| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Department of Investigative Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom
Address all correspondence and requests for reprints to: Professor S. R. Bloom, Department of Investigative Medicine, Hammersmith Hospital, Imperial College London, 6th Floor Commonwealth Building, Du Cane Road, London W12 0NN, United Kingdom. E-mail: s.bloom{at}imperial.ac.uk.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The most recently discovered RFamide gene encodes five peptides including a 26-amino-acid RFamide peptide (26RFa) and a 43-amino-acid peptide with a pyroglutamylated acid residue at the N terminal [pyroglutamylated RFamide peptide 43 (QRFP43)] (2, 3). 26RFa and QRFP43 bind to the previously orphan G protein-coupled receptor 103 (GPR103). There are two rodent orthologs, termed GPR103A and GPR103B in the mouse (4) and QRFP-r1 and QRFP-r2 in the rat (5). The receptors are expressed in the rat, mouse, and human brain (2, 6). Both 26RFa and QRFP43 bind to and activate GPR103, but QRFP43 shows more potent agonistic activity in vivo (4). GPR103 shares structural similarities with neuropeptide FF (NPFF), neuropeptide Y (NPY) Y2 and galanin GalR1 receptors (6), and it has been suggested that 26RFa binds to the NPFF2 receptor (7). However, NPFF and other known peptide ligand G protein-coupled receptor agonists are not functional agonists for GPR103 (3).
26RFa and QRFP43 may regulate energy homeostasis. 26RFa- and QRFP43-like immunoreactivity has been observed in the paraventricular nucleus (PVN) and ventromedial nucleus of the human hypothalamus (8), and QRFP43 is expressed in the periventricular nucleus, arcuate nucleus, and lateral hypothalamus of rats (5). Mouse GPR103 orthologs are expressed in the hypothalamic PVN and lateral hypothalamus, and 26RFa binding sites are present in the rat PVN, ventromedial nucleus, dorsomedial and arcuate nuclei, and the lateral hypothalamus (4, 7). These regions are associated with the regulation of food intake and energy expenditure.
Intracerebroventricular (icv) administration of QRFP43 to male mice has been reported to stimulate food intake (4, 9, 10, 11), and QRFP43 expression is increased in the hypothalamus of fasted mice and mouse models of leptin deficiency (4). However, icv administration of QRFP43 at doses of 50 µg (11 nmol) did not significantly influence food intake in rats (5). The importance of the QRFP system in the regulation of energy homeostasis is therefore unclear.
RFamide peptides are known to play a role in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis (12, 13, 14). QRFP-r2 is highly expressed in the preoptic and anterior hypothalamic areas in the rat, which are associated with the regulation of the HPG axis (5, 15). icv and peripheral administration of 26RFa has recently been reported to stimulate the HPG axis in rats (16). However, the effects of QRFP43 on the HPG axis and the mechanisms by which GPR103 agonists stimulate the HPG axis are unknown.
In the present study, we have investigated the effects of the more potent GPR103 ligand, QRFP43, on the HPG axis in rats and the mechanisms by which QRFP43 mediates its stimulatory effects. We have also investigated the effect of icv administration of QRFP43 on food intake and behavior in rats.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animals
Male adult Wistar rats (specific pathogen free; Charles River, Margate, UK), weighing 250–300 g, were individually housed for cannulation under controlled temperature (21–23 C) and light (12-h light, 12-h dark cycle; lights on at 0700 h) with ad libitum access to food (RM1 diet; SDS Ltd., Witham, UK) and water. Animals weighed 340–380 g when used in the feeding and behavioral studies and the first study investigating the effect of icv administration of QRFP43 on pituitary-gonadal hormones. Animals used in the cetrorelix study weighed 360–400 g. Animals used for peripheral studies and hypothalamic explant and pituitary experiments were group housed (five per cage) under the same conditions. Animal procedures were approved under the British Home Office Animals Scientific Procedures Act 1986.
Cannulation (icv) and injection
Male adult Wistar rats were icv cannulated as described previously (17). Briefly, animals were anesthetized by ip administration of a mixture of ketamine HCl (60 mg/kg, Ketalar; Parke-Davis, Pontypool, UK) and xylazine (12 mg/kg Rompun; Bayer Corp., Bury St. Edmunds, UK). Prophylactic antibiotics flucloxacillin (37.5 mg/kg) and amoxicillin (37.5 mg/kg) were administered ip before surgery. Animals were placed in a Kopf stereotaxic frame (David Kopf Instruments, Tujunga, CA). The cannula position was determined using the coordinates from the Paxinos and Watson rat brain atlas (18) (0.8 mm posterior to bregma in the midline). A permanent 22-gauge stainless steel cannula was implanted 6.5 mm below the outer surface of the skull into the third cerebral ventricle. Three stainless steel screws were inserted into the cranium, and the cannula was fixed to these and the wound sealed with dental cement. After surgery, the animals were sc administered with buprenorphine (45 µg/kg; Schering-Plough Corp., Welwyn Garden City, UK) for analgesia and were rehydrated by an ip injection of 0.9% saline (5 ml/rat).
The animals were allowed 7 d recovery after surgery and then accustomed to handling and weighing on a daily basis. All compounds were injected in a 5-µl volume via a 28-gauge stainless steel injector placed in and projecting 1 mm below the tip of the cannula. Cannula placement was confirmed by a positive dipsogenic response to angiotensin II (150 ng/rat). Animals showing no response were excluded from the study. All animals were acclimatized to the injection process by a subsequent saline injection.
Effect of icv administration of QRFP43 on food intake in ad libitum-fed male rats
Groups of adult male ad libitum-fed, icv-cannulated rats (n = 9–14) were injected with saline, QRFP43 (0.3, 1, or 3 nmol), or 3 nmol neuropeptide Y (NPY) (positive control) (19) in the early light phase (0900–1000 h). Animals were returned to their home cages with a preweighed amount of rat chow. Food intake was measured at 1, 2, 4, 8, and 24 h after injection.
Effect of icv administration of QRFP43 on behavior in male rats
In the feeding study described above, icv administration of 3 nmol QRFP43 was observed to cause minor adverse effects, including a hunched posture, in three of 13 animals. A study was therefore performed to formally assess the effect of icv administration of a lower dose of 2 nmol QRFP43 on behavior. Groups of adult male ad libitum-fed, icv-cannulated rats were injected with saline (n = 12), 2 nmol QRFP43 (n = 12), or 3 nmol neuromedin U (NMU) (n = 5, positive control) in the early light phase (0900–1000 h). This dose of NMU has been shown to robustly increase grooming and motor activity in rats (20, 21). After injection, behavioral patterns were monitored for 60 min by observers blinded to the experimental treatment. Behavior was classified into eight different categories: feeding, drinking, rearing, locomotion, grooming, burrowing, head down, and sleeping, adapted from Fray et al. (22). Each rat was observed for 15 sec every 5 min. Each 15-sec period was divided into three 5-sec periods, and the behavior of each animal was recorded for each 5-sec period.
Effect of icv administration of QRFP43 on pituitary-gonadal hormones in male rats
Adult male, ad libitum-fed, icv-cannulated male rats (n = 8–10) were injected with saline, 2 nmol QRFP43, or 3 nmol kisspeptin-54 (n = 4, positive control) during the early light phase (0900–1000 h). This dose of QRFP43 was used because the behavior study showed no adverse effects of the peptide on behavior at this dose. Kisspeptin (3 nmol) has previously been shown to significantly stimulate the HPG axis after icv administration (23). Food was removed after injection, and rats were decapitated 20 and 40 min after injection. A group of icv-cannulated rats were also decapitated without being treated as a control. Trunk blood was collected in lithium heparin tubes containing aprotinin, and plasma was separated by centrifugation, frozen on dry ice, and stored at –20 C until measurement of LH, FSH, prolactin, and testosterone by RIA.
Effect of ip administration of QRFP43 on pituitary-gonadal hormones in male rats
Group-housed adult male Wistar rats were handled and weighed daily. They received an ip injection of saline on two occasions before the study day to acclimatize them to the injection procedure. On the day of the study, the animals were ip injected with saline or QRFP43 (40, 400, or 1200 nmol/kg) during the early light phase (0900–1000 h) and decapitated at 30 and 60 min after injection. A group of rats were decapitated without receiving an injection as a control. Plasma was collected and stored as described above until measurement by RIA.
Effect of QRFP43 on GnRH release from medial basal hypothalamic explants
The static incubation system was used as previously described (24). Briefly, ad libitum-fed male Wistar rats (aged 51–54 d) were killed by decapitation and the whole brain immediately removed. The brain was mounted with the ventral surface uppermost and placed in a vibrating microtome (Campden Instruments, Loughborough, UK). A 1.7-mm slice was taken from the basal hypothalamus and blocked lateral to the circle of Willis, and rostrally to include the preoptic area. The hypothalamic slices were incubated in individual tubes containing 1 ml artificial cerebrospinal fluid (aCSF) (20 mM NaHCO3, 126 mM NaCl, 0.09 mM Na2HPO4, 6 mM KCl, 1.4 mM CaCl2, 0.09 mM MgSO4, 5 mM glucose, 0.18 mg/ml ascorbic acid, and 100 µg/ml aprotinin) equilibrated with 95% O2 and 5% CO2.
The tubes were placed on a platform in a water bath maintained at 37 C. After an initial 2-h equilibration period, the hypothalami were incubated for 45 min in either 600 µl aCSF (basal) or QRFP43 (at doses of 1, 10, or 100 nM) in 600 µl aCSF (peptide incubation). After 45 min, the treatments were swapped; the hypothalami that received basal during the first 45 min received peptide treatment, whereas the hypothalami that received peptide treatment during the first incubation received 600 µl aCSF. The viability of the tissue was tested by 45 min exposure to aCSF containing 56 mM KCl. Hypothalamic explants that failed to show peptide release above the basal level in response to aCSF containing 56 mM KCl were excluded from the data analysis. Isotonicity was maintained by substituting K+ for Na+. At the end of each period, aCSF was collected and stored at –20 C until measurement of GnRH by RIA.
Effect of QRFP43 on GnRH release from GT1-7 cells
The immortalized hypothalamic GnRH-producing neuron subclone GT1-7 cells (25), were grown in 175-ml plastic culture flasks. They were maintained at 37 C in 5% CO2 in DMEM with L-glutamine (Invitrogen Ltd.) with 25 mM glucose and 1 mM sodium pyruvate, 10% fetal bovine serum, penicillin (100 IU/ml), and streptomycin (100 µg/ml). GT1-7 cells were plated on poly-L-lysine-coated 24-well plates (2 x 106 cells per well) and incubated for 24 h before secretion experiments.
For GnRH secretion experiments, cells were preincubated for 2 h in serum-free medium. Thereafter, the medium was discarded, and the cells were incubated in 0.5 ml serum-free medium (basal) or serum-free medium plus QRFP43 (1, 10, 100, 1000, or 3000 nM) or 100 nM glucagon-like peptide 1 (GLP-1) (positive control). This dose of GLP-1 has been shown to increase GnRH release from GT1-7 cells (26). The cells were incubated at 37 C with the test substances for 60 min after which the medium was removed and stored at –20 C until measurement of GnRH by RIA. The cells were incubated for another 60 min after treatment to measure recovery levels of GnRH.
Effect of QRFP43 on gonadotropin release from pituitary fragments in vitro
The effects of QRFP43 on pituitary LH and FSH release were determined using anterior pituitary segments. The methods were as previously described (27). Group-housed male rats were decapitated during the early light phase, and anterior pituitary glands were harvested immediately and then divided into four pieces of approximately equal size. The segments were randomly placed (one segment per well) in the wells of a 48-well tissue culture plate (Nunc International, Roskilde, Denmark) and incubated in 500 µl aCSF (described above). The anterior pituitary segments were maintained at 37 C in a humidified environment saturated with 95% O2 and 5% CO2 for 2 h, with the medium changed after 1 and 2 h. The segments were then incubated in 0.5 ml aCSF alone, aCSF plus QRFP43 (10, 100, or 1000 nM), or aCSF plus GnRH (100 nM) for 4 h. At the end of this period, the aCSF was collected and stored at –20 C until RIA for LH and FSH.
Effect of icv administration of QRFP43 on pituitary-gonadal hormones in male rats after pretreatment with cetrorelix
The icv-cannulated adult male rats were sc injected with saline or 200 nmol of the GnRH receptor antagonist cetrorelix 30 min before receiving an icv injection of saline, QRFP43 (0.2, 0.6, or 2 nmol), or kisspeptin-54 (1 nmol). Animals were decapitated 40 min after icv injection, and trunk blood was collected and stored as described earlier.
RIAs
LH, FSH, and prolactin plasma levels were measured using reagents and methods obtained from the National Hormone and Pituitary program (Dr. A. Parlow, University of California, Harbor Medical Center, Los Angeles, CA), and the radiolabeled peptides were prepared by the chloramine-T method (28). The RIAs were prepared in 0.06 M phosphate EDTA buffer (pH 7.4 ± 0.1) and left to incubate for 3 d at 4 C before separation by immunoprecipitation. Results were calculated in terms of a National Institute of Diabetes and Digestive and Kidney Diseases standard preparation. The sheep anti-GnRH antibody was provided by Dr. H. M. Fraser, Medical Research Council Reproductive Biology Unit, Edinburgh, UK). The radiolabeled GnRH was prepared by the iodogen method (29). The assay was prepared in 0.06 M phosphate buffer (pH 7.4 ± 0.1) and incubated at 4 C for 3 d before charcoal separation. Total plasma testosterone was measured by a commercial Coat-a-Count assay kit (Euro/DPC Ltd., Caernarfon, UK). GnRH was purchased from Bachem (UK) Ltd. (St. Helens, UK).
Statistical analysis
The results of the in vivo feeding and HPG axis studies were compared by one-way ANOVA with post hoc Tukey’s multiple comparison test. Data from the behavior study were compared using Kruskal-Wallis one-way ANOVA on ranks. The results from the hypothalamic explant release experiments were analyzed using a repeated-measures ANOVA with post hoc Dunnett’s multiple comparison test. Results from GT1-7 cell and pituitary quarters secretion experiments were analyzed by one-way ANOVA with post hoc Dunnett’s multiple comparison test. In all cases, P < 0.05 was considered to be statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
).
|
). This dose was therefore used to investigate the effects of icv QRFP43 on the HPG axis in adult male rats.
|
) (LH: saline 1.40 ± 0.33 ng/ml, 2 nmol QRFP43 5.28 ± 1.04 ng/ml, P < 0.01; FSH: saline 8.69 ± 0.69 ng/ml, 2 nmol QRFP43 11.67 ± 0.71 ng/ml, P < 0.05) (Fig. 3B). The stimulatory effect of icv administration of QRFP43 on LH levels appeared to be larger than that on FSH levels. Plasma prolactin and total testosterone were also measured, but no significant differences were observed (prolactin: saline 20 min 3.70 ± 0.43 ng/ml, 2 nmol QRFP43 20 min 3.23 ± 0.46 ng/ml, saline 40 min 3.64 ± 0.58 ng/ml, 2 nmol QRFP43 40 min 3.23 ± 0.51 ng/ml; testosterone: saline 20 min 13.01 ± 2.13 nmol/liter, 2 nmol QRFP43 6.55 ± 1.14 nmol/liter, saline 40 min 18.61 ± 4.19 nmol/liter, 2 nmol QRFP43 40 min 25.98 ± 3.80 nmol/liter).
|
). However, this increase did not achieve statistical significance. There was no change in plasma prolactin after ip administration of QRFP43.
|
).
|
). GnRH levels after 3000 nM treatment were also raised, but this change did not achieve statistical significance. GnRH recovery levels for the 1- to 2-h period were 31.2 ± 6.8, 50.7 ± 11.7, and 27.0 ± 5.9% of the 0- to 1-h levels for 1000 nM QRFP43, 3000 nM QRFP43, and 100 nM GLP-1, respectively.
|
, A and B). (LH: aCSF 107.71 ± 13.22 ng/ml, 100 nM GnRH 302.58 ± 19.42 ng/ml; FSH: aCSF 101.22 ± 13.47 ng/ml, 100 nM GnRH 233.41 ± 21.81 ng/ml).
|
) (sc saline/icv saline 0.47 ± 0.06 ng/ml, sc saline/icv 2 nmol QRFP43 0.069 ± 0.05 ng/ml, P < 0.05; sc saline/icv saline 0.47 ± 0.06 ng/ml, sc cetrorelix/icv 2 nmol QRFP43 0.21 ± 0.05 ng/ml, P < 0.001). FSH was also measured, but on this occasion, although FSH levels were raised after icv administration of 2 nmol QRFP43, they failed to reach significance (data not shown).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
The icv administration of doses of QRFP43 up to 3 nmol had no significant effect on food intake in male Wistar rats. Previously published studies have shown an increase in food intake after icv QRFP43 administration in mice. Takayasu et al. (4), Moriya et al. (9), and do Rego et al. (10) demonstrated that when administered icv in freely fed mice, doses between 0.2 nmol (10) and 10 nmol (4) QRFP43 significantly increased food intake for up to 2 h after injection in a dose-dependent manner. Chartrel et al. (11, 30) administered the less potent GPR103 agonist 26RFa icv in mice and also observed a dose-dependent increase in food intake at 2 h after injection. However, when Kampe et al. (5) icv administered 10 µg (2.2 nmol) and 50 µg (11 nmol) 26RFa in male Sprague Dawley rats, they observed only a slight elevation in cumulative food intake after 2 h that did not achieve statistical significance. Fukusumi et al. (2) administered QRFP43 icv in rats and also found no significant effect on food intake. These contradictory results may be due to slight methodological differences but more strongly suggest that the orexigenic effects of QRFP43 and 26RFa are species specific. Our results are in accord with this hypothesis. It seems likely that QRFP43 has at most only a minor effect on food intake in rats.
We found that icv administration of 3 nmol QRFP43 was associated with minor behavioral side effects in three of the 13 treated animals. When formally assessed, icv administration of a lower dose of 2 nmol QRFP43 was not associated with any statistically significant changes in the behaviors observed, although it was associated with a nonsignificant reduction in grooming. This dose was therefore used for the subsequent icv studies investigating the effects of QRFP43 on the HPG axis. In accord with these results, Moriya et al. (9) reported that icv infusion of 30 µg/d (6.7 nmol/d) QRFP43 for 10 d did not affect motor activity in mice. In contrast, Takayasu et al. (4) and do Rego et al. (10) observed an increase in locomotor activity in mice after icv administration of 0.02 and 3 nmol QRFP43, respectively. Takayasu et al. (4) also noted a change in grooming after icv administration of 3 nmol QRFP43 in mice. Because the peptide and receptor mRNA distribution of QRFP43 varies between species (2, 4), it is quite possible that QRFP43 regulates physical activity and feeding in mice but not rats. QRFP43 and GPR103B are highly expressed in the lateral hypothalamus of the mouse brain, and GPR103B is also highly expressed in the PVN (4). The PVN and lateral hypothalamus are regions recognized to play a role in the regulation of energy homeostasis. In the rat, the highest level of QRFP43 mRNA in the brain was detected in the retrochiasmatic area and in the posterior regions of the arcuate nucleus, which are also areas implicated in the regulation of energy homeostasis. However, the highest level of expression of QRFP-r2 (the rat homolog of GPR103B) in the rat hypothalamus was in the medial preoptic nucleus and anterior hypothalamus (5), which are areas more associated with the regulation of the HPG axis. Expression of GPR103B has not been reported in the mouse preoptic area (4). It may therefore be that the QFRP43 signaling system regulates the HPG axis but not energy homeostasis in the rat.
The icv administration of 2 nmol QRFP43 significantly increased plasma LH and FSH levels at 40 min after injection. Navarro et al. (16) icv administered 1 nmol 26RFa in male rats but found no significant changes in plasma gonadotropin concentrations at 15, 30, or 60 min after injection. Repeated icv administration of 26RFa (four 1-nmol boluses at 60-min intervals) also failed to raise circulating gonadotropin levels. QRPF43 more potently activates the GPR103 receptor, which may explain why it was able to significantly increase LH and FSH secretion in the current study. QRFP43 may also have a longer half-life in vivo than 26RFa, which could contribute to its greater effect on LH and FSH. However, it is also possible that a 1-nmol dose of 26RFa was simply too low to stimulate the HPG axis. We found that icv administration of a lower dose of 0.6 nmol QRFP43 did not significantly influence circulating gonadotropin levels.
It is interesting that icv administration of 2 nmol QRFP43 did not significantly increase circulating gonadotropin levels at 20 min after injection but did result in a significant rise at 40 min after injection. The stimulatory effects of other HPG-regulating neuropeptides on gonadotropin release can take a similar length of time to peak. For example, although icv administration of 5 nmol galanin-like peptide (GALP) or 3 nmol kisspeptin-10 significantly increased LH levels at 10 min after injection, their maximal effect is observed at later time points (23, 31). Plasma LH levels peak at 30 min after icv injection of 5 nmol galanin-like peptide (31) and at 60 min after icv injection of 3 nmol kisspeptin-10 (23). In the present study, there was a nonsignificant increase in plasma LH levels after icv administration of 2 nmol QRFP43 at 20 min and a significant increase observed at 40 min. However, it is unknown whether these data represent the effects of QRFP43 continuing to stimulate GnRH release for this period after administration or whether they represent, for example, a sustained increase in GnRH release instigated by the initial effects of QRFP43 administration.
Because icv administration of QRFP43 significantly increased gonadotropin secretion, we administered the peptide peripherally. It is unknown whether QRFP43 circulates, but peripheral administration of QRFP43 appears to act directly on the zona glomerulosa to induce aldosterone secretion in rats, suggesting it may have an endocrine role (2). Intraperitoneal injection of QRFP43 in male rats showed a trend toward an increase in LH, FSH, and testosterone levels at 30 min after injection but did not reach statistical significance. In accord with these results, QRFP43 directly on male pituitary segments did not alter the release of LH or FSH. It would be interesting to examine whether QRFP43 might affect pituitary hormone release at longer time points, although this is unfortunately not possible using our current incubation protocol. However, our results suggest that QRFP43 acts centrally, rather than directly on the pituitary, to stimulate the HPG axis.
In accord with this hypothesis, QRFP43 increased GnRH release from male hypothalamic explants and GT1-7 cells, suggesting that QRFP43 stimulates the HPG axis by activating GnRH-secreting neurons. The release of GnRH from hypothalamic explants did not show an obvious dose-dependent effect, but GnRH release after treatment with QRFP43 was consistently higher than basal release. To determine whether QRFP43 mediated its effects via GnRH in vivo, we administered QRFP43 icv in male rats pretreated with the GnRH antagonist cetrorelix. Pretreatment with cetrorelix blocked the QRFP43-induced LH release, strongly suggesting that QRFP43 mediates its effects on the HPG axis via GnRH.
Basal plasma LH levels in this study were lower than those observed in the first icv administration study. This effect might be due to the age of the animals. The animals in the second study were slightly older than those used in the previous icv study, and LH secretion is diminished with age (32, 33). Physical stress can also suppress LH secretion (34). Although the animals in the second study had been handled daily to familiarize them with the experimental procedure, it is possible that the extra stress implicit in receiving an icv injection 30 min after a sc injection resulted in the reduced basal LH levels observed in this study. However, the stimulatory effect of QRFP43 on LH levels was retained in these animals.
In the first study investigating the effects of icv QRFP43 on pituitary-gonadal hormones (Fig. 3
), 2 nmol QRFP43 significantly elevated FSH levels at 40 min after injection. In the last study, icv QRFP43 was associated with a rise in FSH levels at 40 min after injection, but this did not achieve statistical significance (data not shown). This discrepancy may be due to variation between the different groups of animals, as discussed above. In addition, exogenous administration of neuropeptides that stimulate GnRH release often show a more potent effect on LH release than on FSH release (15, 35). It is difficult to accurately reproduce the effects of endogenous neuropeptide signaling; thus, it is unclear whether this effect mimics physiology or represents a pharmacological artifact.
In conclusion, these studies suggest the stimulatory effects of QRFP43 on the HPG axis rats are mediated via GnRH. Further work is now required to elucidate the physiological significance of the QRFP system in the regulation of reproduction.
|
Footnotes |
|---|
Disclosure Statement: The authors have nothing to disclose.
First Published Online June 5, 2008
1 S.R.P. and K.G.M. contributed equally to these studies. 
Abbreviations: aCSF, Artificial cerebrospinal fluid; GLP-1, glucagon-like peptide 1; GPR103, G protein-coupled receptor 103; HPG, hypothalamic-pituitary-gonadal; icv, intracerebroventricular; NMU, neuromedin U; NPFF, neuropeptide FF; PVN, paraventricular nucleus; QRFP43, pyroglutamylated RFamide peptide 43; 26RFa, 26-amino-acid RFamide peptide.
Received November 13, 2007.
Accepted for publication May 28, 2008.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
