Role of kisspeptin in the metabolic regulation of fertility
Reproduction is a metabolically-demanding function which is gated by the state of fuel reserves of the organism. Indeed, conditions of metabolic stress and energy unbalance are frequently coupled to disturbed reproductive maturation and/or compromised fertility. The mechanisms whereby the body energy status influences the development and function of the reproductive axis has begun to be deciphered only recently, and seemingly involve a plethora of neuropeptide hormones and metabolic cues, which impinge and integrate at the hypothalamic centers governing reproduction. Kisspeptins, the peptide products of the KiSS-1 gene, and their receptor, GPR54, have recently emerged as indispensable signals for normal pubertal maturation and gonadal function. Among their key functions in the control of the reproductive axis, solid experimental evidence, obtained in the last three years mostly in laboratory rodents, strongly suggests that the hypothalamic KiSS-1 system operates as a central conduit for conveying metabolic information onto reproductive centers of the brain, in different physiologic and pathophysiologic conditions. This function would involve a putative leptinkisspeptin-GnRH pathway; leptin being a positive modulator of hypothalamic expression of KiSS-1. In addition, recent studies have pointed out additional neuropeptide regulators and novel central effectors, such as Crtc-1 and mTOR, for such metabolic regulation of the KiSS-1 system. Overall, the available evidence supports that kisspeptins are key players in the hypothalamic circuitry responsible for transmitting metabolic information onto the reproductive axis. Such a kisspeptinergic pathway seems relevant for the physiological coupling of body energy status and reproduction, and might eventually contribute to the well-known alterations of fertility linked to conditions of disturbed energy balance, from anorexia nervosa to morbid obesity.