Kisspeptin as a link between metabolism and reproduction: Evidences from rodent and primate studies

Abstract

Changes in metabolic status gate reproductive activity by still incompletely deciphered mechanisms. Many neuropeptides have been shown to be involved in restraining hypothalamic gonadotropin releasing hormone (GnRH) release under conditions of negative energy balance. Broadly, on the basis of their effect on feeding, these can be grouped as orexigenic and anorexigenic neuropeptides. Reciprocally correlated, in response to changes in systemic concentrations of metabolic hormones, the secretion of orexigenic neuropeptides increases while that of anorexigenic neuropeptides decreases during conditions of food restriction. Recently, kisspeptin signaling in hypothalamus has appeared as a pivotal regulator of the GnRH pulse generator. Kisspeptin apparently does not affect feeding, but in light of accumulating data, it has emerged as one of the major conduits in relaying body metabolic status information to GnRH neurons. The present review examines such data obtained from rodent and primate models, which suggest kisspeptin-Kiss1r signaling as a possible pathway providing a link between metabolism and reproduction.

Introduction

In mammals, it is well established that fertility is gated by metabolic status [1], [2]. Metabolic fuel deficiency delays the onset of puberty in pre-pubertal animals [3], [4], while in post-pubertal animals hampers pulsatile gonadotropin releasing hormone (GnRH) release with concomitant hypogonadotropic hypogonadism [1], [2], [5], and the inhibition of sexual behavior [6]. Nutrient intake, after a brief period of food restriction, normalizes the malfunctioning hypothalamic-pituitary-gonadal (HPG) axis, reinstating the process of reproduction [7]. Nevertheless, the mechanistic links between nutrition and the HPG axis, by which food restriction curtails reproduction and food intake transposes it, need to be further elucidated.

Food restriction-associated HPG axis suppression is ultimately caused by a reduction in the release of GnRH from the hypothalamus [8], [9], [10], [11]. Alterations in the secretion of many neuropeptides have been shown to be involved in suppressing hypothalamic GnRH release under conditions of negative energy balance [12], [13], [14]. Broadly, on the basis of their effect on feeding, they can be grouped as orexigenic and anorexigenic peptides. The orexigenic group includes appetite stimulating neuropeptides such as neuropeptide Y (NPY), agouti related protein (AgRP), galanin-like peptide (GALP), and melanin-concentrating hormone (MCH) [15], [16], [17], [18], [19], while the anorexigenic group is comprised of appetite inhibiting neuropeptides, among which are products of the proopiomelanocortin (POMC) precursor, cocaine- and amphetamine-related transcript (CART), and corticotrophin-releasing hormone (CRH) [20], [21], [22], [23]. The majority of the neuronal systems secreting orexigenic and anorexigenic neuropeptides are concentrated in the arcuate nucleus (ARC) (with the exception of CRH neurons, which are mostly populated in the paraventricular nucleus but are interconnected with the ARC [24], [25]), a hypothalamic area critically involved in metabolism and energy homeostasis [16]. The functioning of these neurons is sensitive to circulating concentrations of peripheral metabolic hormones, including ghrelin, insulin, and leptin [26], [27], [28]. Leptin and ghrelin are secreted by adipocytes and gastric cells, respectively, and these hormones act reciprocally to signal metabolic status to the brain [26], [28].

The kisspeptinergic neuronal system, another neuronal system located in the ARC [29], [30], [31], [32], [33], [34], [35], does not appear to affect feeding [36], [37], but in light of accumulating data has been unveiled as one of the major conduits in transferring metabolic status related information to GnRH neurons. Parenthetically, kisspeptinergic neurons have been acknowledged to contain leptin receptors [33]. Kisspeptin (KP) gene (Kiss1 mRNA) expression in the ARC is at nadir in animal models of hypoleptinemia [33], [37], [38], [39], [40], while leptin infusion significantly ameliorates this expression [33], [38], [40]. In short-term fasting situations, which is characterized by disrupted GnRH release with resulting hypogonadotropic hypogonadism [9], [10], [41], [42], Kiss1 as well as KP receptor (Kiss1r) expression is affected [35], [37], [39], [40]. KP administration rescues fasting induced hypogonadotropic hypogonadism in rats [37], while the HPG axis response to KP, both in initiation and quantity, is attenuated by fasting in monkeys [43]. Moreover, expression of both Kiss1r as well as Kiss1 have been detected in a number of peripheral tissues (including the pituitary, pancreas, and adipose tissue) concerned with energy homeostasis and reproduction [44], [45], [46], [47]. KP has also been acclaimed to affect secretion of metabolic hormones, including aldosterone, adiponectin, insulin, growth hormone, oxytocin, and prolactin [48], [49], [50], [51], [52], [53], [54], [55]. All these observations suggest a potential role for KP in connecting metabolic status with reproductive function. Herein, we will review the currently available evidence obtained from rodent and primate studies implicating KP-Kiss1r signaling as a possible central mechanism, which adjusts reproductive function according to energy availability.