Kisspeptin as a link between metabolism and reproduction: Evidences from rodent and primate studies
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.
Section snippets
Biology of KP and Kiss1r
About 16 years ago, the KISS1 gene was isolated as a human melanoma metastasis suppressor gene by Lee et al., [45] using differential display and subtractive hybridization techniques in human melanoma cells. They observed that KISS1 expression was confined only to sound cells while transfection with KISS1 cDNA inhibited metastasis of melanomas without affecting proliferation and migration properties of the cells. They, therefore, named the gene as metastasis suppressor sequence “KiSS1”. The name
Presence of KP secreting neurons in the hypothalamic ARC
Kiss1 mRNA expressing cells have been consistently detected in ARC of several species including both non-primates and primates [29], [30], [31], [32], [34], [35], [37], [68], [69], [70], [71]. The hypothalamic ARC, known as infundibular nucleus in man, is an aggregation of neurons in the mediobasal hypothalamus, adjacent to the third ventricle and the median eminence [16]. Positioned outside the blood-brain barrier, the neuronal networks in the ARC are directly bathed by systemic metabolic
Conclusions and future recommendations
In summary, hypothalamic kisspeptinergic neurons are positioned in such a way to integrate information, regarding nutritional status, from heterogeneous sources (central as well as peripheral) and relay this to the neuroendocrine reproductive axis. There are three possible pathways by which kisspeptinergic neurons may convey metabolic status related information to GnRH neurons (Fig. 2): (1) direct perception of metabolic information and passage of this to GnRH secreting cells; 2) interpretation
Conflict of interest
Disclosure: Authors have nothing to disclose.
Acknowledgments
The experimental work from the authors laboratory summarized in this review has been funded by the Higher Education Commission (HEC), Islamabad, Pakistan. The authors are grateful to Dr. Jeremy Smith, School of Anatomy, Physiology & Human Biology, the University of Western Australia, Nedlands, WA, Australia, for critically reviewing the manuscript and for helpful advice in improving the manuscript.
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