The role of hypothalamic kisspeptin neurons in coordinating reproduction and metabolism

Abstract The hypothalamic control of fertility is a quintessential homeostatic function. Given that reproduction is metabolically demanding, coordination between energy status and reproductive function is essential. Since GnRH neurons lack receptors for key metabolic hormones, nutrient sensing must occur via presynaptic neurons. Among the candidates are anorexigenic POMC and orexigenic NPY/AgRP neurons, both of which are in close apposition to the median eminence, a circumventricular organ permissive to circulating signals. These neurons are inversely regulated by glucose and metabolic hormones, with POMC neurons generally excited by insulin and leptin, and NPY/AgRP neurons inhibited by them. However, their synaptic input to GnRH neurons is sparse, and GnRH neurons may lack the necessary postsynaptic receptors. The discovery of kisspeptin neurons in the early part of this century revolutionized our understanding of reproductive regulation. These neurons project to and control GnRH neuronal excitability. More recently, arcuate kisspeptin neurons (KNDy) have been identified as the command neurons driving pulsatile release of GnRH and are essential for the GnRH/LH surge. Notably, these neurons express both steroid hormone receptors and metabolic hormone receptors and, like POMC neurons, are excited by insulin and leptin. Therefore, arcuate kisspeptin neurons likely serve as a central hub in linking metabolic signals with reproduction. This review will examine how these vital neurons control pulsatile GnRH release, their reciprocal synaptic connections with POMC and NPY/AgRP neurons, and how E2 can regulate their excitability. Through integration of metabolic and hormonal cues, these neurons help align reproductive capacity with the organism's energy status.