Navarro V.M.,University of Washington |
Navarro V.M.,University of Cordoba, Spain |
Navarro V.M.,CIBER ISCIII |
Navarro V.M.,Instituto Maimonides Of Investigaciones Biomedicas Of Cordoba Imibic |
And 3 more authors.
Frontiers in Bioscience - Scholar | Year: 2011
Reproductive function, as essential for the survival of species, is under the control of a vast array of regulatory factors that ultimately modulate the release of GnRH. However, GnRH neurons lack the ability to directly sense most of these signals; hence, intermediate pathways are required. Kisspeptins have recently emerged as a pivotal piece in the reproductive brain, serving primarily as conduits for central and peripheral regulatory cues of GnRH release. Different populations of hypothalamic Kiss1 neurons have been described, which mediate either the positive or negative feedback of sex steroids in the sexually differentiated brain of rodents. Kisspeptins, however, are not the only recently-appointed contributors to this integrative process. Indeed, neurokinin B (NKB) and dynorphin have been described to co-localize within Kiss1 neurons at the arcuate nucleus in different species, and may contribute to the regulation of kisspeptin release. In this work, we provide a concise overview of the major reproductive headlines of kisspeptins, focusing on their role as mediators of sex steroid feedback and their interaction with key neurotransmitters, such as NKB and dynorphin. Source
Castellano J.M.,University of Cordoba, Spain |
Castellano J.M.,Instituto Maimonides Of Investigaciones Biomedicas Of Cordoba Imibic |
Bentsen A.H.,Neurobiology Research Unit |
Sanchez-Garrido M.A.,University of Cordoba, Spain |
And 23 more authors.
Endocrinology | Year: 2011
Kiss1 neurons have recently emerged as a putative conduit for the metabolic gating of reproduction, with leptin being a regulator of hypothalamic Kiss1 expression. Early perturbations of the nutritional status are known to predispose to different metabolic disorders later in life and to alter the timing of puberty; however, the potential underlying mechanisms remain poorly defined. Here we report how changes in the pattern of postnatal feeding affect the onset of puberty and evaluate key hormonal and neuropeptide [Kiss1/kisspeptin (Kp)] alterations linked to these early nutritional manipulations. Female rats were raised in litters of different sizes: small (four pups per dam: overfeeding), normal (12 pups per dam), and large litters (20 pups per litter: underfeeding). Postnatal overfeeding resulted in persistently increased body weight and earlier age of vaginal opening, as an external sign of puberty, together with higher levels of leptin and hypothalamic Kiss1 mRNA. Conversely, postnatal underfeeding caused a persistent reduction in body weight, lower ovarian and uterus weights, and delayed vaginal opening, changes that were paralleled by a decrease in leptin and Kiss1 mRNA levels. Kisspeptin-52 immunoreactivity (Kp-IR) in the hypothalamus displayed similar patterns, with lower numbers of Kp-IR neurons in the arcuate nucleus of postnatally underfed animals, and a trend for increased Kp-positive fibers in the periventricular area of early overfed rats. Yet, gonadotropin responses to Kp at puberty were similar in all groups, except for enhanced responsiveness to low doses of Kp-10 in postnatally underfed rats. In conclusion, our data document that the timing of puberty is sensitive to both overfeeding and subnutrition during early (postnatal) periods and suggest that alterations in hypothalamic expression of Kiss1/kisspeptin may underlie at least part of such programming phenomenon. Copyright © 2011 by The Endocrine Society. Source
Garcia-Galiano D.,University of Cordoba, Spain |
Garcia-Galiano D.,CIBER ISCIII |
Garcia-Galiano D.,Instituto Maimonides Of Investigaciones Biomedicas Of Cordoba Imibic |
Van Ingen Schenau D.,Merck And Co. |
And 20 more authors.
Endocrinology | Year: 2012
Kisspeptins (Kp), products of the Kiss1 gene that act via Gpr54 to potently stimulate GnRH secretion, operate as mediators of other regulatory signals of the gonadotropic axis. Mouse models of Gpr54 and/or Kiss1 inactivation have been used to address the contribution of Kp in the central control of gonadotropin secretion; yet, phenotypic and hormonal differences have been detected among the transgenic lines available. We report here a series of neuroendocrine analyses in male mice of a novel Gpr54 knockout (KO) model, generated by heterozygous crossing of a loxP-Gpr54/Protamine- Cre double mutant line. Gpr54-null males showed severe hypogonadotropic hypogonadism but retained robust responsiveness to GnRH. Gonadotropic responses to the agonist of ionotropic glutamate receptors, N-methyl-D-aspartate, were attenuated, but persisted, in Gpr54-null mice. In contrast, LH secretion after activation of metabotropic glutamate receptors was totally preserved in the absence of Gpr54 signaling. Detectable, albeit reduced, LH responses were also observed in Gpr54 KO mice after intracerebroventricular administration of galanin-like peptide or RF9, putative antagonist of neuropeptide FF receptors for the mammalian ortholog of gonadotropin-inhibiting hormone. In contrast, the stimulatory effect of senktide, agonist of neurokinin B (NKB; cotransmitter of Kiss1 neurons), was totally abrogated in Gpr54 KO males. Lack of Kp signaling also eliminated feedback LH responses to testosterone withdrawal. However, residual but sustained increases of FSH were detected in gonadectomized Gpr54 KO males, in which testosterone replacement failed to fully suppress circulating FSH levels. In sum, our study provides novel evidence for the relative importance of Kp-dependent vs. -independent actions of several key regulators of GnRH secretion, such as glutamate, galanin-like peptide, and testosterone. In addition, our data document for the first time the indispensable role of Kp signaling in mediating the stimulatory effects of NKB on LH secretion, thus supporting the hypothesis that NKB actions on GnRH neurons are indirectly mediated via its ability to regulate Kiss1 neuronal output. Copyright © 2012 by The Endocrine Society. Source