Abstract
The neurohormonal control of reproduction involves a hierarchical network of central and peripheral signals in the hypothalamic–pituitary–gonadal (HPG) axis. Development and function of this neuroendocrine system is the result of a lifelong delicate balance between endogenous regulators and environmental cues, including nutritional and metabolic factors. Kisspeptins are the peptide products of KISS1, which operate via the G-protein-coupled receptor GPR54 (also known as Kiss1R). These peptides have emerged as essential upstream regulators of neurons secreting gonadotropin-releasing hormone (GnRH), the major hypothalamic node for the stimulatory control of the HPG axis. They are potent elicitors of gonadotropin secretion in various species and physiological settings. Moreover, Kiss1 neurons in the hypothalamus participate in crucial features of reproductive maturation and function, such as brain-level sex differentiation, puberty onset and the neuroendocrine regulation of gonadotropin secretion and ovulation. Cotransmitters of Kiss1 neurons, such as neurokinin B, with roles in controlling the HPG axis have been identified by genetic, neuroanatomical and physiological studies. In addition, a putative role has been proposed for Kiss1 neurons in transmitting metabolic information to GnRH neurons, although the precise mechanisms are as yet unclear. In this Review, we present the major reproductive features of kisspeptins, especially their interplay with neurokinin B and potential roles in the metabolic control of puberty and fertility, and suggest new avenues for research.
Key Points
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Kisspeptins, the ligands of the G-protein-coupled receptor GPR54, are encoded in humans by the KISS1 gene and operate as potent stimulators of gonadotropin-releasing hormone (GnRH) in the reproductive brain
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Kisspeptin pathways are involved in the control of crucial aspects of reproductive maturation and function, including puberty onset, sex-steroid control of gonadotropin secretion and ovulation
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Discrete populations of Kiss1 neurons exist in the arcuate nucleus of the hypothalamus in humans and nonprimates and in the rostral periventricular area in rodents; arcuate Kiss1 neurons coexpress neurokinin B
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Hypothalamic expression of Kiss1 is sensitive to negative energy balance (potentially including obesity) and probably acts as a sensor and transmitter of metabolic information to GnRH neurons
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The signals and mechanisms underlying metabolic control of Kiss1 neurons are poorly defined; a role for leptin is proposed, but its mechanisms of action are not yet clear
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Interplay between the Kiss1 system and various molecular mediators and other neuropeptide pathways seems important for energy homeostasis, but data are inconsistent and need to be interpreted with caution
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References
Fink, G. in Neuroendocrinology in physiology and medicine 1st edn Ch. 7 (eds Conn, P. M. & Freeman, M. E.) 107–134 (Humana Press, Totowa, 2000).
Tena-Sempere, M. & Huhtaniemi, I. in Reproductive medicine: molecular, cellular and genetic fundamentals 1st edn Ch. 12 (ed. Fauser, B. C. J. M.) 225–244 (Parthenon Publishing, New York, 2003).
Schwartz, N. B. in Neuroendocrinology in physiology and medicine 1st edn Ch. 8 (eds Conn, P. M. & Freeman, M. E.) 135–146 (Humana Press, Totowa, 2000).
Herbison, A. E. in The physiology of reproduction 3rd edn Vol. 1 Ch. 2 (ed. Neill, J. D.) 1415–1482 (Elsevier, 2006).
Fernandez-Fernandez, R. et al. Novel signals for the integration of energy balance and reproduction. Mol. Cell Endocrinol. 254–255, 127–32 (2006).
Roa, J. & Tena-Sempere, M. Energy balance and puberty onset: emerging role of central mTOR signaling. Trends Endocrinol. Metab. 21, 519–528 (2010).
Hill, J. W., Elmquist, J. K. & Elias, C. F. Hypothalamic pathways linking energy balance and reproduction. Am. J. Physiol. Endocrinol. Metab. 294, E827–E832 (2008).
Castellano, J. M. et al. KiSS-1/kisspeptins and the metabolic control of reproduction: physiologic roles and putative physiopathological implications. Peptides 30, 139–145 (2009).
Roa, J., Aguilar, E., Dieguez, C., Pinilla, L. & Tena-Sempere, M. New frontiers in kisspeptin/GPR54 physiology as fundamental gatekeepers of reproductive function. Front. Neuroendocrinol. 29, 48–69 (2008).
Oakley, A. E., Clifton, D. K. & Steiner, R. A. Kisspeptin signaling in the brain. Endocr. Rev. 30, 713–743 (2009).
Gottsch, M. L., Clifton, D. K. & Steiner, R. A. From KISS1 to kisspeptins: An historical perspective and suggested nomenclature. Peptides 30, 4–9 (2009).
Ohtaki, T. et al. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature 411, 613–617 (2001).
Lee, D. K. et al. Discovery of a receptor related to the galanin receptors. FEBS Lett. 446, 103–107 (1999).
Muir, A. I. et al. AXOR12, a novel human G protein-coupled receptor, activated by the peptide KiSS-1. J. Biol. Chem. 276, 28969–28975 (2001).
Kotani, M. et al. The metastasis suppressor gene KiSS-1 encodes kisspeptins, the natural ligands of the orphan, G. protein-coupled receptor GPR54. J. Biol. Chem. 276, 34631–34636 (2001).
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).
Seminara, S. B. et al. The GPR54 gene as a regulator of puberty. N. Engl. J. Med. 349, 1614–1627 (2003).
Colledge, W. H. Transgenic mouse models to study Gpr54/kisspeptin physiology. Peptides 30, 34–41 (2009).
Irwig, M. S. et al. Kisspeptin activation of gonadotropin releasing hormone neurons and regulation of KiSS-1 mRNA in the male rat. Neuroendocrinology 80, 264–272 (2004).
Navarro, V. M. et al. Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54. Endocrinology 146, 156–163 (2005).
Han, S. K. et al. Activation of gonadotropin-releasing hormone neurons by kisspeptin as a neuroendocrine switch for the onset of puberty. J. Neurosci. 25, 11349–11356 (2005).
Zhang, C., Roepke, T. A., Kelly, M. J. & Rønnekleiv, O. K. Kisspeptin depolarizes gonadotropin-releasing hormone neurons through activation of TRPC-like cationic channels. J. Neurosci. 28, 4423–4434 (2008).
Pielecka-Fortuna, J., Chu, Z. & Moenter, S. M. Kisspeptin acts directly and indirectly to increase gonadotropin-releasing hormone neuron activity and its effects are modulated by estradiol. Endocrinology 149, 1979–1986 (2008).
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).
Messager, S. et al. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G. protein-coupled receptor 54. Proc. Natl Acad. Sci. USA 102, 1761–1766 (2005).
Roseweir, A. K. et al. Discovery of potent kisspeptin antagonists delineate physiological mechanisms of gonadotropin regulation. J. Neurosci. 29, 3920–3929 (2009).
Luque, R. M. et al. Kisspeptin regulates gonadotroph and somatotroph function in nonhuman primate pituitary via common and distinct signaling mechanisms. Endocrinology 152, 957–966 (2011).
Tena-Sempere, M. GPR54 and kisspeptin in reproduction. Hum. Reprod. Update 12, 631–639 (2006).
Smith, J. T. et al. Differential regulation of KiSS-1 mRNA expression by sex steroids in the brain of the male mouse. Endocrinology 146, 2976–2984 (2005).
Smith, J. T., Cunningham, M. J., Rissman, E. F., Clifton, D. K. & Steiner, R. A. Regulation of Kiss1 gene expression in the brain of the female mouse. Endocrinology 146, 3686–3692 (2005).
Kauffman, A. S. et al. Sexual differentiation of Kiss1 gene expression in the brain of the rat. Endocrinology 148, 1774–1783 (2007).
Gottsch, M. L. et al. A role for kisspeptins in the regulation of gonadotropin secretion in the mouse. Endocrinology 145, 4073–4077 (2004).
Cravo, R. M. et al. Characterization of Kiss1 neurons using transgenic mouse models. Neuroscience 173, 37–56 (2011).
Rance, N. E. Menopause and the human hypothalamus: evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides 30, 111–122 (2009).
Shibata, M., Friedman, R. L., Ramaswamy, S. & Plant, T. M. Evidence that down regulation of hypothalamic KiSS-1 expression is involved in the negative feedback action of testosterone to regulate luteinising hormone secretion in the adult male rhesus monkey (Macaca mulatta). J. Neuroendocrinol. 19, 432–438 (2007).
Smith, J. T., Li, Q., Pereira, A. & Clarke, I. J. Kisspeptin neurons in the ovine arcuate nucleus and preoptic area are involved in the preovulatory luteinizing hormone surge. Endocrinology 150, 5530–5538 (2009).
Mikkelsen, J. D. & Simonneaux, V. The neuroanatomy of the kisspeptin system in the mammalian brain. Peptides 30, 26–33 (2009).
Clarkson, J., d'Anglemont de Tassigny, X., Colledge, W. H., Caraty, A. & Herbison, A. E. Distribution of kisspeptin neurones in the adult female mouse brain. J. Neuroendocrinol. 21, 673–682 (2009).
Ramaswamy, S., Guerriero, K. A., Gibbs, R. B. & Plant, T. M. Structural interactions between kisspeptin and GnRH neurons in the mediobasal hypothalamus of the male rhesus monkey (Macaca mulatta) as revealed by double immunofluorescence and confocal microscopy. Endocrinology 149, 4387–4395 (2008).
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).
Krajewski, S. J., Burke, M. C., Anderson, M. J., McMullen, N. T. & Rance, N. E. Forebrain projections of arcuate neurokinin B neurons demonstrated by anterograde tract-tracing and monosodium glutamate lesions in the rat. Neuroscience 166, 680–697 (2010).
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).
Herbison, A. E., de Tassigny, X., Doran, J. & Colledge, W. H. Distribution and postnatal development of Gpr54 gene expression in mouse brain and gonadotropin-releasing hormone neurons. Endocrinology 151, 312–321 (2010).
d'Anglemont de Tassigny, X., Fagg, L. A., Carlton, M. B. & Colledge, W. H. Kisspeptin can stimulate gonadotropin-releasing hormone (GnRH) release by a direct action at GnRH nerve terminals. Endocrinology 149, 3926–3932 (2008).
Rance, N. E., Krajewski, S. J., Smith, M. A., Cholanian, M. & Dacks, P. A. Neurokinin B and the hypothalamic regulation of reproduction. Brain Res. 1364, 116–128 (2010).
Morris, J. A., Jordan, C. L. & Breedlove, S. M. Sexual differentiation of the vertebrate nervous system. Nat. Neurosci. 7, 1034–1039 (2004).
Tena-Sempere, M. Kisspeptin/GPR54 system as potential target for endocrine disruption of reproductive development and function. Int. J. Androl. 33, 360–368 (2010).
Tena-Sempere, M. Roles of kisspeptins in the control of hypothalamic–gonadotropic function: focus on sexual differentiation and puberty onset. Endocr. Dev. 17, 52–62 (2010).
Clarkson, J., Han, S. K., Liu, X., Lee, K. & Herbison, A. E. Neurobiological mechanisms underlying kisspeptin activation of gonadotropin-releasing hormone (GnRH) neurons at puberty. Mol. Cell Endocrinol. 324, 45–50 (2010).
Pineda, R. et al. Critical roles of kisspeptins in female puberty and preovulatory gonadotropin surges as revealed by a novel antagonist. Endocrinology 151, 722–730 (2010).
Christian, C. A. & Moenter, S. M. The neurobiology of preovulatory and estradiol-induced gonadotropin-releasing hormone surges. Endocr. Rev. 31, 544–577 (2010).
Wintermantel, T. M. et al. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron 52, 271–280 (2006).
Mayer, C. et al. Timing and completion of puberty in female mice depend on estrogen receptor alpha-signaling in kisspeptin neurons. Proc. Natl Acad. Sci. USA 107, 22693–22698 (2010).
Dungan, H. M. et al. The role of kisspeptin-GPR54 signaling in the tonic regulation and surge release of gonadotropin-releasing hormone/luteinizing hormone. J. Neurosci. 27, 12088–12095 (2007).
Roa, J. et al. Kisspeptins and the control of gonadotropin secretion in male and female rodents. Peptides 30, 57–66 (2009).
Clarkson, J., d'Anglemont de Tassigny, X., Moreno, A. S., Colledge, W. H. & Herbison, A. E. Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J. Neurosci. 28, 8691–8697 (2008).
Roa, J. et al. Opposite roles of estrogen receptor (ER)-α and ERβ in the modulation of luteinizing hormone responses to kisspeptin in the female rat: implications for the generation of the preovulatory surge. Endocrinology 149, 1627–1637 (2008).
Roa, J. et al. Follicle-stimulating hormone responses to kisspeptin in the female rat at the preovulatory period: modulation by estrogen and progesterone receptors. Endocrinology 149, 5783–5790 (2008).
Lederman, M. A. et al. Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats. Neuropharmacology 58, 314–320 (2010).
Neal-Perry, G. et al. The excitatory peptide kisspeptin restores the luteinizing hormone surge and modulates amino acid neurotransmission in the medial preoptic area of middle-aged rats. Endocrinology 150, 3699–3708 (2009).
Lehman, M. N., Coolen, L. M. & Goodman, R. L. Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion. Endocrinology 151, 3479–3489 (2010).
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).
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).
Wakabayashi, Y. et al. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat. J. Neurosci. 30, 3124–3132 (2010).
Ramaswamy, S. et al. Neurokinin B stimulates GnRH release in the male monkey (Macaca mulatta) and is colocalized with kisspeptin in the arcuate nucleus. Endocrinology 151, 4494–4503 (2010).
Burke, M. C., Letts, P. A., Krajewski, S. J. & Rance, N. E. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus. J. Comp. Neurol. 498, 712–726 (2006).
Topaloglu, A. K. et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009).
Young, J. et al. TAC3 and TACR3 defects cause hypothalamic congenital hypogonadotropic hypogonadism in humans. J. Clin. Endocrinol. Metab. 95, 2287–2295 (2010).
Gianetti, E. et al. TAC3/TACR3 mutations reveal preferential activation of gonadotropin-releasing hormone release by neurokinin B in neonatal life followed by reversal in adulthood. J. Clin. Endocrinol. Metab. 95, 2857–2867 (2010).
Billings, H. J. et al. Neurokinin B acts via the neurokinin-3 receptor in the retrochiasmatic area to stimulate luteinizing hormone secretion in sheep. Endocrinology 151, 3836–3846 (2010).
Navarro, V. M. et al. Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am. J. Physiol. Endocrinol. Metab. 300, E202–E210 (2011).
Roa, J. et al. Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states. Am. J. Physiol. Endocrinol. Metab. 294, E1088–E1096 (2008).
Sandoval-Guzmán, T. & Rance, N. E. Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res. 1026, 307–312 (2004).
Castellano, J. M., Bentsen, A. H., Mikkelsen, J. D. & Tena-Sempere, M. Kisspeptins: bridging energy homeostasis and reproduction. Brain Res. 1364, 129–138 (2010).
Tena-Sempere, M. Ghrelin as a pleotrophic modulator of gonadal function and reproduction. Nat. Clin. Pract. Endocrinol. Metab. 4, 666–674 (2008).
Quennell, J. H. et al. Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology 150, 2805–2812 (2009).
Sexton, W. J. & Jarow, J. P. Effect of diabetes mellitus upon male reproductive function. Urology 49, 508–513 (1997).
Wade, G. N. & Jones, J. E. Neuroendocrinology of nutritional infertility. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R1277–R1296 (2004).
Kalamatianos, T., Grimshaw, S. E., Poorun, R., Hahn, J. D. & Coen, C. W. Fasting reduces KiSS-1 expression in the anteroventral periventricular nucleus (AVPV): effects of fasting on the expression of KiSS-1 and neuropeptide Y in the AVPV or arcuate nucleus of female rats. J. Neuroendocrinol. 20, 1089–1097 (2008).
Luque, R. M., Kineman, R. D. & Tena-Sempere, M. Regulation of hypothalamic expression of KiSS-1 and GPR54 genes by metabolic factors: analyses using mouse models and a cell line. Endocrinology 148, 4601–4611 (2007).
Wahab, F., Ullah, F., Chan, Y. M., Seminara, S. B. & Shahab, M. Decrease in hypothalamic Kiss1 and Kiss1r expression: a potential mechanism for fasting-induced suppression of the HPG axis in the adult male rhesus monkey (Macaca mulatta). Horm. Metab. Res. 43, 81–85 (2011).
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).
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).
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).
Castellano, J. M. et al. Alterations in hypothalamic KiSS-1 system in experimental diabetes: early changes and functional consequences. Endocrinology 150, 784–794 (2009).
Yamada, S. et al. Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats. Endocrinology 148, 2226–2232 (2007).
True, C., Kirigiti, M., Ciofi, P., Grove, K. L. & Smith, M. S. Characterisation of arcuate nucleus kisspeptin/neurokinin B neuronal projections and regulation during lactation in the rat. J. Neuroendocrinol. 23, 52–64 (2011).
Jayasena, C. N. et al. Twice-weekly administration of kisspeptin-54 for 8 weeks stimulates release of reproductive hormones in women with hypothalamic amenorrhea. Clin. Pharmacol. Ther. 88, 840–847 (2010).
Quennell, J. H. et al. Leptin deficiency and diet-induced obesity reduce hypothalamic kisspeptin expression in mice. Endocrinology 152, 1541–1550 (2011).
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 doi:10.1210/en.2010–1415.
Tena-Sempere, M. KiSS-1 and reproduction: focus on its role in the metabolic regulation of fertility. Neuroendocrinology 83, 275–281 (2006).
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).
Chou, S. H. et al. Leptin is an effective treatment for hypothalamic amenorrhea. Proc. Natl Acad. Sci. USA 108, 6585–6590 (2011).
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).
Louis, G. W. et al. Molecular mapping of the neural pathways linking leptin to the neuroendocrine reproductive axis. Endocrinology 152, 2302–2310 (2011).
Tena-Sempere, M. & Barreiro, M. L. Leptin in male reproduction: the testis paradigm. Mol. Cell Endocrinol. 188, 9–13 (2002).
True, C., Kirigiti, M. A., Kievit, P., Grove, K. L. & Susan Smith, M. Leptin is not the critical signal for kisspeptin or luteinising hormone restoration during exit from negative energy balance. J. Neuroendocrinol. doi:10.1111/j.1365-2826.2011.02144.x.
Backholer, K., Smith, J. & Clarke, I. J. Melanocortins may stimulate reproduction by activating orexin neurons in the dorsomedial hypothalamus and kisspeptin neurons in the preoptic area of the ewe. Endocrinology 150, 5488–5497 (2009).
Schwartz, M. W., Seeley, R. J., Campfield, L. A., Burn, P. & Baskin, D. G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).
Kim, G. L., Dhillon, S. S. & Belsham, D. D. Kisspeptin directly regulates neuropeptide Y synthesis and secretion via the ERK1/2 and p38 mitogen-activated protein kinase signaling pathways in NPY-secreting hypothalamic neurons. Endocrinology 151, 5038–5047 (2010).
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).
Stengel, A., Wang, L., Goebel-Stengel, M. & Taché, Y. Centrally injected kisspeptin reduces food intake by increasing meal intervals in mice. Neuroreport 22, 253–257 (2011).
Wu, M., Dumalska, I., Morozova, E., van den Pol, A. & Alreja, M. Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction. Proc. Natl Acad. Sci. USA 106, 17217–17222 (2009).
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).
Hiney, J. K., Srivastava, V. K., Pine, M. D. & Les Dees, W. Insulin-like growth factor-I activates KiSS-1 gene expression in the brain of the prepubertal female rat. Endocrinology 150, 376–384 (2009).
Todd, B. J., Fraley, G. S., Peck, A. C., Schwartz, G. J. & Etgen, A. M. Central insulin-like growth factor 1 receptors play distinct roles in the control of reproduction, food intake, and body weight in female rats. Biol. Reprod. 77, 492–503 (2007).
Kinsey-Jones, J. S. et al. Down-regulation of hypothalamic kisspeptin and its receptor, Kiss1r, mRNA expression is associated with stress-induced suppression of luteinising hormone secretion in the female rat. J. Neuroendocrinol. 21, 20–29 (2009).
Cantó, C. & Auwerx, J. PGC-1α, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr. Opin. Lipidol 20, 98–105 (2009).
Naïmi, M., Arous, C. & Van Obberghen, E. Energetic cell sensors: a key to metabolic homeostasis. Trends Endocrinol. Metab. 21, 75–82 (2010).
Cota, D. et al. Hypothalamic mTOR signaling regulates food intake. Science 312, 927–930 (2006).
Woods, S. C., Seeley, R. J. & Cota, D. Regulation of food intake through hypothalamic signaling networks involving mTOR. Annu. Rev. Nutr. 28, 295–311 (2008).
Villanueva, E. C. et al. Complex regulation of mammalian target of rapamycin complex 1 in the basomedial hypothalamus by leptin and nutritional status. Endocrinology 150, 4541–4551 (2009).
Altarejos, J. Y. et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat. Med. 14, 1112–1117 (2008).
Breuillaud, L., Halfon, O., Magistretti, P. J., Pralong, F. P. & Cardinaux, J. R. Mouse fertility is not dependent on the CREB coactivator Crtc1. Nat. Med. 15, 989–990; author reply 991 (2009).
d'Anglemont de Tassigny, X., Ackroyd, K. J., Chatzidaki, E. E. & Colledge, W. H. Kisspeptin signaling is required for peripheral but not central stimulation of gonadotropin-releasing hormone neurons by NMDA. J. Neurosci. 30, 8581–8590 (2010).
Pielecka-Fortuna, J. & Moenter, S. M. Kisspeptin increases gamma-aminobutyric acidergic and glutamatergic transmission directly to gonadotropin-releasing hormone neurons in an estradiol-dependent manner. Endocrinology 151, 291–300 (2010).
Mayer, C. & Boehm, U. Female reproductive maturation in the absence of kisspeptin/GPR54 signaling. Nat. Neurosci. 14, 704–710 (2011).
Herbison, A. E., Porteous, R., Pape, J. R., Mora, J. M. & Hurst, P. R. Gonadotropin-releasing hormone neuron requirements for puberty, ovulation, and fertility. Endocrinology 149, 597–604 (2008).
Acknowledgements
We thank the members of the research team at the Physiology Section of the University of Cordóba, Cordóba, Spain, who actively participated in the generation of experimental data. We thank R. A. Steiner, University of Washington, WA, USA, for discussion and support. Part of the work summarized in this article was supported by grant BFU 2008-00984 (Ministerio de Ciencia e Innovación, Spain), funds from Instituto de Salud Carlos III (Project PI042082; Ministerio de Sanidad, Spain), Project P08-CVI-03788 (Junta de Andalucía, Spain), European Union research contract DEER FP7-ENV-2007-1 and the Marie Curie Outgoing International Fellowships within the seventh Framework Programme of the European Union. CIBERobn (Centro de Investigación Biomédica en Red de la Fisiopatología de la Obesidad y Nutrición) is an initiative of Instituto de Salud Carlos III (Ministerio de Sanidad, Spain).
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M. Tena-Sempere declares receiving grant support from Organon/MSD for basic research and consultancy on topics (Kiss1 receptor related pathways) partially related with the general contents of the review article. The research activities concerning NKB/kisspeptin interactions or metabolic regulation of Kiss1 system, extensively reviewed and major component of this article, have not been supported by any grants from private institutions. The grant support disclosed above has by no means influenced the interpretation of this article. V. M. Navarro declares no competing interests.
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Navarro, V., Tena-Sempere, M. Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility. Nat Rev Endocrinol 8, 40–53 (2012). https://doi.org/10.1038/nrendo.2011.147
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DOI: https://doi.org/10.1038/nrendo.2011.147
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Cellular and Molecular Life Sciences (2018)