scholarly journals Neonatal Lipopolysaccharide Exposure Exacerbates Stress-Induced Suppression of Luteinizing Hormone Pulse Frequency in Adulthood

Endocrinology ◽  
2007 ◽  
Vol 148 (12) ◽  
pp. 5984-5990 ◽  
Author(s):  
X. F. Li ◽  
J. S. Kinsey-Jones ◽  
A. M. I. Knox ◽  
X. Q. Wu ◽  
D. Tahsinsoy ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Pulse Frequency ◽  
Inhibitory Influence ◽  
Adult Rats ◽  
Treatment Groups ◽  
Early Life Exposure ◽  
Stress Responsivity ◽  
17Β Estradiol ◽  
Lh Secretion

Early life exposure to immunological challenge has programming effects on the adult hypothalamo-pituitary-adrenocortical axis stress responsivity, and stress is known to suppress GnRH pulse generator activity, especially LH pulses. We investigated the effects of neonatal exposure to endotoxin on stress-induced suppression of pulsatile LH secretion and the involvement of corticotropin-releasing factor (CRF) receptor mechanisms in adult rats. Pups at 3 and 5 d of age were administered lipopolysaccharide (LPS, 50 μg/kg, ip). At 12 wk of age, they were ovariectomized and implanted with sc 17β-estradiol capsules and iv cannulas. Blood samples (25 μl) were collected every 5 min for 5 h for LH measurement. After 2 h of sampling, rats were given LPS (25 μg/kg, iv). CRF and CRF-R1 and CRF-R2 receptor mRNA was determined by RT-PCR in medial preoptic area (mPOA) micropunches collected at 3 h after LPS administration. There was no difference in basal LH pulse frequency between neonatal LPS- and neonatal saline-treated controls. However, neonatal endotoxin-treated rats exhibited a significantly greater LPS stress-induced suppression of LH pulse frequency. Basal mPOA CRF-R1 expression was unchanged in neonatal LPS- and neonatal saline-treated rats. However, CRF-R1 expression was significantly increased in response to LPS stress in neonatal LPS-treated animals but not in neonatal saline-treated controls. CRF and CRF-R2 expression was unchanged in all treatment groups. These data demonstrate that exposure to bacterial endotoxin in early neonatal life programs long-term sensitization of the GnRH pulse generator to the inhibitory influence of stress in adulthood, an effect that might involve up-regulation of CRF-R1 expression in the mPOA.

Pulsatile LH secretion in streptozotocin-induced diabetes in the rat

1991 ◽  
Vol 131 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Q. Dong ◽  
R. M. Lazarus ◽  
L. S. Wong ◽  
M. Vellios ◽  
D. J. Handelsman
Keyword(s):  
Weight Loss ◽  
Insulin Treatment ◽  
Pulse Generator ◽  
Latin Square ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Metabolic Effect ◽  
Male Rat ◽  
Free Access ◽  
Lh Secretion

ABSTRACT This study aimed to determine the effect of streptozotocin (STZ)-induced diabetes on pulsatile LH secretion in the mature male rat. LH pulse frequency was reduced by 56% and pulse amplitude by 54%, with a consequential decrease of 72% in mean LH levels 8 days after i.v. administration of STZ (55 mg/kg) to castrated Wistar rats compared with castrated non-diabetic controls. Twice daily insulin treatment completely reversed all parameters of pulsatile LH secretion to control values. Food-restricted non-diabetic controls, studied to distinguish the metabolic effect of diabetes from that of concurrent weight loss, demonstrated a 34% reduction in LH pulse frequency but no significant changes in LH pulse amplitude or mean LH levels compared with non-diabetic controls given free access to food. To distinguish whether the decreased LH pulse amplitude in diabetes was due to a reduction in either the quantity of hypothalamic gonadotrophin-releasing hormone (GnRH) released per secretory episode or to decreased pituitary responsiveness to GnRH, the responsiveness of the pituitary to exogenous GnRH (1–1000 ng/kg body weight) was tested in diabetic rats after castration, using a full Latin square experimental design. The net LH response (total area under response curve over 40 min following GnRH) was decreased by 33% (P=0·001) in diabetic compared with control rats. The decreased LH pulse frequency in STZ-induced diabetes therefore suggests that the metabolic effect of diabetes is to decelerate directly the firing rate of the hypothalamic GnRH pulse generator independent of testicular feed-back. These effects were fully reversed by insulin treatment and were only partly due to the associated weight loss. The impaired pituitary responsiveness to GnRH is at least partly involved in the reduction of LH pulse amplitude. Journal of Endocrinology (1991) 131, 49–55

scholarly journals Neural Determinants of Pulsatile Luteinizing Hormone Secretion in Male Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (2) ◽  
Author(s):  
Su Young Han ◽  
Isaiah Cheong ◽  
Tim McLennan ◽  
Allan E Herbison
Keyword(s):  
Luteinizing Hormone ◽  
High Frequency ◽  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Frequency ◽  
Male Mice ◽  
Intact Male ◽  
Luteinizing Hormone Secretion ◽  
Pulse Profile ◽  
Lh Secretion

Abstract The gonadotrophin-releasing hormone (GnRH) pulse generator drives pulsatile luteinizing hormone (LH) secretion essential for fertility. However, the constraints within which the pulse generator operates to drive efficient LH pulsatility remain unclear. We used optogenetic activation of the arcuate nucleus kisspeptin neurons, recently identified as the GnRH pulse generator, to assess the efficiency of different pulse generator frequencies in driving pulsatile LH secretion in intact freely behaving male mice. Activating the pulse generator at 45-minute intervals generated LH pulses similar to those observed in intact male mice while 9-minute interval stimulation generated LH profiles indistinguishable from gonadectomized (GDX) male mice. However, more frequent activation of the pulse generator resulted in disordered LH secretion. Optogenetic experiments directly activating the distal projections of the GnRH neuron gave the exact same results, indicating the pituitary to be the locus of the high frequency decoding. To evaluate the state-dependent behavior of the pulse generator, the effects of high-frequency activation of the arcuate kisspeptin neurons were compared in GDX and intact mice. The same stimulus resulted in an overall inhibition of LH release in GDX mice but stimulation in intact males. These studies demonstrate that the GnRH pulse generator is the primary determinant of LH pulse profile and that a nonlinear relationship exists between pulse generator frequency and LH pulse frequency. This may underlie the ability of stimulatory inputs to the pulse generator to have opposite effects on LH secretion in intact and GDX animals.

scholarly journals Suppression of the GnRH Pulse Generator by Neurokinin B Involves a κ-Opioid Receptor-Dependent Mechanism

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4894-4904 ◽  
Author(s):  
P. Grachev ◽  
X. F. Li ◽  
J. S. Kinsey-Jones ◽  
A. L. di Domenico ◽  
R. P. Millar ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pulse Generator ◽  
Pulse Frequency ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Neurokinin B ◽  
Kndy Neurons ◽  
Lh Secretion ◽  
Dose Dependent

Abstract Neurokinin B (NKB) and its receptor (NK3R) are coexpressed with kisspeptin, Dynorphin A (Dyn), and their receptors [G-protein-coupled receptor-54 (GPR54)] and κ-opioid receptor (KOR), respectively] within kisspeptin/NKB/Dyn (KNDy) neurons in the hypothalamic arcuate nucleus (ARC), the proposed site of the GnRH pulse generator. Much previous research has employed intracerebroventricular (icv) administration of KNDy agonists and antagonists to address the functions of KNDy neurons. We performed a series of in vivo neuropharmacological experiments aiming to determine the role of NKB/NK3R signaling in modulating the GnRH pulse generator and elucidate the interaction between KNDy neuropeptide signaling systems, targeting our interventions to ARC KNDy neurons. First, we investigated the effect of intra-ARC administration of the selective NK3R agonist, senktide, on pulsatile LH secretion using a frequent automated serial sampling method to obtain blood samples from freely moving ovariectomized 17β-estradiol-replaced rats. Our results show that senktide suppresses LH pulses in a dose-dependent manner. Intra-ARC administration of U50488, a selective KOR agonist, also caused a dose-dependent, albeit more modest, decrease in LH pulse frequency. Thus we tested the hypothesis that Dyn/KOR signaling localized to the ARC mediates the senktide-induced suppression of the LH pulse by profiling pulsatile LH secretion in response to senktide in rats pretreated with nor-binaltorphimine, a selective KOR antagonist. We show that nor-binaltorphimine blocks the senktide-induced suppression of pulsatile LH secretion but does not affect LH pulse frequency per se. In order to address the effects of acute activation of ARC NK3R, we quantified (using quantitative RT-PCR) changes in mRNA levels of KNDy-associated genes in hypothalamic micropunches following intra-ARC administration of senktide. Senktide down-regulated expression of genes encoding GnRH and GPR54 (GNRH1 and Kiss1r, respectively), but did not affect the expression of Kiss1 (which encodes kisspeptin). We conclude that NKB suppresses the GnRH pulse generator in a KOR-dependent fashion and regulates gene expression in GnRH neurons.

Stimulatory Adrenocortical Effects of a Selective Estrogen Receptor Modulator in Ovariectomized Female Macaques

2011 ◽  
Vol 40 (1) ◽  
pp. 55-61 ◽  
Author(s):  
Charles E. Wood ◽  
Ronda C. Stavisky ◽  
Jette Nowak ◽  
Jay R. Kaplan
Keyword(s):  
Estrogen Receptor ◽  
Macaca Fascicularis ◽  
Dehydroepiandrosterone Sulfate ◽  
Selective Estrogen Receptor Modulator ◽  
Adrenocortical Function ◽  
Target Dose ◽  
Treatment Groups ◽  
Receptor Modulator ◽  
17Β Estradiol

Here, we report the effects of estrogen and the selective estrogen receptor modulator (SERM) levormeloxifene on adrenocortical measures in ovariectomized female cynomolgus monkeys ( Macaca fascicularis). Animals were randomized into one of five treatment groups, each containing 23 to 26 animals: (1) placebo, (2) 0.016 mg/kg 17β-estradiol (E2), (3) 0.5 mg/kg levormeloxifene (L1), (4) 1.0 mg/kg levormeloxifene (L2), and (5) 5.0 mg/kg levormeloxifene (L3). Treatments were administered orally each day for 18 mo. All doses of levormeloxifene resulted in adrenal weights at least 50% greater than placebo ( p < .0001 for all). The target dose of levormeloxifene (L2) resulted in higher serum concentrations of cortisol (+63%), dehydroepiandrosterone-sulfate (+73%), and androstenedione (+37%) compared with the placebo group ( p < .05 for all). In contrast, E2 resulted in no significant differences in adrenal weight or adrenocortical steroids. Oral E2 and all SERM doses resulted in similar reductions in serum gonadotropins and at least threefold greater uterine weight versus placebo ( p < .0001 for all). Results indicate that the SERM levormeloxifene, in contrast to E2, may have robust stimulatory effects on adrenocortical hormones in a postmenopausal model. These findings warrant further investigation into long-term SERM effects on adrenocortical function.

scholarly journals Effect of Short- and Long-Term Administration of Baclofen on Spatial Learning and Memory in Rats

2018 ◽  
pp. 133-141 ◽  
Author(s):  
M. HOLAJOVA ◽  
M. FRANEK
Keyword(s):  
Learning And Memory ◽  
Spatial Learning ◽  
Receptor Agonist ◽  
Gabab Receptor ◽  
Spatial Learning And Memory ◽  
Adult Rats ◽  
Treatment Groups ◽  
Term Administration ◽  
Short And Long Term

Baclofen is the only clinically available metabotropic GABAB receptor agonist. In our experiment, we tested the hypothesis that long-term baclofen administration can impair learning and memory in rats. The experiment consisted of three parts. In the first part of the study the drug was administered simultaneously with the beginning of the behavioral tests. In the second and third part of the experiment baclofen was administered daily for 14 days and for one month before the tests. In each part of the experiment, adult rats were randomly divided into four treatment groups. Three groups were given an injection of baclofen at doses of 1 mg/kg, 5 mg/kg, 10 mg/kg, while the fourth group was injected with saline. The injections were given after each session. Spatial learning and memory were tested using the Morris water maze, involving three types of tests: Acquisition, Probe, and Re-acquisition. This work reveals that baclofen did not affect spatial learning at any of the tested doses and regardless of the length of administration. Memory was observed to be affected, but only at the highest dose of baclofen and only temporarily. This conclusion is in line with previously published clinical cases.

Reversal of long-term LH deprivation on testosterone secretion and Leydig cell volume, number and proliferation in adult rats

1990 ◽  
Vol 127 (1) ◽  
pp. 47-NP ◽  
Author(s):  
D. S. Keeney ◽  
R. L. Sprando ◽  
B. Robaire ◽  
B. R. Zirkin ◽  
L. L. Ewing
Keyword(s):  
Cell Volume ◽  
Leydig Cell ◽  
Leydig Cells ◽  
Cell Number ◽  
Implant Removal ◽  
Adult Rats ◽  
Testosterone Secretion ◽  
Lh Secretion

ABSTRACT The purpose of this study was to determine whether Leydig cell volume and function could recover fully from long-term LH deprivation upon restoration of endogenous LH secretion, and whether the restoration of LH would elicit a mitogenic response, i.e. stimulate Leydig cell proliferation or affect Leydig cell number per testis. LH secretion was inhibited by treating adult rats with testosterone and oestradiol-filled (TO) silicone elastomer implants (16 weeks), and was restored by removing the implants. Changes in serum concentrations of LH and FSH, LH-stimulated testosterone secretion by testes perfused in vitro, Leydig cell volume and number per testis, average Leydig cell volume and Leydig cell [3H]thymidine incorporation were measured at weekly intervals following implant removal. The TO implants inhibited (P < 0·01) LH secretion, but serum concentrations of FSH were not significantly different (P > 0·10) from control values. After implant removal, serum LH returned to control values within 1 week, whereas serum FSH increased twofold (P < 0·01) and returned to control values at 4 weeks. LH-stimulated in-vitro testosterone secretion was inhibited by more than 99% in TO-implanted rats, but increased (P < 0·01) to 80% of control values by 8 weeks after implant removal. The total volume of Leydig cells per testis and the volume of an average Leydig cell were 14 and 19% of control values respectively, after 16 weeks of TO implantation (P < 0·01), but returned to 83 and 86% of controls (P > 0·10) respectively, by 6 weeks after implant removal. Leydig cell proliferation ([3H]thymidine labelling index) was low (< 0·1%) in both control and TO-implanted rats, increased (P < 0·01) fivefold from 1 to 4 weeks after implant removal and then declined to control values at 6 weeks. The increase in Leydig cell [3H]thymidine incorporation was mimicked by treating TO-implanted rats with exogenous LH, but not FSH. Leydig cells were identified in both the interstitium and the lamina propria of the seminiferous epithelium. The proportion of Leydig cell nuclei in the lamina propria was 30-fold greater (P < 0·01) at 1 and 3 weeks after implant removal (3%) compared with that for control and TO-implanted rats (0·1%). Total Leydig cell number per testis was marginally but not significantly (P = 0·06) decreased in rats treated with TO implants for 16 weeks when compared with controls (18·4±2·2 vs 25·4±1·2 × 106). Three weeks after implant removal, the numbers of Leydig cells per testis were identical (26·8±2·8 × 106) to those in control animals. These results not only demonstrate dramatic morphogenic effects of LH on mature rat Leydig cells, but also suggest that endogenous LH might be mitogenic at least to a subpopulation of Leydig cells. Journal of Endocrinology (1990) 127,47–58

Evidence of gonadal steroid-independent changes in activity of the central LH-releasing hormone pulse generator in developing bull calves

1986 ◽  
Vol 111 (1) ◽  
pp. 67-73 ◽  
Author(s):  
M. J. D'Occhio ◽  
D. R. Gifford ◽  
T. Weatherly ◽  
B. P. Setchell
Keyword(s):  
Pulse Generator ◽  
Age Groups ◽  
Pulse Frequency ◽  
Releasing Hormone ◽  
Age Related ◽  
Bull Calves ◽  
Serum Lh ◽  
Transient Rise ◽  
Lh Releasing Hormone ◽  
Lh Secretion

ABSTRACT To ascertain whether temporal changes in activity of the hypothalamo-pituitary axis in prepubertal bulls may occur independently of shifts in sensitivity to steroid feedback, the acute post-castration rise in serum gonadotrophins was monitored in bull calves castrated at monthly intervals from 4 to 9 months of age. Since a major feature of the gonadotrophin profiles of developing bulls is a change in LH pulse frequency early in life, pulsatile LH secretion after castration was used as an index of activity of the central LH-releasing hormone (LHRH) pulse generator. Relative to the day of castration (day 0) bull calves (n = 4) were bled at 20-min intervals for 8 h on day −3 and at 10-min intervals for 4 h on days 3, 5 and 7. During the first week after castration, 4-month-old bulls showed a higher (P<0·05) frequency of LH pulses compared with bulls at 8 and 9 months (1·13, 0·88 and 0·75 pulses/h respectively; pooled s.e.m.= 0·13). Mean LH levels before castration were higher (P<0·05) in 4-month-old bulls than in bulls at 7, 8 and 9 months (0·92, 0·37, 0·31, 0·38 μg/l respectively; pooled s.e.m. = 0·12). After castration mean LH levels did not differ with age. Mean FSH levels did not differ among age groups either before or after castration. Increased serum LH levels in 4-month-old bulls confirmed the transient rise in LH secretion that occurs at this time in developing bull calves. Age-related differences in LH pulse frequency observed after castration suggested that in prepubertal bulls changes in activity of the central LHRH pulse generator can occur independently of steroid feedback mechanisms. J. Endocr. (1986) 111, 67–73

scholarly journals Kisspeptin, Neurokinin B, and Dynorphin Act in the Arcuate Nucleus to Control Activity of the GnRH Pulse Generator in Ewes

Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4259-4269 ◽  
Author(s):  
Robert L. Goodman ◽  
Stanley M. Hileman ◽  
Casey C Nestor ◽  
Katrina L. Porter ◽  
John M. Connors ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Pulse Generator ◽  
Pulse Frequency ◽  
Afferent Input ◽  
Pulse Generation ◽  
Orphanin Fq ◽  
Neurokinin B ◽  
Control Activity ◽  
Kndy Neurons ◽  
Lh Secretion

Recent work has led to the hypothesis that kisspeptin/neurokinin B/dynorphin (KNDy) neurons in the arcuate nucleus play a key role in GnRH pulse generation, with kisspeptin driving GnRH release and neurokinin B (NKB) and dynorphin acting as start and stop signals, respectively. In this study, we tested this hypothesis by determining the actions, if any, of four neurotransmitters found in KNDy neurons (kisspeptin, NKB, dynorphin, and glutamate) on episodic LH secretion using local administration of agonists and antagonists to receptors for these transmitters in ovariectomized ewes. We also obtained evidence that GnRH-containing afferents contact KNDy neurons, so we tested the role of two components of these afferents: GnRH and orphanin-FQ. Microimplants of a Kiss1r antagonist briefly inhibited LH pulses and microinjections of 2 nmol of this antagonist produced a modest transitory decrease in LH pulse frequency. An antagonist to the NKB receptor also decreased LH pulse frequency, whereas NKB and an antagonist to the receptor for dynorphin both increased pulse frequency. In contrast, antagonists to GnRH receptors, orphanin-FQ receptors, and the N-methyl-D-aspartate glutamate receptor had no effect on episodic LH secretion. We thus conclude that the KNDy neuropeptides act in the arcuate nucleus to control episodic GnRH secretion in the ewe, but afferent input from GnRH neurons to this area does not. These data support the proposed roles for NKB and dynorphin within the KNDy neural network and raise the possibility that kisspeptin contributes to the control of GnRH pulse frequency in addition to its established role as an output signal from KNDy neurons that drives GnRH pulses.

scholarly journals Optogenetic stimulation of kisspeptin neurones within the posterodorsal medial amygdala increases LH pulse frequency in female mice

2018 ◽  
Author(s):  
Geffen Lass ◽  
Xiaofeng Li ◽  
Ross de Burgh ◽  
Wen He ◽  
Yanping Kuang ◽  
...  
Keyword(s):  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Frequency ◽  
Oscillatory Activity ◽  
Central Component ◽  
Medial Amygdala ◽  
Continuous Stimulation ◽  
Optogenetic Stimulation ◽  
Lh Secretion ◽  
Generator Frequency

Kisspeptin within the arcuate nucleus of the hypothalamus is a critical neuropeptide in the regulation of reproduction. Together with neurokinin and dynorphin A, arcuate kisspeptin provides the oscillatory activity that drives the pulsatile secretion of GnRH, and therefore LH pulses, and is believed to be a central component of the GnRH pulse generator. It is well established that the amygdala also exerts an influence over gonadotrophic hormone secretion and reproductive physiology. The discovery of kisspeptin and its receptor within the posterodorsal medial amygdala (MePD), and our recent finding showing that intra-MePD administration of kisspeptin or a kisspeptin receptor antagonist results in increased LH secretion and decreased LH pulse frequency, respectively, suggests an important role for amygdala kisspeptin signalling in the regulation of the GnRH pulse generator. To further investigate the function of amygdala kisspeptin, the present study used an optogenetic approach to selectively stimulate MePD kisspeptin neurones and examine the effect on pulsatile LH secretion. MePD kisspeptin neurones in conscious Kiss1-CRE mice were virally infected to express a channelrhodopsin protein and selectively stimulated by light via a chronically implanted fibre optic cannula. Continuous stimulation using 5 Hz resulted in an increased LH pulse frequency, which was not observed at the lower stimulation frequencies of 0.5 and 2 Hz. In wild-type animals, continuous stimulation at 5 Hz did not affect LH pulse frequency. These results demonstrate that selective activation of MePD Kiss1 neurons can modulate hypothalamic GnRH pulse generator frequency.

scholarly journals Contrasting effects of different levels of food intake and adiposity on LH secretion and hypothalamic gene expression in sheep

2002 ◽  
Vol 175 (2) ◽  
pp. 383-393 ◽  
Author(s):  
ZA Archer ◽  
SM Rhind ◽  
PA Findlay ◽  
CE Kyle ◽  
L Thomas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Food Intake ◽  
Leptin Receptor ◽  
In Situ Hybridisation ◽  
Plasma Concentrations ◽  
Pulse Amplitude ◽  
Pulse Frequency ◽  
Hypothalamic Arcuate Nucleus ◽  
Lh Secretion

Body reserves (long-term) and food intake (short-term) both contribute nutritional feedback to the hypothalamus. Reproductive neuroendocrine output (GnRH/LH) is stimulated by increased food intake and not by high adiposity in sheep, but it is unknown whether appetite-regulating hypothalamic neurons show this differential response. Castrated male sheep (Scottish Blackface) with oestradiol implants were studied in two 4 week experiments. In Experiment 1, sheep were fed to maintain the initial body condition (BC) score of 2.0+/-0.00 (lower BC (LBC), n=7) or 2.9+/-0.09 (higher BC (HBC), n=9), and liveweight of 43+/-1.1 and 59+/-1.6 kg respectively. LBC and HBC sheep had similar mean plasma LH concentration, pulse frequency and amplitude, but HBC animals had higher mean plasma concentrations of insulin (P<0.01), leptin (P<0.01) and glucose (P<0.01). Gene expression (measured by in situ hybridisation) in the hypothalamic arcuate nucleus (ARC) was higher in LBC than HBC sheep for neuropeptide Y (NPY; 486% of HBC, P<0.01), agouti-related peptide (AGRP; 467%, P<0.05) and leptin receptor (OB-Rb; 141%, P<0.05), but lower for cocaine- and amphetamine-regulated transcript (CART; 92%, P<0.05) and similar between groups for pro-opiomelanocortin (POMC). In Experiment 2, sheep with initial mean BC score 2.4+/-0.03 and liveweight 55+/-0.8 kg were fed a liveweight-maintenance ration (low intake, LI, n=7) while sheep with initial mean BC score 2.0+/-0.03 and liveweight 43+/-1.4 kg were fed freely so that BC score increased to 2.5+/-0.00 and liveweight increased to 54+/-1.4 kg (high intake, HI, n=9). Compared with LI, HI sheep had higher mean plasma LH (P<0.05), baseline LH (P<0.01) and pulse amplitude (P<0.01) and showed a trend towards higher pulse frequency. Although there were no differences in final mean plasma concentrations, there were significant increases over time in mean concentrations of insulin (P<0.001), leptin (P<0.05) and glucose (P<0.001) in HI sheep. Gene expression for AGRP in the ARC was higher in HI than LI animals (453% of LI; P<0.05), but expression levels were similar for NPY, OB-Rb, CART and POMC. Thus, the hypothalamus shows differential responses to steady-state adiposity as opposed to an increase in food intake, in terms of both reproductive neuroendocrine activity and hypothalamic appetite-regulating pathways. Differences in hypothalamic gene expression were largely consistent with contemporary levels of systemic leptin and insulin feedback; however, increased nutritional feedback was stimulatory to GnRH/LH whereas constant high feedback was not. The hypothalamus therefore has the ability to retain a nutritional memory that can influence subsequent responses.

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