kim DW, Cetin A, Harris J et al. 2019. Connectional architecture of a mouse hypothalamic circuit node controlling social behavior. PNAS 116:7503–12
    [Google Scholar]
  135. 135. 
    Xu X, Coats JK, Yang CF, Wang A, Ahmed OM et al. 2012. Modular genetic control of sexually dimorphic behaviors. Cell 148:596–607
    [Google Scholar]
  136. 136. 
    Kim DW, Yao Z, Graybuck LT, Kim TK, Nguyen TN et al. 2019. Multimodal analysis of cell types in a hypothalamic node controlling social behavior. Cell 179:713–28.e17
    [Google Scholar]
  137. 137. 
    van Veen JE, Kammel LG, Bunda PC, Shum M, Reid MS et al. 2020. Hypothalamic estrogen receptor alpha establishes a sexually dimorphic regulatory node of energy expenditure. Nat. Metab. 2:351–63
    [Google Scholar]
  138. 138. 
    Hashikawa K, Hashikawa Y, Tremblay R, Zhang J, Feng JE et al. 2017. Esr1+ cells in the ventromedial hypothalamus control female aggression. Nat. Neurosci. 20:1580–90
    [Google Scholar]
  139. 139. 
    Musatov S, Chen W, Pfaff DW, Mobbs CV, Yang XJ et al. 2007. Silencing of estrogen receptor α in the ventromedial nucleus of hypothalamus leads to metabolic syndrome. PNAS 104:2501–6
    [Google Scholar]
  140. 140. 
    Martinez de Morentin PB, Gonzalez-Garcia I, Martins L, Lage R, Fernandez-Mallo D et al. 2014. Estradiol regulates brown adipose tissue thermogenesis via hypothalamic AMPK. Cell Metab. 20:41–53
    [Google Scholar]
  141. 141. 
    Xu P, Cao X, He Y, Zhu L, Yang Y et al. 2015. Estrogen receptor-α in medial amygdala neurons regulates body weight. J. Clin. Investig. 125:2861–76
    [Google Scholar]
  142. 142. 
    Handgraaf S, Riant E, Fabre A, Waget A, Burcelin R et al. 2013. Prevention of obesity and insulin resistance by estrogens requires ERα activation function-2 (ERαAF-2), whereas ERαAF-1 is dispensable. Diabetes 62:4098–108
    [Google Scholar]
  143. 143. 
    Taxier LR, Gross KS, Frick KM. 2020. Oestradiol as a neuromodulator of learning and memory. Nat. Rev. Neurosci. 21:535–50
    [Google Scholar]
  144. 144. 
    Tran PV, Akana SF, Malkovska I, Dallman MF, Parada LF, Ingraham HA. 2006. Diminished hypothalamic bdnf expression and impaired VMH function are associated with reduced SF-1 gene dosage. J. Comp. Neurol. 498:637–48
    [Google Scholar]
  145. 145. 
    Unger TJ, Calderon GA, Bradley LC, Sena-Esteves M, Rios M. 2007. Selective deletion of Bdnf in the ventromedial and dorsomedial hypothalamus of adult mice results in hyperphagic behavior and obesity. J. Neurosci. 27:14265–74
    [Google Scholar]
  146. 146. 
    Fagan MP, Ameroso D, Meng A, Rock A, Maguire J, Rios M. 2020. Essential and sex-specific effects of mGluR5 in ventromedial hypothalamus regulating estrogen signaling and glucose balance. PNAS 117:19566–77
    [Google Scholar]
  147. 147. 
    Kow LM, Easton A, Pfaff DW 2005. Acute estrogen potentiates excitatory responses of neurons in rat hypothalamic ventromedial nucleus. Brain Res. 1043:124–31
    [Google Scholar]
  148. 148. 
    Canteras NS, Simerly RB, Swanson LW. 1994. Organization of projections from the ventromedial nucleus of the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J. Comp. Neurol. 348:41–79
    [Google Scholar]
  149. 149. 
    Ma T, Wong SZH, Lee B, Ming GL, Song H 2021. Decoding neuronal composition and ontogeny of individual hypothalamic nuclei. Neuron 109:1150–67.e6
    [Google Scholar]
  150. 150. 
    Mickelsen LE, Bolisetty M, Chimileski BR, Fujita A, Beltrami EJ et al. 2019. Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons. Nat. Neurosci. 22:642–56
    [Google Scholar]
  151. 151. 
    Luo SX, Huang J, Li Q, Mohammad H, Lee CY et al. 2018. Regulation of feeding by somatostatin neurons in the tuberal nucleus. Science 361:76–81
    [Google Scholar]
  152. 152. 
    Hrvatin S, Sun S, Wilcox OF, Yao H, Lavin-Peter AJ et al. 2020. Neurons that regulate mouse torpor. Nature 583:115–21
    [Google Scholar]
  153. 153. 
    Takahashi TM, Sunagawa GA, Soya S, Abe M, Sakurai K et al. 2020. A discrete neuronal circuit induces a hibernation-like state in rodents. Nature 583:109–14
    [Google Scholar]
  154. 154. 
    Zhang Z, Reis FMCV, He Y, Park JW, DiVittorio JR et al. 2020. Estrogen-sensitive medial preoptic area neurons coordinate torpor in mice. Nat. Commun. 11:6378
    [Google Scholar]
  155. 155. 
    Sanchez-Alavez M, Alboni S, Conti B 2011. Sex- and age-specific differences in core body temperature of C57Bl/6 mice. Age 33:89–99
    [Google Scholar]
  156. 156. 
    Villa A, Della Torre S, Maggi A. 2019. Sexual differentiation of microglia. Front. Neuroendocrinol. 52:156–64
    [Google Scholar]
  157. 157. 
    Sohrabji F. 2007. Guarding the blood-brain barrier: a role for estrogen in the etiology of neurodegenerative disease. Gene Expr. 13:311–19
    [Google Scholar]
  158. 158. 
    Lu Y, Sareddy GR, Wang J, Zhang Q, Tang FL et al. 2020. Neuron-derived estrogen is critical for astrocyte activation and neuroprotection of the ischemic brain. J. Neurosci. 40:7355–74
    [Google Scholar]
  159. 159. 
    Valdearcos M, Douglass JD, Robblee MM, Dorfman MD, Stifler DR et al. 2017. Microglial inflammatory signaling orchestrates the hypothalamic immune response to dietary excess and mediates obesity susceptibility. Cell Metab. 26:185–97.e3
    [Google Scholar]
  160. 160. 
    Villa A, Gelosa P, Castiglioni L, Cimino M, Rizzi N et al. 2018. Sex-specific features of microglia from adult mice. Cell Rep. 23:3501–11
    [Google Scholar]
  161. 161. 
    Morselli E, Fuente-Martin E, Finan B, Kim M, Frank A et al. 2014. Hypothalamic PGC-1α protects against high-fat diet exposure by regulating ERα. Cell Rep. 9:633–45
    [Google Scholar]
  162. 162. 
    Goossens GH, Jocken JWE, Blaak EE. 2021. Sexual dimorphism in cardiometabolic health: the role of adipose tissue, muscle and liver. Nat. Rev. Endocrinol. 17:47–66
    [Google Scholar]
  163. 163. 
    Fischer AW, Cannon B, Nedergaard J. 2018. Optimal housing temperatures for mice to mimic the thermal environment of humans: an experimental study. Mol. Metab. 7:161–70
    [Google Scholar]
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