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.

Fig. 1 |. The HPG axis with the two main populations of kisspeptin neurons.

Arcuate kisspeptin (kisspeptin^ARC) neuron together with neurokinin B and dynorphin are involved in the tonic (pulsatile) release of kisspeptin (positive and negative symbols indicate the effect on kisspeptin release) and, therefore, gonadotropin-releasing hormone (GnRH). By contrast, anteroventral periventricular/periventricular nucleus kisspeptin (kisspeptin^AVPV/PeN) neurons are involved in the control of the luteinizing hormone (LH) surge and are almost absent in the male brain. Major peripheral metabolic factors are depicted (leptin, insulin and ghrelin) acting at the level of the brain to regulate kisspeptin output. ARC, arcuate nucleus; FSH, follicle-stimulating hormone; HPG axis, hypothalamic–pituitary–gonadal axis; KOR, κ-opioid receptor; NK3R, neurokinin B receptor; WAT, white adipose tissue.

Fig. 2 |. Levels of metabolic regulation of kisspeptin neurons throughout development.

Schematic representation of the different developmental stages in which metabolic factors might affect the expression of the Kiss1 gene. First, epigenetic effects (DNA methylation, histone modification and non-coding RNAs) might permanently affect the expression of Kiss1. This effect can occur transgenerationally or at any stage of development. Second, during the perinatal period there is a critical window in which conformational changes in kisspeptin neurons might happen as a consequence of the exposure to metabolic factors. These pre-existing modifications (epigenetic and conformational during development) might determine the timing of the activation of kisspeptin neurons (puberty onset) and their function in adulthood (luteinizing hormone (LH) pulses and surge). Nonetheless, during and after development, kisspeptin neurons can still be regulated by metabolic factors at different levels: epigenetic, nutrient sensing and central and peripheral factors. AMPK, 5'-AMP-activated protein kinase; E13.5, embryonic day 13.5; GnRH, gonadotropin-releasing hormone; mTOR, mammalian target of rapamycin.

Fig. 3 |. Neuroendocrine circuits involved in the metabolic role of kisspeptin neurons.

Representation of a sagittal section of the mouse brain depicting documented (solid lines) and predicted (dotted lines) connections from kisspeptin^ARC neurons to and from known metabolic nuclei. AgRP, agouti-related peptide; ARC, arcuate nucleus; BnST, bed nucleus of the stria terminalis; DMH, dorsomedial hypothalamus; LH, lateral hypothalamus; LPBN, lateral parabrachial nucleus; NPY, neuropeptide Y; NTS, nucleus of the solitary tract; POMC, proopiomelanocortin; PVH, paraventricular hypothalamic nucleus.