KiSS-1/kisspeptins and the metabolic control of reproduction: Physiologic roles and putative physiopathological implications

Abstract

It is well established that reproductive function is gated by the state of energy reserves of the organism; conditions of metabolic stress and energy insufficiency being frequently coupled to disturbed reproductive maturation and/or infertility. In addition, obesity is also commonly linked to altered puberty onset and reproductive impairment. Such an impact of energy status on the reproductive axis is conveyed through a number of neuropeptide hormones and metabolic cues, whose nature and mechanisms of action have begun to be deciphered only in recent years. In this context, the emergence of kisspeptins, encoded by the KiSS-1 gene, and their receptor, GPR54, as indispensable signals for normal pubertal maturation and gonadal function, has raised the possibility that the KiSS-1/GRP54 system might also participate in coupling body energy status and reproduction. We revise herein the experimental evidence, gathered in rodent models, supporting the contention that the hypothalamic KiSS-1 system operates as a central conduit for conveying metabolic information onto the centers governing reproductive function, through a putative leptin–kisspeptin–GnRH pathway. Admittedly, key aspects of this ‘metabolic’ network involving the KiSS-1 system, such as its different peripheral regulators and central effectors, have not been fully elucidated. Nonetheless, the proposed hypothalamic circuitry, responsible for transmitting metabolic information onto the reproductive axis through KiSS-1 neurons, might explain, at least in part, the mechanisms for the well-known alterations of fertility linked to conditions of disturbed energy balance in humans, from anorexia nervosa to morbid obesity.

Introduction

Reproductive maturation and function is sensitive to the state of energy reserves of the organism [12], [24]. Such a functional coupling between energy homeostasis and fertility is especially, but not exclusively, present in the female, where threshold energy reserves are needed in order to successfully face the considerable metabolic drainage of pregnancy and lactation [3]. Nonetheless, in both sexes, conditions of altered energy homeostasis, ranging from cachexia to morbid obesity, are frequently linked to variable degrees of disturbed reproductive capacity [12], [25]. The basis for those alterations remains partially unknown, but this is likely a multi-faceted phenomenon that involves numerous bidirectional interactions between the neuroendocrine networks governing energy balance and gonadotropic function that take place at different levels of the hypothalamic–pituitary–gonadal axis [12]. In this context, our knowledge of the physiologic mechanisms whereby the reproductive brain ‘senses’ the magnitude of fuel (fat) reserves and the metabolic status of the organism has significantly enlarged in recent years, with the identification of the effects on the reproductive system of a number of peripheral hormones from the adipose, gastrointestinal tract and pancreas, as well as other nutritional and metabolic cues [12], [24]. Admittedly, however, characterization of the central pathways that ultimately transmit metabolic information onto the centers governing reproductive function has remained elusive for decades.