Navarro V.M.,University of Cordoba, Spain |
Navarro V.M.,CIBER ISCIII |
Navarro V.M.,Instituto Maimonides Of Investigaciones Biomedicas Of Cordoba |
Navarro V.M.,Harvard University
Frontiers in Endocrinology
Gonadotropin-releasing hormone (GnRH) is the ultimate output signal of an intricate network of neuroendocrine factors that, acting on the pituitary, trigger gonadotropin release. In turn, gonadotropins exert their trophic action on the gonads to stimulate the synthesis of sex steroids thus completing the gonadotropic axis through feedback regulatory mechanisms of GnRH release.These feedback loops are predominantly inhibitory in both sexes, leading to tonic pulsatile release of GnRH from puberty onward. However, in the female, rising levels of estradiol along the estrous cycle evoke an additional positive feedback that prompts a surge-like pattern of GnRH release prior to ovulation. Kisspeptins, secreted from hypothalamic Kiss1 neurons, are poised as major conduits to regulate this dual secretory pathway. Kiss1 neurons are diverse in origin, nature, and function, convening distinct neuronal populations in two main hypothalamic nuclei: the arcuate nucleus (ARC) and the anteroventral periventricular nucleus. Recent studies from our group and others point out Kiss1 neurons in the ARC as the plausible generator of GnRH pulses through a system of pulsatile kisspeptin release shaped by the coordinated action of neurokinin B (NKB) and dynorphin A (Dyn) that are co-expressed in Kiss1 neurons (so-called KNDy neurons). In this review, we aim to document the recent findings and working models directed toward the identification of the Kiss1-dependent mechanisms of GnRH release through a synoptic overview of the state-of-the-art in the field. © 2012 Navarro. Source
Pineda R.,University of Cordoba, Spain |
Pineda R.,CIBER ISCIII |
Garcia-Galiano D.,University of Cordoba, Spain |
Garcia-Galiano D.,CIBER ISCIII |
And 14 more authors.
Kisspeptins (Kp) have recently emerged as master regulators of the reproductive axis and among the most potent elicitors of GnRH-gonadotropin secretion. Despite their paramount importance in reproductive physiology and their potential therapeutic implications, development of Kp antagonists has remained elusive, and only recently has the first compound with the ability to block Kp actions in vitro and in vivo, namely p234, been reported. However, previous in vivo studies all used acute central injections, whereas characterization of the effects of the antagonist after continuous or systemic administration, which poses pharmacological challenges, is still pending. We report herein a comprehensive series of analyses on the impact of continuous intracerebroventricular infusion of p234 on puberty onset and the preovulatory surge of gonadotropins in the female rat. In addition, the effects ofsystemic (ip)administrationofataggedp234-penetratin, withapredictedhigherpermeabilityatthe blood-brain barrier, on Kp-10 induced gonadotropin secretion were evaluated. Central infusion of p234 to pubertal females delayed vaginal opening and decreased uterine and ovarian weights at the expected time of puberty, without affecting body weight. Likewise, chronic intracerebroventricular administration of p234 for 4 d prevented the preovulatory surges of LH and FSH. In addition, systemic (ip) administration of p234-penetratin significantly attenuated acute LH and FSH responses to Kp-10, either after intracerebroventricular or ip injection of Kp. Our data document the validity of p234 for antagonizing Kp actions in vivo and provide direct experimental evidence for the important role of Kp signaling in the key events of female reproduction, such as puberty onset and the preovulatory surge of gonadotropins. Copyright © 2010 by The Endocrine Society. Source
Tasset I.,University of Cordoba, Spain |
Tasset I.,Instituto Maimonides Of Investigaciones Biomedicas Of Cordoba |
Drucker-Colin R.,National Autonomous University of Mexico |
Pena J.,University of Cordoba, Spain |
And 6 more authors.
We studied the effects of transcranial magnetic stimulation (TMS, 60 Hz and 0.7 mT for 4 h/day for 14 days) on oxidative and cell damage caused by olfactory bulbectomy (OBX) in Wistar rats. The levels of lipid peroxidation products and caspase-3 were enhanced by OBX, whereas it prompted a reduction in reduced glutathione (GSH) content and antioxidative enzymes activities. The treatment with TMS reverted towards normality the biomarkers indicative of oxidative stress and apoptosis. In conclusion, our data show that TMS induced a protection against cell and oxidative damage induced by OBX, as well as they support the hypothesis that oxidative stress may play an important role in depression. © 2010 Springer Science+Business Media, LLC. Source
Moreno-Navarrete J.M.,Institute Dinvestigacio Biomedica Of Girona Catalonia |
Catalan V.,University of Navarra |
Whyte L.,University of Aberdeen |
Diaz-Arteaga A.,University of Santiago de Compostela |
And 13 more authors.
GPR55 is a putative cannabinoid receptor, and L-α- lysophosphatidylinositol (LPI) is its only known endogenous ligand. We investigated 1) whether GPR55 is expressed in fat and liver; 2) the correlation of both GPR55 and LPI with several metabolic parameters; and 3) the actions of LPI on human adipocytes. We analyzed CB1, CB2, and GPR55 gene expression and circulating LPI levels in two independent cohorts of obese and lean subjects, with both normal or impaired glucose tolerance and type 2 diabetes. Ex vivo experiments were used to measure intracellular calcium and lipid accumulation. GPR55 levels were augmented in the adipose tissue of obese subjects and further so in obese patients with type 2 diabetes when compared with nonobese subjects. Visceral adipose tissue GPR55 correlated positively with weight, BMI, and percent fat mass, particularly in women. Hepatic GPR55 gene expression was similar in obese and type 2 diabetic subjects. Circulating LPI levels were increased in obese patients and correlated with fat percentage and BMI in women. LPI increased the expression of lipogenic genes in visceral adipose tissue explants and intracellular calcium in differentiated visceral adipocytes. These findings indicate that the LPI/GPR55 system is positively associated with obesity in humans. © 2012 by the American Diabetes Association. Source
Navarro V.M.,University of Washington |
Navarro V.M.,University of Cordoba, Spain |
Gottsch M.L.,University of Washington |
Wu M.,Yale University |
And 18 more authors.
Kisspeptin (Kiss1) and neurokinin B (NKB) (encoded by the Kiss1 and Tac2 genes, respectively) are indispensable for reproduction. In the female of many species, Kiss1 neurons in the arcuate nucleus (ARC) coexpress dynorphin A and NKB. Such cells have been termed Kiss1/NKB/Dynorphin (KNDy) neurons, which are thought to mediate the negative feedback regulation of GnRH/LH secretion by 17β-estradiol. However, we have less knowledge about the molecular physiology and regulation of Kiss1/Kiss1-expressing neurons in the ARC of the male. Our work focused on the adult male mouse, where we sought evidence for coexpression of these neuropeptides in cells in the ARC, assessed the role of Kiss1 neurons in negative feedback regulation of GnRH/LH secretion by testosterone (T), and investigated the action of NKB on KNDy and GnRH neurons. Results showed that 1) the mRNA encoding Kiss1, NKB, and dynorphin are coexpressed in neurons located in the ARC; 2) Kiss1 and dynorphin A mRNA are regulated by T through estrogen and androgen receptordependent pathways; 3) senktide, an agonist for theNKBreceptor (neurokinin 3 receptor, encoded by Tacr3), stimulates gonadotropin secretion; 4) KNDy neurons express Tacr3, whereas GnRH neurons do not; and 5) senktide activates KNDy neurons but has no discernable effect on GnRH neurons. These observations corroborate the putative role for KNDy neurons in mediating the negative feedback effects of T on GnRH/LH secretion and provide evidence that NKB released from KNDy neurons is part of an auto-feedback loop that generates the pulsatile secretion of Kiss1 and GnRH in the male. Copyright © 2011 by The Endocrine Society. Source