Metabolic regulation of kisspeptin — the link between energy balance and reproduction

Abstract

Hypothalamic kisspeptin neurons serve as the nodal regulatory centre of reproductive function. These neurons are subjected to a plethora of regulatory factors that ultimately affect the release of kisspeptin, which modulates gonadotropin-releasing hormone (GnRH) release from GnRH neurons to control the reproductive axis. The presence of sufficient energy reserves is critical to achieve successful reproduction. Consequently, metabolic factors impose a very tight control over kisspeptin synthesis and release. This Review offers a synoptic overview of the different steps in which kisspeptin neurons are subjected to metabolic regulation, from early developmental stages to adulthood. We cover an ample array of known mechanisms that underlie the metabolic regulation of KISS1 expression and kisspeptin release. Furthermore, the novel role of kisspeptin neurons as active players within the neuronal circuits that govern energy balance is discussed, offering evidence of a bidirectional role of these neurons as a nexus between metabolism and reproduction.

Key points

  • Metabolic factors can modulate the development and function of kisspeptin neurons at multiple developmental stages.

  • These metabolic changes induced on kisspeptin neurons can be transient (for example, depending on the existing energetic reserves) or permanent (for example, epigenetic modifications).

  • Kisspeptin neuron activity can be regulated by metabolic factors at subcellular, neuroendocrine and endocrine levels, which enables kisspeptin neurons to directly adapt to circulating metabolites and to the overall energetic state.

  • Kisspeptin neurons serve as the main conveyor of metabolic cues to control the reproductive axis, thus determining the timing of puberty onset and reproductive success.

  • Controversy exists regarding the role of kisspeptin neurons on food intake; however, mounting data suggest a predominant role of kisspeptin neurons in energy expenditure, potentially mediated by kisspeptin and/or its co-transmitters, such as glutamate.

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Fig. 1: The HPG axis with the two main populations of kisspeptin neurons.
Fig. 2: Levels of metabolic regulation of kisspeptin neurons throughout development.
Fig. 3: Neuroendocrine circuits involved in the metabolic role of kisspeptin neurons.

References

  1. 1.

    Manfredi-Lozano, M., Roa, J. & Tena-Sempere, M. Connecting metabolism and gonadal function: novel central neuropeptide pathways involved in the metabolic control of puberty and fertility. Front. Neuroendocrinol. 48, 37–49 (2018). This study is important in demonstrating the interaction between the melanocortin system and the reproductive axis, indicating that the reproductive action of melanocortins is kisspeptin-dependent.

    CAS  PubMed  Article  Google Scholar 

  2. 2.

    Navarro, V. M. & Tena-Sempere, M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat. Rev. Endocrinol. 8, 40–53 (2011).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    Goodman, R. L. et al. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology 148, 5752–5760 (2007).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Navarro, V. M. et al. Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. J. Neurosci. 29, 11859–11866 (2009). The first study demonstrating the concept of kisspeptin ARC neurons as the GnRH pulse generator.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Clarkson, J. et al. Definition of the hypothalamic GnRH pulse generator in mice. Proc. Natl Acad. Sci. USA 114, E10216–E10223 (2017). This study demonstrates through a series of optogenetic approaches that kisspeptin ARC neurons are indeed the GnRH pulse generator.

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Zhang, C., Bosch, M. A., Qiu, J., Ronnekleiv, O. K. & Kelly, M. J. 17β-Estradiol increases persistent Na(+) current and excitability of AVPV/PeN Kiss1 neurons in female mice. Mol. Endocrinol. 29, 518–527 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Silveira, L. G. et al. Mutations of the KISS1 gene in disorders of puberty. J. Clin. Endocrinol. Metab. 95, 2276–2280 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    de Roux, N. et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc. Natl Acad. Sci. USA 100, 10972–10976 (2003).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Seminara, S. B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003).

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Teles, M. G. et al. A GPR54-activating mutation in a patient with central precocious puberty. N. Engl. J. Med. 358, 709–715 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Navarro, V. M. & Kaiser, U. B. Metabolic influences on neuroendocrine regulation of reproduction. Curr. Opin. Endocrinol. Diabetes Obes. 20, 335–341 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Manfredi-Lozano, M. et al. Defining a novel leptin-melanocortin-kisspeptin pathway involved in the metabolic control of puberty. Mol. Metab. 5, 844–857 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Shalitin, S. & Kiess, W. Putative effects of obesity on linear growth and puberty. Horm. Res. Paediatr. 88, 101–110 (2017).

    CAS  PubMed  Article  Google Scholar 

  14. 14.

    Calderon, B. et al. Prevalence of male secondary hypogonadism in moderate to severe obesity and its relationship with insulin resistance and excess body weight. Andrology 4, 62–67 (2016).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Lamm, S., Chidakel, A. & Bansal, R. Obesity and hypogonadism. Urol. Clin. North. Am. 43, 239–245 (2016).

    PubMed  Article  Google Scholar 

  16. 16.

    Ahmed, M. L., Ong, K. K. & Dunger, D. B. Childhood obesity and the timing of puberty. Trends Endocrinol. Metab. 20, 237–242 (2009).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Li, W. et al. Association between obesity and puberty timing: a systematic review and meta-analysis. Int. J. Env. Res. Public. Health 14, E1266 (2017).

    Article  Google Scholar 

  18. 18.

    Sandhu, J., Ben-Shlomo, Y., Cole, T. J., Holly, J. & Davey Smith, G. The impact of childhood body mass index on timing of puberty, adult stature and obesity: a follow-up study based on adolescent anthropometry recorded at Christ’s Hospital (1936–1964). Int. J. Obes. 30, 14–22 (2006).

    CAS  Article  Google Scholar 

  19. 19.

    He, Y., Tian, J., Oddy, W. H., Dwyer, T. & Venn, A. J. Association of childhood obesity with female infertility in adulthood: a 25-year follow-up study. Fertil. Steril. 110, 596–604.e1 (2018).

    PubMed  Article  Google Scholar 

  20. 20.

    Vilmann, L. S., Thisted, E., Baker, J. L. & Holm, J. C. Development of obesity and polycystic ovary syndrome in adolescents. Horm. Res. Paediatr. 78, 269–278 (2012).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Brunton, P. J. & Russell, J. A. Endocrine induced changes in brain function during pregnancy. Brain Res. 1364, 198–215 (2010).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Eckel, L. A. The ovarian hormone estradiol plays a crucial role in the control of food intake in females. Physiol. Behav. 104, 517–524 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Butera, P. C. Estradiol and the control of food intake. Physiol. Behav. 99, 175–180 (2010).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Rivera, H. M. & Stincic, T. L. Estradiol and the control of feeding behavior. Steroids 133, 44–52 (2018).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Allan, C. A. & McLachlan, R. I. Androgens and obesity. Curr. Opin. Endocrinol. Diabetes Obes. 17, 224–232 (2010).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Brand, J. S., van der Tweel, I., Grobbee, D. E., Emmelot-Vonk, M. H. & van der Schouw, Y. T. Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. Int. J. Epidemiol. 40, 189–207 (2011).

    PubMed  Article  Google Scholar 

  27. 27.

    Aiken, C. E. & Ozanne, S. E. Transgenerational developmental programming. Hum. Reprod. Update 20, 63–75 (2014).

    PubMed  Article  Google Scholar 

  28. 28.

    Vickers, M. H. Developmental programming and transgenerational transmission of obesity. Ann. Nutr. Metab. 64 (Suppl. 1), 26–34 (2014).

    CAS  PubMed  Article  Google Scholar 

  29. 29.

    Zambrano, E. The transgenerational mechanisms in developmental programming of metabolic diseases. Rev. Invest. Clin. 61, 41–52 (2009).

    CAS  PubMed  Google Scholar 

  30. 30.

    Baptissart, M. et al. Multigenerational impacts of bile exposure are mediated by TGR5 signaling pathways. Sci. Rep. 8, 16875 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    Huypens, P. et al. Epigenetic germline inheritance of diet-induced obesity and insulin resistance. Nat. Genet. 48, 497–499 (2016).

    CAS  PubMed  Article  Google Scholar 

  32. 32.

    Miranda, A. & Sousa, N. Maternal hormonal milieu influence on fetal brain development. Brain Behav. 8, e00920 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Moog, N. K. et al. Influence of maternal thyroid hormones during gestation on fetal brain development. Neuroscience 342, 68–100 (2017).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Zeltser, L. M. & Leibel, R. L. Roles of the placenta in fetal brain development. Proc. Natl Acad. Sci. USA 108, 15667–15668 (2011).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Ciofi, P. The arcuate nucleus as a circumventricular organ in the mouse. Neurosci. Lett. 487, 187–190 (2011).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Ciofi, P. et al. Brain-endocrine interactions: a microvascular route in the mediobasal hypothalamus. Endocrinology 150, 5509–5519 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Norsted, E., Gomuc, B. & Meister, B. Protein components of the blood-brain barrier (BBB) in the mediobasal hypothalamus. J. Chem. Neuroanat. 36, 107–121 (2008).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Li, C., McDonald, T. J., Wu, G., Nijland, M. J. & Nathanielsz, P. W. Intrauterine growth restriction alters term fetal baboon hypothalamic appetitive peptide balance. J. Endocrinol. 217, 275–282 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Plagemann, A. et al. Observations on the orexigenic hypothalamic neuropeptide Y-system in neonatally overfed weanling rats. J. Neuroendocrinol. 11, 541–546 (1999).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Vogt, M. C. et al. Neonatal insulin action impairs hypothalamic neurocircuit formation in response to maternal high-fat feeding. Cell 156, 495–509 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Kumar, D., Periasamy, V., Freese, M., Voigt, A. & Boehm, U. In utero development of kisspeptin/GnRH neural circuitry in male mice. Endocrinology 156, 3084–3090 (2015).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Kumar, D. et al. Murine arcuate nucleus kisspeptin neurons communicate with GnRH neurons in utero. J. Neurosci. 34, 3756–3766 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Clarkson, J. & Herbison, A. E. Postnatal development of kisspeptin neurons in mouse hypothalamus; sexual dimorphism and projections to gonadotropin-releasing hormone neurons. Endocrinology 147, 5817–5825 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Yip, S. H., Boehm, U., Herbison, A. E. & Campbell, R. E. Conditional viral tract tracing delineates the projections of the distinct kisspeptin neuron populations to gonadotropin-releasing hormone (GnRH) neurons in the mouse. Endocrinology 156, 2582–2594 (2015).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Semaan, S. J. et al. BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 151, 5807–5817 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Castellano, J. M. et al. Early metabolic programming of puberty onset: impact of changes in postnatal feeding and rearing conditions on the timing of puberty and development of the hypothalamic kisspeptin system. Endocrinology 152, 3396–3408 (2011). This study is important in demonstrating the effect of perinatal metabolic alterations in the function of kisspeptin neurons in adulthood, probably due to epigenetic changes.

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Day, F. R., Perry, J. R. & Ong, K. K. Genetic regulation of puberty timing in humans. Neuroendocrinology 102, 247–255 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Ojeda, S. R., Lomniczi, A., Sandau, U. & Matagne, V. New concepts on the control of the onset of puberty. Endocr. Dev. 17, 44–51 (2010).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Funes, S. et al. The KiSS-1 receptor GPR54 is essential for the development of the murine reproductive system. Biochem. Biophys. Res. Commun. 312, 1357–1363 (2003).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Bentsen, A. H. et al. Maturation of kisspeptinergic neurons coincides with puberty onset in male rats. Peptides 31, 275–283 (2010).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Castellano, J. M. et al. Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition. Endocrinology 146, 3917–3925 (2005).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Gill, J. C. et al. Reproductive hormone-dependent and -independent contributions to developmental changes in kisspeptin in GnRH-deficient hypogonadal mice. PLoS One 5, e11911 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  53. 53.

    Navarro, V. M. et al. Developmental and hormonally regulated messenger ribonucleic acid expression of KiSS-1 and its putative receptor, GPR54, in rat hypothalamus and potent luteinizing hormone-releasing activity of KiSS-1 peptide. Endocrinology 145, 4565–4574 (2004).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Navarro, V. M. Interactions between kisspeptins and neurokinin B. Adv. Exp. Med. Biol. 784, 325–347 (2013).

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Navarro, V. M. et al. Role of neurokinin B in the control of female puberty and its modulation by metabolic status. J. Neurosci. 32, 2388–2397 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Ruiz-Pino, F. et al. Neurokinin B and the control of the gonadotropic axis in the rat: developmental changes, sexual dimorphism, and regulation by gonadal steroids. Endocrinology 153, 4818–4829 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Gordon, C. M. et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J. Clin. Endocrinol. Metab. 102, 1413–1439 (2017).

    PubMed  Article  Google Scholar 

  58. 58.

    Abbara, A. et al. A second dose of kisspeptin-54 improves oocyte maturation in women at high risk of ovarian hyperstimulation syndrome: a phase 2 randomized controlled trial. Hum. Reprod. 32, 1915–1924 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Hrabovszky, E. et al. The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin-releasing hormone and neurokinin B neurons. Eur. J. Neurosci. 31, 1984–1998 (2010).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Matsuyama, S. et al. Morphological evidence for direct interaction between kisspeptin and gonadotropin-releasing hormone neurons at the median eminence of the male goat: an immunoelectron microscopic study. Neuroendocrinology 94, 323–332 (2011).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Yeo, S. H. et al. Visualisation of Kiss1 neurone distribution using a Kiss1-CRE transgenic mouse. J. Neuroendocrinol. https://doi.org/10.1111/jne.12435 (2016).

  62. 62.

    Hardie, D. G., Ross, F. A. & Hawley, S. A. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat. Rev. Mol. Cell Biol. 13, 251–262 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Obri, A. & Claret, M. The role of epigenetics in hypothalamic energy balance control: implications for obesity. Cell Stress 3, 208–220 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Roa, J. et al. Metabolic regulation of female puberty via hypothalamic AMPK-kisspeptin signaling. Proc. Natl Acad. Sci. USA 115, E10758–E10767 (2018). This study demonstrates the role of AMPK in kisspeptin neurons as an essential regulatory pathway in the release of kisspeptin.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Torsoni, M. A. et al. AMPKalpha2 in Kiss1 neurons is required for reproductive adaptations to acute metabolic challenges in adult female mice. Endocrinology 157, 4803–4816 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Roland, A. V. & Moenter, S. M. Glucosensing by GnRH neurons: inhibition by androgens and involvement of AMP-activated protein kinase. Mol. Endocrinol. 25, 847–858 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Andrade, J., Quinn, J., Becker, R. Z. & Shupnik, M. A. AMP-activated protein kinase is a key intermediary in GnRH-stimulated LHβ gene transcription. Mol. Endocrinol. 27, 828–839 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Khaleghpour, K., Pyronnet, S., Gingras, A. C. & Sonenberg, N. Translational homeostasis: eukaryotic translation initiation factor 4E control of 4E-binding protein 1 and p70 S6 kinase activities. Mol. Cell Biol. 19, 4302–4310 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  71. 71.

    Inoki, K., Kim, J. & Guan, K. L. AMPK and mTOR in cellular energy homeostasis and drug targets. Annu. Rev. Pharmacol. Toxicol. 52, 381–400 (2012).

    CAS  PubMed  Article  Google Scholar 

  72. 72.

    Jing, K. et al. Docosahexaenoic acid induces autophagy through p53/AMPK/mTOR signaling and promotes apoptosis in human cancer cells harboring wild-type p53. Autophagy 7, 1348–1358 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Egan, D., Kim, J., Shaw, R. J. & Guan, K. L. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR. Autophagy 7, 643–644 (2011).

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Kim, J., Kundu, M., Viollet, B. & Guan, K. L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 13, 132–141 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Roa, J. et al. The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology 150, 5016–5026 (2009). This study demonstrates the role of mTOR in kisspeptin neurons of rodents in the context of reproduction.

    CAS  PubMed  Article  Google Scholar 

  76. 76.

    Edwards, B. S., Isom, W. J. & Navratil, A. M. Gonadotropin releasing hormone activation of the mTORC2/Rictor complex regulates actin remodeling and ERK activity in LβT2 cells. Mol. Cell. Endocrinol. 439, 346–353 (2017).

    CAS  PubMed  Article  Google Scholar 

  77. 77.

    Fiedler, E. C. & Shaw, R. J. AMPK regulates the epigenome through phosphorylation of TET2. Cell Metab. 28, 534–536 (2018).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Wu, D. et al. Glucose-regulated phosphorylation of TET2 by AMPK reveals a pathway linking diabetes to cancer. Nature 559, 637–641 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Zhang, T. et al. Phosphorylation of TET2 by AMPK is indispensable in myogenic differentiation. Epigenetics Chromatin 12, 32 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Arora, P. Obesity genetics and epigenetics: dissecting causality. Circ. Cardiovasc. Genet. 7, 395–396 (2014).

    PubMed  Article  Google Scholar 

  81. 81.

    Herrera, B. M., Keildson, S. & Lindgren, C. M. Genetics and epigenetics of obesity. Maturitas 69, 41–49 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Horsthemke, B. A critical view on transgenerational epigenetic inheritance in humans. Nat. Commun. 9, 2973 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  83. 83.

    Pigeyre, M., Yazdi, F. T., Kaur, Y. & Meyre, D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin. Sci. 130, 943–986 (2016).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Rohde, K. et al. Genetics and epigenetics in obesity. Metabolism 92, 37–50 (2019).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Sun, X. et al. From genetics and epigenetics to the future of precision treatment for obesity. Gastroenterol. Rep. 5, 266–270 (2017).

    Article  Google Scholar 

  86. 86.

    Zhu, Z., Cao, F. & Li, X. Epigenetic programming and fetal metabolic programming. Front. Endocrinol. 10, 764 (2019).

    Article  Google Scholar 

  87. 87.

    Nugent, B. M. & Bale, T. L. The omniscient placenta: metabolic and epigenetic regulation of fetal programming. Front. Neuroendocrinol. 39, 28–37 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Sookoian, S., Gianotti, T. F., Burgueno, A. L. & Pirola, C. J. Fetal metabolic programming and epigenetic modifications: a systems biology approach. Pediatr. Res. 73, 531–542 (2013).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Heerwagen, M. J., Miller, M. R., Barbour, L. A. & Friedman, J. E. Maternal obesity and fetal metabolic programming: a fertile epigenetic soil. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R711–R722 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Li, Y. Epigenetic mechanisms link maternal diets and gut microbiome to obesity in the offspring. Front. Genet. 9, 342 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  91. 91.

    Candler, T., Kuhnen, P., Prentice, A. M. & Silver, M. Epigenetic regulation of POMC; implications for nutritional programming, obesity and metabolic disease. Front. Neuroendocrinol. 54, 100773 (2019).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Abreu, A. P. & Kaiser, U. B. Pubertal development and regulation. Lancet Diabetes Endocrinol. 4, 254–264 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Jaenisch, R. & Bird, A. Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals. Nat. Genet. 33, 245–254 (2003).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Loh, M., Zhou, L., Ng, H. K. & Chambers, J. C. Epigenetic disturbances in obesity and diabetes: epidemiological and functional insights. Mol. Metab. 27S, S33–S41 (2019).

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Semaan, S. J., Dhamija, S., Kim, J., Ku, E. C. & Kauffman, A. S. Assessment of epigenetic contributions to sexually-dimorphic Kiss1 expression in the anteroventral periventricular nucleus of mice. Endocrinology 153, 1875–1886 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Wyatt, A. K. et al. Changes in methylation patterns of kiss1 and kiss1r gene promoters across puberty. Genet. Epigenet 5, 51–62 (2013). This study demonstrates the epigenetic modifications in the kisspeptin system that determine the timing of puberty onset.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Luo, L. et al. Identification of differential genomic DNA methylation in the hypothalamus of pubertal rat using reduced representation bisulfite sequencing. Reprod. Biol. Endocrinol. 15, 81 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    Uenoyama, Y. et al. Molecular and epigenetic mechanism regulating hypothalamic Kiss1 gene expression in mammals. Neuroendocrinology 103, 640–649 (2016).

    CAS  PubMed  Article  Google Scholar 

  99. 99.

    He, Y. F. et al. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science 333, 1303–1307 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Hu, L. et al. Structural insight into substrate preference for TET-mediated oxidation. Nature 527, 118–122 (2015).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Ito, S. et al. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science 333, 1300–1303 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Kurian, J. R. et al. The methylcytosine dioxygenase ten-eleven translocase-2 (tet2) enables elevated GnRH gene expression and maintenance of male reproductive function. Endocrinology 157, 3588–3603 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074–1080 (2001).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Gao, T., Diaz-Hirashi, Z. & Verdeguer, F. Metabolic signaling into chromatin modifications in the regulation of gene expression. Int. J. Mol. Sci. 19, E4108 (2018).

    PubMed  Article  Google Scholar 

  105. 105.

    Mikula, M., Majewska, A., Ledwon, J. K., Dzwonek, A. & Ostrowski, J. Obesity increases histone H3 lysine 9 and 18 acetylation at Tnfa and Ccl2 genes in mouse liver. Int. J. Mol. Med. 34, 1647–1654 (2014).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Tomikawa, J. et al. Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in the mouse brain. Proc. Natl Acad. Sci. USA 109, E1294–E1301 (2012).

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Rickert, E. et al. Neuronal SIRT1 regulates metabolic and reproductive function and the response to caloric restriction. J. Endocr. Soc. 3, 427–445 (2019).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Vazquez, M. J. et al. SIRT1 mediates obesity- and nutrient-dependent perturbation of pubertal timing by epigenetically controlling Kiss1 expression. Nat. Commun. 9, 4194 (2018). This study is important in demonstrating the action of SIRT1 in the epigenetic regulation of kisspeptin neurons.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  109. 109.

    Choi, I., Rickert, E., Fernandez, M. & Webster, N. J. G. SIRT1 in astrocytes regulates glucose metabolism and reproductive function. Endocrinology 160, 1547–1560 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  110. 110.

    Duteil, D. et al. Lsd1 ablation triggers metabolic reprogramming of brown adipose tissue. Cell Rep. 17, 1008–1021 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Duteil, D., Tosic, M. & Schule, R. Lsd1, a metabolic sensor of environment requirements that prevents adipose tissue from aging. Adipocyte 6, 298–303 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Duteil, D. et al. Lsd1 prevents age-programed loss of beige adipocytes. Proc. Natl Acad. Sci. USA 114, 5265–5270 (2017).

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Campbell, J. N. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484–496 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Ahmed, K. et al. Loss of microRNA-7a2 induces hypogonadotropic hypogonadism and infertility. J. Clin. Invest. 127, 1061–1074 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Herzer, S., Silahtaroglu, A. & Meister, B. Locked nucleic acid-based in situ hybridisation reveals miR-7a as a hypothalamus-enriched microRNA with a distinct expression pattern. J. Neuroendocrinol. 24, 1492–1504 (2012).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Fang, Y., Xue, J. L., Shen, Q., Chen, J. & Tian, L. MicroRNA-7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3-kinase/Akt pathway in hepatocellular carcinoma. Hepatology 55, 1852–1862 (2012).

    CAS  PubMed  Article  Google Scholar 

  117. 117.

    Sangiao-Alvarellos, S., Pena-Bello, L., Manfredi-Lozano, M., Tena-Sempere, M. & Cordido, F. Perturbation of hypothalamic microRNA expression patterns in male rats after metabolic distress: impact of obesity and conditions of negative energy balance. Endocrinology 155, 1838–1850 (2014). This study demonstrates the critical role of miRNAs in the control of metabolic function.

    PubMed  Article  CAS  Google Scholar 

  118. 118.

    Corre, C. et al. Sex-specific regulation of weight and puberty by the Lin28/let-7 axis. J. Endocrinol. 228, 179–191 (2016).

    CAS  PubMed  Article  Google Scholar 

  119. 119.

    Sangiao-Alvarellos, S. et al. Changes in hypothalamic expression of the Lin28/let-7 system and related microRNAs during postnatal maturation and after experimental manipulations of puberty. Endocrinology 154, 942–955 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Zhu, H. et al. Lin28a transgenic mice manifest size and puberty phenotypes identified in human genetic association studies. Nat. Genet. 42, 626–630 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Heras, V. et al. Hypothalamic miR-30 regulates puberty onset via repression of the puberty-suppressing factor, Mkrn3. PLoS Biol. 17, e3000532 (2019). This study provides important information on the role of a newly describes miRNA (miR-30) in the control of Kiss1 expression via Mkrn3.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Abreu, A. P. et al. Central precocious puberty caused by mutations in the imprinted gene MKRN3. N. Engl. J. Med. 368, 2467–2475 (2013).

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Zhan, C. et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624–3632 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  124. 124.

    Lowell, B. B. New neuroscience of homeostasis and drives for food, water, and salt. N. Engl. J. Med. 380, 459–471 (2019).

    CAS  PubMed  Article  Google Scholar 

  125. 125.

    Dicken, M. S., Tooker, R. E. & Hentges, S. T. Regulation of GABA and glutamate release from proopiomelanocortin neuron terminals in intact hypothalamic networks. J. Neurosci. 32, 4042–4048 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Stincic, T. L., Grachev, P., Bosch, M. A., Ronnekleiv, O. K. & Kelly, M. J. Estradiol drives the anorexigenic activity of proopiomelanocortin neurons in female mice. eNeuro 5, ENEURO.0103-18.2018 (2018).

  127. 127.

    Xu, Y. et al. Glutamate mediates the function of melanocortin receptor 4 on Sim1 neurons in body weight regulation. Cell Metab. 18, 860–870 (2013).

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Millington, G. W. The role of proopiomelanocortin (POMC) neurones in feeding behaviour. Nutr. Metab. 4, 18 (2007).

    Article  CAS  Google Scholar 

  129. 129.

    Garfield, A. S. et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat. Neurosci. 18, 863–871 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Padilla, S. L. et al. AgRP to Kiss1 neuron signaling links nutritional state and fertility. Proc. Natl Acad. Sci. USA 114, 2413–2418 (2017). This study demostrates that AgRP neurons contact both populations of kisspeptin neurons directly and regulate their activity through AgRP and GABA release.

    CAS  PubMed  Article  Google Scholar 

  131. 131.

    Wu, Q., Whiddon, B. B. & Palmiter, R. D. Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. Proc. Natl Acad. Sci. USA 109, 3155–3160 (2012).

    CAS  PubMed  Article  Google Scholar 

  132. 132.

    Sandrock, M. et al. Reduction in corpora lutea number in obese melanocortin-4-receptor-deficient mice. Reprod. Biol. Endocrinol. 7, 24 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  133. 133.

    Lehman, M. N., Ebling, F. J., Moenter, S. M. & Karsch, F. J. Distribution of estrogen receptor-immunoreactive cells in the sheep brain. Endocrinology 133, 876–886 (1993).

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    de Souza, F. S. J. et al. The estrogen receptor α colocalizes with proopiomelanocortin in hypothalamic neurons and binds to a conserved motif present in the neuron-specific enhancer nPE2. Eur. J. Pharmacol. 660, 181–187 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  135. 135.

    Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab. 14, 453–465 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Fu, L. Y. & van den Pol, A. N. Kisspeptin directly excites anorexigenic proopiomelanocortin neurons but inhibits orexigenic neuropeptide Y cells by an indirect synaptic mechanism. J. Neurosci. 30, 10205–10219 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Cravo, R. M. et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173, 37–56 (2011).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Israel, D. D. et al. Effects of leptin and melanocortin signaling interactions on pubertal development and reproduction. Endocrinology 153, 2408–2419 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Lau, J. & Herzog, H. CART in the regulation of appetite and energy homeostasis. Front. Neurosci. 8, 313 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    True, C., Verma, S., Grove, K. L. & Smith, M. S. Cocaine- and amphetamine-regulated transcript is a potent stimulator of GnRH and kisspeptin cells and may contribute to negative energy balance-induced reproductive inhibition in females. Endocrinology 154, 2821–2832 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Zandi, M. R. et al. Hypothalamic expression of melanocortin-4 receptor and agouti-related peptide mRNAs during the estrous cycle of rats. Int. J. Mol. Cell Med. 3, 183–189 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142.

    Bohler, H. C. Jr., Tracer, H., Merriam, G. R. & Petersen, S. L. Changes in proopiomelanocortin messenger ribonucleic acid levels in the rostral periarcuate region of the female rat during the estrous cycle. Endocrinology 128, 1265–1269 (1991).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Ahima, R. S., Dushay, J., Flier, S. N., Prabakaran, D. & Flier, J. S. Leptin accelerates the onset of puberty in normal female mice. J. Clin. Invest. 99, 391–395 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999).

    CAS  PubMed  Article  Google Scholar 

  145. 145.

    Mathew, H., Castracane, V. D. & Mantzoros, C. Adipose tissue and reproductive health. Metabolism 86, 18–32 (2018).

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Welt, C. K. et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997 (2004).

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Donato, J. Jr., Cravo, R. M., Frazao, R. & Elias, C. F. Hypothalamic sites of leptin action linking metabolism and reproduction. Neuroendocrinology 93, 9–18 (2011).

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Leshan, R. L., Bjornholm, M., Munzberg, H. & Myers, M. G. Jr. Leptin receptor signaling and action in the central nervous system. Obesity 14 (Suppl. 5), 208S–212S (2006).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Chan, J. L. & Mantzoros, C. S. Leptin and the hypothalamic-pituitary regulation of the gonadotropin-gonadal axis. Pituitary 4, 87–92 (2001).

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Quennell, J. H. et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 150, 2805–2812 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Donato, J. Jr. et al. Leptin’s effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. J. Clin. Invest. 121, 355–368 (2011).

    PubMed  Article  Google Scholar 

  152. 152.

    Zuure, W. A., Roberts, A. L., Quennell, J. H. & Anderson, G. M. Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function. J. Neurosci. 33, 17874–17883 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Martin, C. et al. Leptin-responsive GABAergic neurons regulate fertility through pathways that result in reduced kisspeptinergic tone. J. Neurosci. 34, 6047–6056 (2014). This study demonstrates that the action of leptin in regulating reproductive function occurs through GABAergic neurons in the mouse.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  154. 154.

    Vong, L. et al. Leptin action on GABAergic neurons prevents obesity and reduces inhibitory tone to POMC neurons. Neuron 71, 142–154 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  155. 155.

    Chen, H. et al. Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84, 491–495 (1996).

    CAS  PubMed  Article  Google Scholar 

  156. 156.

    Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    CAS  PubMed  Article  Google Scholar 

  157. 157.

    Dehghani, M. R. et al. Potential role of gender specific effect of leptin receptor deficiency in an extended consanguineous family with severe early-onset obesity. Eur. J. Med. Genet. 61, 465–467 (2018).

    PubMed  Article  Google Scholar 

  158. 158.

    Johnson, L. M. & Sidman, R. L. A reproductive endocrine profile in the diabetes (db) mutant mouse. Biol. Reprod. 20, 552–559 (1979).

    CAS  PubMed  Article  Google Scholar 

  159. 159.

    Xu, Y. et al. Glutamate release mediates leptin action on energy expenditure. Mol. Metab. 2, 109–115 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Cavalcante, J. C., Bittencourt, J. C. & Elias, C. F. Distribution of the neuronal inputs to the ventral premammillary nucleus of male and female rats. Brain Res. 1582, 77–90 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Egan, O. K., Inglis, M. A. & Anderson, G. M. Leptin signaling in AgRP neurons modulates puberty onset and adult fertility in mice. J. Neurosci. 37, 3875–3886 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Ross, R. A. et al. PACAP neurons in the ventral premammillary nucleus regulate reproductive function in the female mouse. eLife 7, e35960 (2018). This study demonstrates that neurons from additional hypothalamic nuclei (outside the arcuate and the preoptic area) might contact directly and regulate kisspeptin neurons, transmitting the information on the metabolic state via LEPR to the HPG axis.

    PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Dandona, P. & Dhindsa, S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J. Clin. Endocrinol. Metab. 96, 2643–2651 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Gevi, F., Fanelli, G. & Zolla, L. Metabolic patterns in insulin-resistant male hypogonadism. Cell Death Dis. 9, 671 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  165. 165.

    Bruning, J. C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    CAS  PubMed  Article  Google Scholar 

  166. 166.

    Qiu, X. et al. Insulin and leptin signaling interact in the mouse Kiss1 neuron during the peripubertal period. PLoS One 10, e0121974 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. 167.

    Thon, M., Hosoi, T. & Ozawa, K. Possible integrative actions of leptin and insulin signaling in the hypothalamus targeting energy homeostasis. Front. Endocrinol. 7, 138 (2016).

    Article  Google Scholar 

  168. 168.

    Castellano, J. M. et al. Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes 55, 2602–2610 (2006).

    CAS  PubMed  Article  Google Scholar 

  169. 169.

    Frazao, R. et al. Estradiol modulates Kiss1 neuronal response to ghrelin. Am. J. Physiol. Endocrinol. Metab. 306, E606–E614 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Forbes, S., Li, X. F., Kinsey-Jones, J. & O’Byrne, K. Effects of ghrelin on Kisspeptin mRNA expression in the hypothalamic medial preoptic area and pulsatile luteinising hormone secretion in the female rat. Neurosci. Lett. 460, 143–147 (2009).

    CAS  PubMed  Article  Google Scholar 

  171. 171.

    Chen, S. R. et al. Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons. J. Neurochem. 142, 512–520 (2017).

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Wang, Q. et al. Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Mol. Metab. 3, 64–72 (2014).

    CAS  PubMed  Article  Google Scholar 

  173. 173.

    Wu, C. S. et al. Suppression of GHS-R in AgRP neurons mitigates diet-induced obesity by activating thermogenesis. Int. J. Mol. Sci. 18, E832 (2017).

    PubMed  Article  CAS  Google Scholar 

  174. 174.

    Sun, Y., Ahmed, S. & Smith, R. G. Deletion of ghrelin impairs neither growth nor appetite. Mol. Cell Biol. 23, 7973–7981 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  175. 175.

    Stengel, A., Wang, L., Goebel-Stengel, M. & Tache, Y. Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport 22, 253–257 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  176. 176.

    Talbi, R., Laran-Chich, M. P., Magoul, R., El Ouezzani, S. & Simonneaux, V. Kisspeptin and RFRP-3 differentially regulate food intake and metabolic neuropeptides in the female desert jerboa. Sci. Rep. 6, 36057 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Saito, R. et al. Centrally administered kisspeptin suppresses feeding via nesfatin-1 and oxytocin in male rats. Peptides 112, 114–124 (2019).

    CAS  PubMed  Article  Google Scholar 

  178. 178.

    Sahin, Z., Canpolat, S., Ozcan, M., Ozgocer, T. & Kelestimur, H. Kisspeptin antagonist prevents RF9-induced reproductive changes in female rats. Reproduction 149, 465–473 (2015).

    CAS  PubMed  Article  Google Scholar 

  179. 179.

    Backholer, K. et al. Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology 151, 2233–2243 (2010).

    PubMed  Article  Google Scholar 

  180. 180.

    Smith, J. T., Acohido, B. V., Clifton, D. K. & Steiner, R. A. KiSS-1 neurones are direct targets for leptin in the ob/ob mouse. J. Neuroendocrinol. 18, 298–303 (2006).

    CAS  PubMed  Article  Google Scholar 

  181. 181.

    Tolson, K. P. et al. Impaired kisspeptin signaling decreases metabolism and promotes glucose intolerance and obesity. J. Clin. Invest. 124, 3075–3079 (2014). This is the first study demonstrating a potentially active role of kisspeptin in the control of energy balance.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  182. 182.

    Nestor, C. C. et al. Optogenetic stimulation of arcuate nucleus Kiss1 neurons reveals a steroid-dependent glutamatergic input to POMC and AgRP neurons in male mice. Mol. Endocrinol. 30, 630–644 (2016). This is an important study in demonstrating for the first time that kisspeptin neurons might regulate the activity of POMC and AgRP neurons through glutamate. This finding might have critical implications in the bidirectional regulation of energy balance and reproduction.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Qiu, J. et al. Estrogenic-dependent glutamatergic neurotransmission from kisspeptin neurons governs feeding circuits in females. eLife 7, e35656 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  184. 184.

    Padilla, S. L. et al. Kisspeptin neurons in the arcuate nucleus of the hypothalamus orchestrate circadian rhythms and metabolism. Curr. Biol. 29, 592–604.e4 (2019). This is a seminal study that demonstrates the increase in body weight in mice after ablation of kisspeptin ARC neurons and the disruption of the circadian feeding behaviour and activity, uncovering a novel role for kisspeptin ARC neurons.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Izzi-Engbeaya, C. et al. The effects of kisspeptin on β-cell function, serum metabolites and appetite in humans. Diabetes Obes. Metab. 20, 2800–2810 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Velasco, I. et al. Gonadal hormone-dependent vs. -independent effects of kisspeptin signaling in the control of body weight and metabolic homeostasis. Metabolism 98, 84–94 (2019). This study is critical to understanding the part of the metabolic phenotype in Kiss1r KO mice that is due to the direct action of kisspeptin versus the absence of sex steroids (hypogonadism) induced by the absence of kisspeptin.

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Fenselau, H. et al. A rapidly acting glutamatergic ARC→PVH satiety circuit postsynaptically regulated by α-MSH. Nat. Neurosci. 20, 42–51 (2017).

    CAS  PubMed  Article  Google Scholar 

  188. 188.

    Chaix, A., Lin, T., Le, H. D., Chang, M. W. & Panda, S. Time-restricted feeding prevents obesity and metabolic syndrome in mice lacking a circadian clock. Cell Metab. 29, 303–319.e4 (2019).

    CAS  PubMed  Article  Google Scholar 

  189. 189.

    Yeo, S. H. & Herbison, A. E. Projections of arcuate nucleus and rostral periventricular kisspeptin neurons in the adult female mouse brain. Endocrinology 152, 2387–2399 (2011).

    CAS  PubMed  Article  Google Scholar 

  190. 190.

    Padilla, S. L., Johnson, C. W., Barker, F. D., Patterson, M. A. & Palmiter, R. D. A neural circuit underlying the generation of hot flushes. Cell Rep. 24, 271–277 (2018).This study demonstrates the role of kisspeptin neurons in thermorregulation through the projections to the medial preoptic area and the release of neurokinin B.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  191. 191.

    Krajewski-Hall, S. J. et al. Glutamatergic neurokinin 3 receptor neurons in the median preoptic nucleus modulate heat-defense pathways in female mice. Endocrinology 160, 803–816 (2019). This is an important study investigating the characteristics of the neurons in the preoptic area that receive direct contact from kisspeptin ARC neurons in the context of thermoregulation.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  192. 192.

    Mittelman-Smith, M. A., Williams, H., Krajewski-Hall, S. J., McMullen, N. T. & Rance, N. E. Role for kisspeptin/neurokinin B/dynorphin (KNDy) neurons in cutaneous vasodilatation and the estrogen modulation of body temperature. Proc. Natl Acad. Sci. USA 109, 19846–19851 (2012).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Kokay, I. C., Petersen, S. L. & Grattan, D. R. Identification of prolactin-sensitive GABA and kisspeptin neurons in regions of the rat hypothalamus involved in the control of fertility. Endocrinology 152, 526–535 (2011).

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    Gerardo-Gettens, T., Moore, B. J., Stern, J. S. & Horwitz, B. A. Prolactin stimulates food intake in a dose-dependent manner. Am. J. Physiol. 256, R276–R280 (1989).

    CAS  PubMed  Google Scholar 

  195. 195.

    Ladyman, S. R. et al. Prolactin receptors in Rip-cre cells, but not in AgRP neurones, are involved in energy homeostasis. J. Neuroendocrinol. 29, e12474 (2017).

    Article  CAS  Google Scholar 

  196. 196.

    Weems, P. W., Goodman, R. L. & Lehman, M. N. Neural mechanisms controlling seasonal reproduction: principles derived from the sheep model and its comparison with hamsters. Front. Neuroendocrinol. 37, 43–51 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Clarke, I. J. Sex and season are major determinants of voluntary food intake in sheep. Reprod. Fertil. Dev. 13, 577–582 (2001).

    CAS  PubMed  Article  Google Scholar 

  198. 198.

    Iason, G., Sim, D., Foreman, E., Fenn, P. & Elston, D. Seasonal variation of voluntary food intake and metabolic rate in three contrasting breeds of sheep. Anim. Prod. 58, 381–387 (1994).

    Google Scholar 

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Acknowledgements

The author acknowledges the support of NIH/NICHD R01HD090151 and R21HD095383.

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Glossary

Precocial

Born mature, without the need for parental care for feeding.

Altricial

Born undeveloped, requiring parental care for feeding.

Functional hypothalamic amenorrhoea

A condition derived from the insufficient secretion of GnRH from the hypothalamus, leading to anovulation and hypogonadotropic hypogonadism.

Dioestrus

Phase of the oestrous cycle in female mice, which precedes the ovulation phase, that is proestrus.

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Navarro, V.M. Metabolic regulation of kisspeptin — the link between energy balance and reproduction. Nat Rev Endocrinol (2020). https://doi.org/10.1038/s41574-020-0363-7

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