Metabolic Impact on the Hypothalamic Kisspeptin-Kiss1r Signaling Pathway

Abstract

A large body of data has established the hypothalamic kisspeptin (KP) and its receptor, KISS1R, as major players in the activation of the neuroendocrine reproductive axis at the time of puberty and maintenance of reproductive capacity in the adult. Due to its strategic location, this ligand-receptor pair acts as an integrator of cues from gonadal steroids as well as of circadian and seasonal variation-related information on the reproductive axis. Besides these cues, the activity of the hypothalamic KP signaling is very sensitive to the current metabolic status of the body. In conditions of energy imbalance, either positive or negative, a number of alterations in the hypothalamic KP signaling pathway have been documented in different mammalian models including nonhuman primates and human. Deficiency of metabolic fuels during fasting causes a marked reduction of Kiss1 gene transcript levels in the hypothalamus and, hence, decreases the output of KP-containing neurons. Food intake or exogenous supply of metabolic cues, such as leptin, reverses metabolic insufficiency-related changes in the hypothalamic KP signaling. Likewise, alterations in Kiss1 expression have also been reported in other situations of energy imbalance like diabetes and obesity. Information related to the body’s current metabolic status reaches to KP neurons both directly as well as indirectly via a complex network of other neurons. In this review article, we have provided an updated summary of the available literature on the regulation of the hypothalamic KP-Kiss1r signaling by metabolic cues. In particular, the potential mechanisms of metabolic impact on the hypothalamic KP-Kiss1r signaling, in light of available evidence, are discussed.

Reversible male hypogonadotropic hypogonadism due to energy deficit

“…In healthy men, short‐term (72 hours) starvation leads to marked reductions in leptin levels out of proportion to the degree of fat mass loss, associated with blunted GnRH pulsatility and reductions in circulating testosterone . In this experimental setting, replacement doses of recombinant leptin administered during fasting prevented the starvation‐associated gonadal axis suppression and maintained GnRH pulsatility, suggesting that leptin acts upstream of GnRH, potentially through stimulation of GnRH secretion via kisspeptin . Similar evidence for efficacy of recombinant leptin in improving reproductive functions has also been reported in a controlled study of women with hypothalamic amenorrhoea due to energy deficit.…”

“…Recent evidence suggests that KNDy (kisspeptin/neurokinin B/dynorphin) neurons in the arcuate nucleus of the mediobasal hypothalamus are major upstream regulators of GnRH neuron activity . Infusion of kisspeptin has been demonstrated to increase LH pulsatility in women with hypothalamic amenorrhoea and to increase LH pulse frequency and LH secretion in obese men with low testosterone, suggesting that both energy deficit and excess lead to central gonadal axis dysregulation by similar mechanisms.…”

Targeted Deletion of PTEN in Kisspeptin Cells Results in Brain Region- and Sex-Specific Effects on Kisspeptin Expression and Gonadotropin Release

“…States of negative energy balance, such as nutritional deprivation, results in suppression of gonadotropin release in females and are associated with a decrease in hypothalamic kisspeptin expression [3]. mTOR is both a cellular nutrient sensor and an important central regulator of energy homeostasis [17,18].…”

“…In this regard, hypothalamic kisspeptin-expressing cells have emerged as major GnRH afferent neurons, which are sensitive to peripheral signals including steroid hormones and metabolic cues [2,3].…”

“…Additionally, kisspeptin expression is regulated in the ARC, a central hypothalamic nucleus that regulates energy homeostasis, by integrating metabolic cues such as leptin and insulin. As such, metabolic alterations that affect the production of these peripheral metabolic hormones, such as obesity or undernutrition, can impact GnRH and gonadotropin release by hypothalamic kisspeptin neurons [2,3]. However, the intracellular signaling mechanisms that integrate these signals within kisspeptin neurons remain unclear.…”