Lactation is an important physiological model of negative energy balance that involves activation of potent appetitive neuropeptide systems coupled to a profound inhibition of pulsatile GnRH/LH secretion. There appear to be multiple systems that contribute to the chronic hyperphagia: suppression of the metabolic hormones, leptin and insulin, activation of systems in the ARH and LHA, and induction of NPY in the DMH. These changes ensure adequate energy intake to meet the metabolic needs of milk production (). The overlap in these systems with the regulation of GnRH could provide several redundancies in this regulation as well (). In addition to an overall increase in inhibitory tone acting on GnRH cell bodies that is brought about by alterations in NPY, MCH, OX and Kiss1 input, there are also effects at the ARH to disrupt KNDy neuronal function, leading to a possible disruption of pulsatile GnRH release (). While the low levels of leptin and insulin are important to the changes in ARH appetitive systems, they do not appear to be necessary for the suppression of ARH Kiss1 or NKB. It is a reasonable hypothesis that the inhibition of Kiss1 may be the key factor in the suppression of GnRH during lactation, although the mechanisms responsible for its inhibition are unknown.
Although the study of kisspeptin has greatly advanced our understanding of the regulation of GnRH, there are important questions that remain to be answered about how energy balance and reproduction are integrated. What is the importance of the special adaptations of lactation, such as induction of NPY in the DMH and MCH in the median preoptic nucleus? Do they function as redundant systems or are they critically important? How are changes in the activity of the various neuropeptide systems (NPY, MCH, OX) acting directly on GnRH cell bodies integrated to affect function? Does Kiss1 input from the AVPV to GnRH cell bodies play a role in basal pulsatile GnRH release? What are the factors responsible for the inhibition of Kiss1 in the AVPV and ARH? How is the ARH KNDy neuron differentially regulated such that Kiss1 and NKB are inhibited but DYN is unaffected? What role do suckling-activated brainstem populations play in driving hyperphagia and GnRH inhibition? What are the factors responsible for the active suppression of leptin during lactation? Since leptin plays a role in both brain and peripheral adaptations (promotes fuel sparing for milk production) to lactation, its suppression seems to be a critical factor. What is the role of leptin in linking energy balance and reproduction; is it a key factor or a modulatory one? Is the role of leptin the same for the various models of negative energy balance, such as lactation, fasting, or caloric restriction? To resolve these issues will require using the same animal model and comparing effects of restoring leptin and insulin to physiological levels in the various states of negative energy balance. Are our views too “leptin-centric” and “ARH-centric”, such that we ignore other possibly important areas, such as the brainstem? Given our current understanding, it is reasonable to propose that brainstem pathways activated by the suckling stimulus are the primary determinants of the changes in hypothalamic targets, such as the ARH, DMH, LHA and PMV, that drive the hyperphagia and suppression of gonadotropin secretion during lactation.