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  • Review Article
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Neuroendocrine control by kisspeptins: role in metabolic regulation of fertility

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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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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Figure 1: A tentative model for the regulation of GnRH secretion by two distinct Kiss1 neuronal populations, located in the ARC and AVPV/PeN, as in rodents, is presented.
Figure 2: Major hormonal, neuropeptide and molecular metabolic regulators of Kiss1 neurons.

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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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Correspondence to Manuel Tena-Sempere.

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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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