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

Nature Reviews Endocrinology volume 16, pages 407–420 (2020)Cite this article

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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.

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Acknowledgements

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

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  1. Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    Víctor M. Navarro

  2. Harvard Graduate Program in Neuroscience, Boston, MA, USA

    Víctor M. Navarro

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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 16, 407–420 (2020). https://doi.org/10.1038/s41574-020-0363-7

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