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

• Published in: Nature reviews. Endocrinology 2020-08, Vol.16 (8), p.407-420
• Main Author: Navarro, Víctor M.
• Format: Article
• Language: English
• Subjects: 631/443/319/1557; 631/443/319/367/1562; Animals; Bioenergetics; Developmental stages; Dynorphins - physiology; Endocrinology; Energy balance; Energy metabolism; Energy Metabolism - physiology; Female; Gonadotropin-releasing hormone; Gonadotropin-Releasing Hormone - physiology; Gonadotropins; Homeostasis; Humans; Hypothalamo-Hypophyseal System - physiology; Hypothalamus; Hypothalamus - cytology; Hypothalamus - physiology; Kiss1 protein; Kisspeptins - genetics; Kisspeptins - physiology; Life cycle, Human; Luteinizing Hormone - physiology; Medicine; Medicine & Public Health; Metabolic regulation; Metabolism; Neurokinin B - physiology; Neurons; Neurons - physiology; Neuropeptides; Ovary - physiology; Physiological aspects; Physiological research; Pituitary (anterior); Puberty - physiology; Reproduction; Reproduction - physiology; Review Article
• ISSN: 1759-5029; 1759-5037
• DOI: 10.1038/s41574-020-0363-7

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. Kisspeptin neurons in the hypothalamus exert key regulatory control over reproduction and are subjected to tight control by metabolic factors. This Review highlights the mechanisms by which kisspeptin neurons undergo metabolic regulation, from early developmental stages through to adulthood. 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.