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

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.