Kisspeptin signaling and the control of puberty: consensus knowledge and future directions (#9)
Puberty is a key developmental transition that is under the control of sophisticated regulatory networks that impinge upon brain centers governing the reproductive axis. While much has been learnt on mammalian puberty in the last decades, recent developments have substantially expanded our knowledge of the neuroendocrine and molecular basis of puberty onset. Among those, identification of the essential roles of kisspeptins, products of the Kiss1 gene that act via the receptor, Gpr54 (aka Kiss1r), is recognized as major breakthrough in pubertal pathophysiology. Indeed, experimental studies have documented a complex pattern of developmental maturation/activation of hypothalamic Kiss1 neurons that is essential for proper timing of puberty. Likewise, evidence has been presented that Kiss1 neurons are (directly or indirectly) sensitive to sex steroids and metabolic cues before/during pubertal transition, and may participate in conveying the regulatory effects of these factors on puberty onset. Yet, the actual nature and mechanisms of kisspeptin actions, as well as their interplay with other neuropeptide modulators, in the regulation of puberty are still incompletely characterized. We summarize here consensus knowledge on the pubertal roles of kisspeptins and present recent work aiming to expand our understanding of how Kiss1 neurons participate in the control of puberty, which are their major interactive partners and what are their key regulatory mechanisms. Special attention will focus on (1) the potential interplay of kisspeptins with other putative regulators of puberty, such as NKB and melanocortins; (2) the roles of epigenetics and microRNAs in the regulation of Kiss1 neurons and puberty onset; and (3) the pubertal roles and potential interaction with Kiss1 pathways of key cellular energy sensors, such as AMPK and Sirt1. In doing so, we intend to provide an updated view of the actual roles, putative modes of action and regulatory mechanisms of kisspeptins in the control of puberty in mammals.