Kisspeptins: Bridging energy homeostasis and reproduction

Body energy reserves and metabolic state are relevant modifiers of puberty onset and fertility; forms of metabolic stress ranging from persistent energy insufficiency to morbid obesity are frequently linked to reproductive disorders. The mechanisms for such a close connection between energy balance and reproduction have been the subject of considerable attention; however, our understanding of the neurobiological basis for this phenomenon is still incomplete. In mid 1990s, the adipose-hormone, leptin, was proven as an essential signal for transmitting metabolic information onto the centers governing puberty and reproduction; yet, the ultimate mode of action of leptin on GnRH neurons has remained contentious for years. More recently, kisspeptins, a family of neuropeptides encoded by the Kiss1 gene, have emerged as conduits for the metabolic regulation of reproduction and putative effectors of leptin actions on GnRH neurons. This review recapitulates the experimental evidence obtained to date, mostly in laboratory rodents, supporting the function of kisspeptins in bridging energy balance and reproduction, with special emphasis on recent developments in this field, such as the recognition of mTOR (mammalian target of rapamycin) and Crtc1 (Creb1-regulated transcription coactivator-1) as putative mediators for leptin regulation of Kiss1 expression, as well as the identification of other potential metabolic modulators of kisspeptin signaling, such as ghrelin, neuropeptide Y (NPY) and melanin-concentrating hormone (MCH).

Research Highlights
► The hypothalamic Kiss1 system, as major gatekeeper and stimulatory factor of the HPG axis, is sensitive to body energy/metabolic status.
► Leptin, as essential permissive factor for puberty and fertility, is a major regulator of hypothalamic Kiss1 expression, although its sites of action for this effect are yet to be unfolded.
► Central mTOR and Crtc1 signaling pathways are potential mediators for leptin effects on Kiss1 expression.
► Ghrelin and other metabolic signals known to modulate the HPG axis, such as NPY, melanocortins and MCH, are additional putative regulators of the hypothalamic Kiss1 system.
► The hypothalamic Kiss1 system is proposed to play a prominent role as central conduit for the metabolic regulation of puberty onset and reproductive function.