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S Tovar

Publications and source records attributed to S Tovar.

16 recordsLinked to original sources
PubMed2006

Perinatal overfeeding in rats results in increased levels of plasma leptin but unchanged cerebrospinal leptin in adulthood.

OBJECTIVE: To study the effect of perinatal programming and overfeeding on the hypothalamic control mechanisms of food intake in adult rats. DESIGN: Neonatal programming effects on body weight, food intake, central and peripheral leptin levels, hypothalamic neuropeptides, leptin receptors and central leptin responsiveness in adult rats. MEASUREMENTS: Plasma and cerebrospinal fluid (CSF) leptin levels were analyzed using radioimmunoassay. Neuropeptide mRNA levels were analyzed using in situ hybridization. Leptin receptor mRNA levels were analyzed using reverse transcriptase-polymerase chain reaction. RESULTS: Perinatally overfed rats growing up in small litters (SL) maintain their obese and hyperleptinemic phenotype in adulthood. However, leptin levels in CSF are abnormally low considering the plasmatic hyperleptinemia. In contrast to the already reported changes in perinatally overfed juvenile rats, perinatally overfed adult rats did not show any alteration in the expression of leptin receptor isoforms and evaluated neuropeptides. Moreover, SL adult rats showed a normal sensitivity regarding the inhibitory effect of intracerebroventricular leptin administration on food intake. CONCLUSION: Perinatal overfeeding does not induce alterations in either the anorectic response to central leptin administration or expression of leptin receptors and neuropeptides in adulthood. The leptin resistance to peripheral leptin in SL adult rats may be related to impaired leptin transport across the blood-brain barrier.

Animals↗
PubMed2006

Novel role of 26RFa, a hypothalamic RFamide orexigenic peptide, as putative regulator of the gonadotropic axis.

The close link between reproductive function and body energy stores relies on a complex neuroendocrine network of common regulatory signals, the nature of which is yet to be fully elucidated. Recently, 26RFa was identified in amphibians and mammals as a conserved hypothalamic neuropeptide of the RFamide family, with a potent orexigenic activity. Yet, despite its proposed role as hypophysiotropic factor, the function of 26RFa in the control of pituitary gonadotropins and, hence, of the reproductive axis remains unexplored. In the present study, the effects of 26RFa on gonadotropin secretion were evaluated in the rat by a combination of in vitro and in vivo approaches. At the pituitary, 26RFa dose-dependently enhanced basal and gonadotropin-releasing hormone (GnRH)-stimulated luteinizing hormone (LH) secretion from male and cyclic female rats. This effect was mimicked by the active fragment 26RFa(20-26), as well as by the related 43RFa peptide. Moreover, expression of the genes encoding 26RFa and its putative receptor, GPR103, was demonstrated in rat pituitary throughout postnatal development. In vivo, intracerebral injection of 26RFa evoked a significant increase in serum LH levels in cyclic and ovariectomized females; this response which was also observed after central injection of 26RFa(20-26) and 43RFa peptides, as well as after systemic administration of 26RFa. Conversely, central and systemic injection of 26RFa failed to significantly modify gonadotropin secretion in adult male rats, even after repeated administration of the peptide. In summary, we present herein novel evidence for the potential role of the orexigenic peptide 26RFa in the control of the gonadotropic axis, thus suggesting its potential involvement in the joint control of energy balance and reproduction, especially in the female.

Amino Acid Sequence↗
PubMed2006

Effects of single or repeated intravenous administration of kisspeptin upon dynamic LH secretion in conscious male rats.

The ability of kisspeptins, ligands of the G protein-coupled receptor 54, to potently elicit LH secretion is now undisputed. Yet, most of the pharmacological characterization of their gonadotropin-releasing effects has been conducted after intracerebral administration. In contrast, the effects of peripheral injection of kisspeptin remains less well defined. In this study, dynamic LH secretory responses to iv administration of kisspeptin-10 in different experimental settings are presented, and compared with those evoked by kisspeptin-52, using a protocol of serial blood sampling in conscious, freely moving male rats. LH responsiveness to peripheral administration of kisspeptin appeared extremely sensitive, as doses as low as 0.3 nmol/kg (0.1 microg/rat) evoked robust LH bursts, the magnitude of which was dose-dependent and apparently maximal in response to 3.0 and 30 nmol/kg kisspeptin-10. The ability of kisspeptin-10 to stimulate LH release was fully preserved, and even doubled in terms of relative increases, after short-term fasting despite suppression of prevailing LH levels. Repeated injections of kisspeptin-10 (four boluses, at 75-min intervals) evoked associated LH secretory pulses, the magnitude of which remained constant along the study period. Moreover, in this setting, in vivo LH responses to a terminal injection of GnRH were preserved, whereas basal and depolarization-induced GnRH release ex vivo was significantly enhanced. Finally, iv administration of kisspeptin-52 elicited dynamic LH responses analogous to that of kisspeptin-10; yet, their net magnitude and duration was slightly greater. In summary, we present in this study a series of experiments on the effects of systemic (iv) injection of single or repeated doses of kisspeptin upon dynamic LH secretion in conscious male rats. Aside from potential physiologic relevance, our present data might contribute to setting the basis for the rational therapeutic use of kisspeptin analogs in the pharmacological manipulation of the gonadotropic axis.

Animals↗
PubMed2006

Comparative analysis of the effects of ghrelin and unacylated ghrelin on luteinizing hormone secretion in male rats.

Ghrelin, the endogenous ligand of GH secretagogue receptor type 1a, has emerged as pleiotropic modulator of diverse biological functions, including energy homeostasis and, recently, reproduction. Although inhibitory actions of ghrelin on LH secretion and puberty onset have been reported previously, the receptor mechanisms mediating these actions, and the potential gonadotropic effects of the unacylated isoform of ghrelin (UAG), remain unclear. In this work, the effects of single and repeated administration of ghrelin or UAG on LH secretion were compared in pubertal and adult male rats. In addition, the effects of ghrelin were assessed in models of transient or persistent hypergonadotropism. Daily injection of ghrelin or UAG throughout puberty similarly decreased LH levels and partially delayed balanopreputial separation. Likewise, chronic infusion of ghrelin or UAG to adult males resulted in significant decreases in circulating LH and FSH concentrations. Moreover, acute injection of ghrelin induced a transient reduction in LH levels in freely moving males, an effect that was fully mimicked by administration of UAG. Yet in contrast to ghrelin, UAG failed to modify GH secretion. Finally, injection of ghrelin moderately, but significantly, reduced the duration of LH secretory responses to the potent gonadotropin secretagogue kisspeptin-10, whereas ghrelin infusion in a model of chronic elevation of serum gonadotropin levels (the transgenic growth retarded male rat) evoked a significant reduction of LH concentrations. Altogether our present results further substantiate the inhibitory effect of ghrelin on basal and stimulated LH secretion in a wide array of experimental conditions. Moreover, our data are the first to demonstrate the ability of UAG, originally considered an inert form of the molecule, to mimic the actions of acylated ghrelin on LH release. These observations reinforce the contention that ghrelin, as putative signal for energy insufficiency, may operate as negative modifier of male puberty and LH secretion, an effect that might be, at least partially, conducted through a GH secretagogue receptor type 1a-independent mechanism.

Animals↗
PubMed2005

Changes in hypothalamic KiSS-1 system and restoration of pubertal activation of the reproductive axis by kisspeptin in undernutrition.

Activation of the gonadotropic axis critically depends on sufficient body energy stores, and conditions of negative energy balance result in lack of puberty onset and reproductive failure. Recently, KiSS-1 gene-derived kisspeptin, signaling through the G protein-coupled receptor 54 (GPR54), has been proven as a pivotal regulator in the control of gonadotropin secretion and puberty. However, the impact of body energy status upon hypothalamic expression and function of this system remains unexplored. In this work, we evaluated the expression of KiSS-1 and GPR54 genes at the hypothalamus as well as the ability of kisspeptin-10 to elicit GnRH and LH secretion in prepubertal rats under short-term fasting. In addition, we monitored the actions of kisspeptin on food intake and the effects of its chronic administration upon puberty onset in undernutrition. Food deprivation induced a concomitant decrease in hypothalamic KiSS-1 and increase in GPR54 mRNA levels in prepubertal rats. In addition, LH responses to kisspeptin in vivo were enhanced, and its GnRH secretagogue action in vitro was sensitized, under fasting conditions. Central kisspeptin administration failed to change food intake patterns in animals fed ad libitum or after a 12-h fast. However, chronic treatment with kisspeptin was able to restore vaginal opening (in approximately 60%) and to elicit gonadotropin and estrogen responses in a model of undernutrition. In summary, our data are the first to show an interaction between energy status and the hypothalamic KiSS-1 system, which may constitute a target for disruption (and eventual therapeutic intervention) of pubertal development in conditions of negative energy balance.

Animals↗
PubMed2005

Effects of chronic hyperghrelinemia on puberty onset and pregnancy outcome in the rat.

Ghrelin, the endogenous ligand of the GH secretagogue receptor, has been recently involved in a wide array of biological functions, including signaling of energy insufficiency and energy homeostasis. On the basis of the proven reproductive effects of other regulators of energy balance, such as the adipocyte-derived hormone leptin, we hypothesized that systemic ghrelin may participate in the control of key aspects of reproductive function. To test this hypothesis, the effects of daily treatment with ghrelin were assessed in rats, pair-fed with control animals, in two relevant reproductive states, puberty and gestation, which are highly dependent on proper energy stores. Daily sc injection of ghrelin (0.5 nmol/12 h; between postnatal d 33 and 43) significantly decreased serum LH and testosterone levels and partially prevented balano-preputial separation (as an external index of puberty onset) in pubertal male rats. On the contrary, chronic administration of ghrelin to prepubertal females, between postnatal d 23 and 33, failed to induce major changes in serum levels of gonadotropins and estradiol, nor did it modify the timing of puberty, as estimated by the ages at vaginal opening and first estrus. Moreover, females treated with ghrelin at puberty subsequently displayed normal estrous cyclicity and were fertile. Conversely, ghrelin administration (0.5 nmol/12 h) during the first half of pregnancy (d 1-11) resulted in a significant decrease in pregnancy outcome, as estimated by the number of pups born per litter, without changes in the number of successful pregnancies at term or gestational length. Overall, our data indicate that persistently elevated ghrelin levels, as a putative signal for energy insufficiency, may operate as a negative modifier of key reproductive states, such as pregnancy and (male) puberty onset.

Animals↗
PubMed2005

Effects of KiSS-1 peptide, the natural ligand of GPR54, on follicle-stimulating hormone secretion in the rat.

KiSS-1 was originally identified as a metastasis suppressor gene encoding an array of structurally related peptides, namely kisspeptins, which acting through the G protein-coupled receptor GPR54 are able to inhibit tumor progression. Unexpectedly, a reproductive facet of this newly discovered system has recently arisen, and characterization of the role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion has been initiated. However, such studies have been so far mostly restricted to LH, and very little is known about the actual contribution of this system in the regulation of FSH release. To address this issue, the effects of KiSS-1 peptide on FSH secretion were monitored in vivo and in vitro under different experimental conditions. Intracerebroventricular administration of KiSS-1 peptide significantly stimulated FSH secretion in prepubertal and adult rats. Yet, dose-response analyses in vivo demonstrated an ED(50) value for the FSH-releasing effects of KiSS-1 of 400 pmol, i.e. approximately 100-fold higher than that of LH. In addition, systemic (ip and iv) injection of KiSS-1 significantly stimulated FSH secretion in vivo. However, KiSS-1 failed to elicit basal FSH release directly at the pituitary level, although it moderately enhanced GnRH-stimulated FSH secretion in vitro. Finally, mechanistic studies revealed that the ability of KiSS-1 to elicit FSH secretion was abolished by the blockade of endogenous GnRH actions, but it was persistently observed in different models of leptin insufficiency and after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e. relevant signals in the neuroendocrine control of gonadotropin secretion. In summary, our results extend previous recent observations on the role of KiSS-1 in the control of LH secretion and provide solid evidence for a stimulatory effect of KiSS-1 on FSH release, acting at central level. Overall, it is proposed that the KiSS-1/GPR54 system is a novel, pivotal downstream element in the neuroendocrine network governing gonadotropin secretion.

Animals↗
PubMed2005

Regulation of peroxisome proliferator activated receptor-gamma in rat pituitary.

Peroxisome proliferator activated-receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily and, in addition to its relation with obesity and insulin sensitivity, it has recently been localized in human and mice pituitary, indicating a functional significance of PPARgamma in adenopituitary tumours. In the present study, we localized the PPARgamma mRNA and protein in different cell types of rat pituitary. Moreover, using the real-time polymerase chain reaction, we assessed the mRNA expression of PPARgamma in different physiological and pathological settings known to be associated with alterations in anterior pituitary cell proliferation and/or function. Our experiments have shown that PPARgamma mRNA levels were repressed by oestrogen through an oestrogen receptor-alpha effect. However, PPARgamma protein levels were only modified in males but not in females. On the other hand, PPARgamma mRNA expression was increased in dwarf rats in comparison with Lewis rats. Finally, nutritional, thyroid status or pregnancy did not change PPARgamma expression. Taken together, we provide new data regarding the regulation of pituitary PPARgamma mRNA by hormonal and metabolic status.

Animals↗
PubMed2004

A possible role of neuropeptide Y, agouti-related protein and leptin receptor isoforms in hypothalamic programming by perinatal feeding in the rat.

AIM/HYPOTHESIS: Perinatal overfeeding predisposes humans and rats to obesity and diabetes in later life. One classical model for studying the effect of early feeding is manipulation of the size of rat litters. Rats growing up in small litters gain more weight than rats growing up in normal-sized litters. Interestingly, these obese rats maintain this phenotype in adulthood. Conversely, rats raised in large litters show a delay in growth and a decrease in body weight. The aim of this work was to assess the hypothalamic control mechanisms of food intake regulated by perinatal feeding. METHODS: Leptin levels were analysed using RIA. Leptin receptor mRNA levels were analysed using RT-PCR. Neuropeptide mRNA levels were analysed using in situ hybridisation. RESULTS: Perinatally overfed neonatal male rats exhibited hyperleptinaemia and a decrease in hypothalamic mRNA levels of the long isoform of the leptin receptor (OB-Rb), explaining their leptin resistance. Moreover, this obese model showed an increase in the mRNA expression of cocaine- and amphetamine-regulated transcript, neuropeptide Y and agouti-related protein in the hypothalamic arcuate nucleus (ARC). In contrast, perinatally underfed neonatal male rats with hypoleptinaemia showed an increase in hypothalamic mRNA of the short isoforms of the leptin receptor. Furthermore, they exhibited an increase in expression of neuropeptide Y and agouti-related protein in the ARC. CONCLUSIONS/INTERPRETATION: Rats overfed during early postnatal life show a leptin-resistant state mediated by down-regulation of the hypothalamic OB-Rb. These data, together with the increased expression of neuropeptide Y and agouti-related protein in specific neurons in the ARC, might indicate the existence of regulated programming in this nucleus and may provide a new aetiopathogenic concept in susceptibility to obesity.

Aging↗
PubMed2004

Characterization of the potent luteinizing hormone-releasing activity of KiSS-1 peptide, the natural ligand of GPR54.

Loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been recently associated with hypogonadotropic hypogonadism, in both rodents and humans. Yet the actual role of the KiSS-1/GPR54 system in the neuroendocrine control of gonadotropin secretion remains largely unexplored. To initiate such analysis, the effects of KiSS-1 peptide on LH secretion were monitored using in vivo and in vitro settings under different experimental conditions. Central intracerebroventricular administration of KiSS-1 peptide potently elicited LH secretion in vivo over a range of doses from 10 pmol to 1 nmol. The effect of centrally injected KiSS-1 appeared to be mediated via the hypothalamic LHRH. However, no effect of central administration of KiSS-1 was detected on relative LHRH mRNA levels. Likewise, systemic (i.p. and i.v.) injection of KiSS-1 markedly stimulated LH secretion. This effect was similar in terms of maximum response to that of central administration of KiSS-1 and might be partially attributed to its ability to stimulate LH secretion directly at the pituitary. Finally, the LH-releasing activity of KiSS-1 was persistently observed after blockade of endogenous excitatory amino acid and nitric oxide pathways, i.e. relevant neurotransmitters in the neuroendocrine control of LH secretion. In summary, our results provide solid evidence for a potent stimulatory effect of KiSS-1 on LH release, acting at central levels (likely the hypothalamus) and eventually at the pituitary, and further document a novel role of the KiSS-1/GPR54 system as a relevant downstream element in the neuroendocrine network governing LH secretion.

Animals↗
PubMed2000

Regulation of in vivo TSH secretion by leptin.

Leptin, the product of the ob gene, is a hormone secreted by adipocytes that regulates food intake and energy expenditure. The hypothalamus-pituitary-thyroid axis is markedly influenced by the metabolic status, being suppressed during food deprivation. The aim of the present study was to assess whether leptin can act as a metabolic signal connecting the adipose tissue with the pituitary-thyroid axis. We studied the effect of leptin administration (10 microg, i.c.v.) on spontaneous TSH secretion and TSH responses to TRH in euthyroid and hypothyroid food-deprived rats. Spontaneous TSH secretion was assessed over 6 h with samples taken every 7 min. Administration of leptin to food-deprived euthyroid rats led to a reversal of the inhibitory effect exerted by fasting on spontaneous TSH secretion. This stimulatory effect of leptin on spontaneous TSH appears to be dependent on the thyroid status since it could not be observed in hypothyroid rats. This data suggests that blunted spontaneous TSH secretion in food-deprived rats is a functional and reversible state, and that the decreased leptin concentrations could be the primary event responsible for the suppression of the hypothalamic-pituitary-thyroid-axis in food-deprived rats.

Animals↗
PubMed2000

Ghrelin elicits a marked stimulatory effect on GH secretion in freely-moving rats.

Ghrelin is a growth hormone-releasing acylated peptide from stomach. The purified peptide consist of 28 amino acids in which the serine 3 residue is n-octanoylated. Ghrelin has been reported to increase in vitro GH secretion as well as in vivo plasma GH levels in pentobarbital anaesthetized rats. The aim of this work was to characterize the stimulatory effect of Ghrelin on in vivo GH secretion in freely-moving rats. Furthermore, we compare the effect of Ghrelin with GHRH. In addition to vehicle, we administered different doses of Ghrelin (3 nmol/Kg, 12 nmol/Kg and 60 nmol/Kg); GHRH (3 nmol/Kg and 12 nmol/kg). Plasma GH levels were measured in blood samples taken at 5, 10, 15, 20, 30 and 45 min after their administration as an i.v. bolus at 0 min. Administration of Ghrelin led to an increase in plasma GH levels at all time-points tested (5, 10, 15, 20 and 30 min, P<0.01; and 45 min, P<0.05) in comparison to control untreated rats. A maximal stimulatory effect on plasma GH was observed following administration of 12 nmol/Kg of Ghrelin, the effect being similar to the one obtained with 60 nmol/Kg in terms of both AUC and mean peak GH levels. At the dose of 3 nmol/Kg GHRH and Ghrelin exhibited a similar stimulatory effect in term of both, AUC and mean peak GH levels. However following administration of a dose of 12 nmol/Kg, the effect of Ghrelin was much greater than the same dose of GHRH in terms of both AUC and mean peak GH levels. In summary, this study provides the first evidences that Ghrelin exert a marked stimulatory effect in plasma GH levels in freely-moving rats and provides further evidences that Ghrelin may play an important role in the physiological control of GH secretion.

Animals↗
PubMed1996

Gender influences the magnitude of the inflammatory response within embolic cerebral infarcts in young rats.

BACKGROUND AND PURPOSE: The inflammatory response within cerebral infarcts may have an influence on tissue damage. Since old animals with an impaired immune response have decreased inflammation after experimental cerebral infarction, we postulated that female animals with an increased immune response will have an increased inflammatory response after cerebral infarction. METHODS: Embolic cerebral infarcts were produced by photochemical irradiation of the right carotid artery in 12 female Fischer rats. The inflammatory response within 4-day-old infarcts was quantitated by histology with the use of computer-assisted image analysis and compared with that in 12 male rats from a previous series. RESULTS: Severe infarcts had the most pronounced inflammatory response. Female rats had an increased inflammatory response in infarcts of all severity, which was statistically significant in severe cerebral infarcts even after adjustment for infarct size. Severe infarcts in males were significantly larger than those in females. CONCLUSIONS: Gender influences the outcome of embolic cerebral infarcts after photochemical damage to the carotid artery, both in terms of the magnitude of the inflammatory response and infarct size. There are numerous gender-related differences in neurochemicals, cytokine production, and drug metabolism that may influence tissue damage after stroke and responsiveness to therapeutic intervention. The preponderance of male animals in stroke research may produce results not applicable to female stroke patients. The use of female animals will be required to provide adequate models for the study of stroke in women.

Animals↗
PubMedDate not supplied

Percutaneous mitral commissurotomy.

Rheumatic fever is the most common cause of acquired heart disease in children and young adults worldwide, mainly in developing countries, and is the reason that a large number of patients with mitral stenosis will require some modality of treatment during their life span. The early therapeutic approach for this condition was solely surgical, but since the early 1960s, several balloon catheter interventional techniques have emerged as alternatives to surgical treatment. In 1976 Inoue described a novel single-balloon device designed specifically for percutaneous transvenous mitral commissurotomy (PMC), and in 1982 the first clinical application of Inoue's technique was successfully accomplished. Ever since several clinical trials established PMC as an effective and safe procedure for severe mitral stenosis in more than 30,000 patients worldwide, percutaneous balloon techniques have been considered the method of choice in selected patients (functional class >II, mitral valve area <1.5 cm2, and Wilkins' score <8) for several reasons. PMC is a nonsurgical method with results similar to those of surgical intervention, but without the unnecessary risks and complications of general anesthesia and extracorporeal circulation pump. Both PMC and surgical commissurotomy yield comparable acute and long-term results and similar restenosis rates. Moreover, PMC is the strategy of choice in symptomatic pregnant women with mitral stenosis, as well as in some cases with restenosis after a previous PMC. Patient selection and procedural technique are reviewed in detail.

Adolescent↗