Hypothalamic Ghrelin Research Articles

Acylated ghrelin is not required for the surge in pituitary growth hormone observed in pregnant mice

Objective: Ghrelin is produced by the stomach, hypothalamus and pituitary. It circulates as acylated ghrelin (AG, which stimulates growth hormone (GH) secretion) and unacylated ghrelin (UAG). Acylation is mediated by the enzyme ghrelin O-acyltransferase (GOAT). In mice, pregnancy is associated with a marked increase in circulating pituitary GH. We investigated the role of AG and UAG in the surge of plasma GH concentrations in pregnant mice at the end of pregnancy. Design: Using a mouse model generated on a C57BL/6 background (wild type, WT) in which the GOAT gene has been deleted (KO), we measured plasma AG, UAG and GH concentrations and tissue (stomach, pituitary and hypothalamus) preproghrelin and GOAT mRNA in non-pregnant (NP) and pregnant (P), WT and KO mice. Results: GOAT deletion was associated with undetectable concentrations of AG. UAG concentrations were similar in all groups. In both WT and KO animals, mean GH concentrations increased 30 to 50 times during pregnancy. There was a tendency toward lower median GH concentrations in KO (301ng/mL) compared to WT (428ng/mL) mice (p=0.059). Preproghrelin expression was not affected by GOAT deletion or by pregnancy in the stomach. In contrast, pituitary and hypothalamic ghrelin gene expression were lower in KO-NP and KO-P mice compared to their WT counterparts. Conclusion: The complete absence of ghrelin acylation, which is associated with undetectable AG concentrations, does not prevent the marked increase in pituitary GH concentrations observed in pregnant mice, suggesting that AG is not the major mediator of GH secretion during pregnancy.

The role of ghrelin signalling for sexual behaviour in male mice.

Ghrelin, a gut-brain signal, is well known to regulate energy homeostasis, food intake and appetite foremost via hypothalamic ghrelin receptors (GHS-R1A). In addition, ghrelin activates the reward systems in the brain, namely the mesolimbic dopamine system, and regulates thereby the rewarding properties of addictive drugs as well as of palatable foods. Given that the mesolimbic dopamine system mandates the reinforcing properties of addictive drugs and natural rewards, such as sexual behaviour, we hypothesize that ghrelin plays an important role for male sexual behaviour, a subject for the present studies. Herein we show that ghrelin treatment increases, whereas pharmacological suppression (using the GHSR-1A antagonist JMV2959) or genetic deletion of the GHS-R1A in male mice decreases the sexual motivation for as well as sexual behaviour with female mice in oestrus. Pre-treatment with L-dopa (a dopamine precursor) prior to treatment with JMV2959 significantly increased the preference for female mouse compared with vehicle treatment. On the contrary, treatment with 5-hydroxythyptohan (a precursor for serotonin) prior to treatment with JMV2959 decreased the sexual motivation compared to vehicle. In separate experiments, we show that ghrelin and GHS-R1A antagonism do not affect the time spent over female bedding as measured in the androgen-dependent bedding test. Collectively, these data show that the hunger hormone ghrelin and its receptor are required for normal sexual behaviour in male mice and that the effects of the ghrelin signalling system on sexual behaviour involve dopamine neurotransmission.

Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats

Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia.

The role of ghrelin signalling in second-generation antipsychotic-induced weight gain

Based on clinical and animal studies, this review suggests a tri-phasic effect of second-generation antipsychotics (SGAs) on circulating ghrelin levels: an initial increase exerted by the acute effect of SGAs; followed by a secondary decrease possibly due to the negative feedback from the SGA-induced body weight gain or hyperphagia; and a final re-increase to reach the new equilibrium. Moreover, the results can also vary depending on individual SGAs, other hormonal states, dietary choices, and other confounding factors including medical history, co-treatments, age, gender, and ghrelin measurement techniques. Interestingly, rats treated with olanzapine, an SGA with high weight gain liabilities, are associated with increased hypothalamic ghrelin receptor (GHS-R1a) levels. In addition, expressions of downstream ghrelin signalling parameters at the hypothalamus, including neuropeptide Y (NPY)/agouti-related peptide (AgRP) and proopiomelanocortin (POMC) are also altered under SGA treatments. Thus, understanding the role of ghrelin signalling in antipsychotic drug-induced weight gain should offer potential novel pharmacological targets for tackling the obesity side-effect of SGAs and its associated metabolic syndrome.

Ghrelin-Induced Orexigenic Effect in Rats Depends on the Metabolic Status and Is Counteracted by Peripheral CB1 Receptor Antagonism

Ghrelin is an endogenous regulator of energy homeostasis synthesized by the stomach to stimulate appetite and positive energy balance. Similarly, the endocannabinoid system is part of our internal machinery controlling food intake and energy expenditure. Both peripheral and central mechanisms regulate CB1-mediated control of food intake and a functional relationship between hypothalamic ghrelin and cannabinoid CB1 receptor has been proposed. First of all, we investigated brain ghrelin actions on food intake in rats with different metabolic status (negative or equilibrate energy balance). Secondly, we tested a sub-anxiogenic ultra-low dose of the CB1 antagonist SR141716A (Rimonabant) and the peripheral-acting CB1 antagonist LH-21 on ghrelin orexigenic actions. We found that: 1) central administration of ghrelin promotes food intake in free feeding animals but not in 24 h food-deprived or chronically food-restricted animals; 2) an ultra-low dose of SR141716A (a subthreshold dose 75 folds lower than the EC50 for induction of anxiety) completely counteracts the orexigenic actions of central ghrelin in free feeding animals; 3) the peripheral-restricted CB1 antagonist LH-21 blocks ghrelin-induced hyperphagia in free feeding animals. Our study highlights the importance of the animaĺs metabolic status for the effectiveness of ghrelin in promoting feeding, and suggests that the peripheral endocannabinoid system may interact with ghrelińs signal in the control of food intake under equilibrate energy balance conditions.

Uremic anorexia and gastrointestinal motility dysfunction correlate with the changes of ghrelin system in hypothalamus

Ghrelin can act as a signal for meal initiation and play a role in the regulation of gastrointestinal (GI) motility via hypothalamic circuit. This study investigated the correlation between changes of hypothalamic ghrelin system and GI motility dysfunction and anorexia in rats with chronic renal failure (CRF). Sprague-Dawley (SD) rats (male/female 1:1, 180 ± 20 g) were randomly classified into a CRF group and control group (n = 8 per group). 5/6 nephrectomy was used to construct the CRF model. When plasma creatinine concentration (PCr) and blood urea nitrogen (BUN) in the CRF group were twice higher than the normal, food intake (g/24 h) and gastrointestinal interdigestive myoelectric complex (IMC) were detected. Then all rats were killed for assessment of the mRNA expression of ghrelin and growth hormone secretagogue receptor (GHS-R) in hypothalamus using reverse transcription-polymerase chain reaction. Analysis of variance, Student-Newman-Keuls-q-test and Correlation Analysis were used to do statistical analysis. P < 0.05 was considered as statistically significant. Compared to the control group, the CRF group was obviously decreased in the food intake (g/24 h), the phase III duration and amplitude and the ghrelin and GHS-R expression in the hypothalamus (P < 0.05). There was a positive correlation between them (P < 0.05). Changes of ghrelin and GHS-R in the hypothalamus correlate with gastrointestinal motility dysfunction and anorexia in rats with CRF.

Ghrelin-immunopositive hypothalamic neurons tie the circadian clock and visual system to the lateral hypothalamic arousal center

Ghrelin, a circulating gut-hormone, has emerged as an important regulator of growth hormone release and appetite. Ghrelin-immunopositive neurons have also been identified in the hypothalamus with a unique anatomical distribution. Here, we report that ghrelin-labeled neurons receive direct synaptic input from the suprachiasmatic nucleus, the central circadian timekeeper of the brain, and lateral geniculate nucleus, a visual center, and project synaptically to the lateral hypothalamic orexin/hypocretin system, a region of the brain critical for arousal. Hypothalamic ghrelin mRNA oscillates in a circadian pattern peaking in the dark phase prior to the switch from arousal to sleep. Ghrelin inhibits the electrophysiological activity of identified orexin/hypocretin neurons in hypothalamic slices. These observations indicate that the hypothalamic neurons identified by ghrelin immunolabeling may be a key mediator of circadian and visual cues for the hypothalamic arousal system.

Is there altered sensitivity to ghrelin-receptor ligands in leptin-deficient mice?: importance of satiety state and time of day

Several fine-tuned and interconnected hypothalamic peptidergic systems orchestrate the regulation of energy homeostasis in the body. The orexigenic peptide ghrelin and the anorexigenic peptide leptin are among the most important, and both have been implicated in the development of eating disorders from obesity to anorexia nervosa. The goal of these studies was to examine the response of leptin-deficient ob/ob mice in ghrelin-receptor ligands in a food intake task. Changes in cumulative food intake were measured after peripheral administration of ghrelin (1 and 2nmol/10g) and the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 and 133.3nmol/10g) in obese and lean control mice during the light and dark cycle as well as in a state of food restriction. Hypothalamic ghrelin and ghrelin-receptor expression was measured in ob/ob and lean mice at two different timepoints. Ghrelin increased food intake in lean and obese mice in the light and dark cycle, whereas the ghrelin-receptor antagonist caused significantly stronger reduction in food intake in obese mice only in the dark cycle. After fasting, ob/ob mice displayed decreased light cycle sensitivity to the anorexigenic effects of the ghrelin-receptor antagonist. Hypothalamic expression levels of ghrelin were unaltered during the light cycle but decreased during the dark cycle in ob/ob mice; whereas, although unchanged in the light cycle, ghrelin-receptor expression was increased in the dark cycle in obese mice. The functionality and sensitivity of the ghrelinergic system is dependent on the time of day and the satiety state in leptin-deficient ob/ob mice.

P.1.019 Olanzapine-induced weight gain is associated with increased hypothalamic ghrelin receptor expression

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Reduced Ghrelin Secretion in the Hypothalamus of Rats due to Cisplatin-Induced Anorexia

Although chemotherapy with cisplatin is a widely used and effective cancer treatment, the undesirable gastrointestinal side effects associated with it, such as nausea, vomiting, and anorexia, markedly decrease patients' quality of life. To elucidate the mechanism underlying chemotherapy-induced anorexia, focusing on the hypothalamic ghrelin secretion-anorexia association, we measured hypothalamic ghrelin secretion in fasted and cisplatin-treated rats. Hypothalamic ghrelin secretion changes after vagotomy or administration of cisplatin. Cisplatin + rikkunshito, a serotonin 2C receptor antagonist or serotonin 3 receptor antagonist, was investigated. The effects of intracerebroventricular (icv) administration of ghrelin or the serotonin 2C receptor antagonist SB242084 on food intake were also evaluated in cisplatin-treated rats. Hypothalamic ghrelin secretion significantly increased in 24-h-fasted rats compared to freely fed rats and was markedly reduced 24 and 48 h after cisplatin treatment in cisplatin-treated rats compared to saline-treated rats, although their plasma ghrelin levels were comparable. In cisplatin-treated rats, icv ghrelin administration reversed the decrease in food intake, vagotomy partially restored hypothalamic ghrelin secretion, and hypothalamic serotonin 2C receptor mRNA expression increased significantly. Administration of rikkunshito (an endogenous ghrelin enhancer) or a serotonin 2C receptor antagonist reversed the decrease in hypothalamic ghrelin secretion and food intake 24 h after cisplatin treatment. Cisplatin-induced anorexia is mediated through reduced hypothalamic ghrelin secretion. Cerebral serotonin 2C receptor activation partially induces decrease in hypothalamic ghrelin secretion, and rikkunshito suppresses cisplatin-induced anorexia by enhancing this secretion.

W1364 Role of Hypothalamic Ghs-R1a on Appetite Loss During Chemotherapy

Background/Aim: Because ghrelin is a strong orexigenic peptide, targeted depletion of the ghrelin receptor is expected to have a significant effect on feeding behavior. Although recent loss-of-function studies using GHS-R1a knockout animals have raised questions regarding the physiological significance of ghrelin on feeding, the roles of central GHS-R1a in anorexia models have not been investigated. To clarify that the gut-brain axis is associated with the regulation of appetite and the hypothalamic ghrelin signal, we investigated hypothalamic GHS-R1a gene expression and studied chemotherapy-induced dyspepsia in rats. Methods: We first examined the effects of an intracerebroventricular (ICV) injection of exogenous ghrelin on food intake with or without cisplatin treatment, as well as those of 48-h fasting and cisplatin or a 5-HT receptor agonist treatment on hypothalamic GHS-R1a mRNA expression. To identify the mechanism of the cisplatin-induced decrease in hypothalamic GHSR1a mRNA expression, we evaluated the effects of SB242084, a 5-HT2C receptor antagonist, and Rikkunshito (RKT), a ghrelin receptor activator (Endocrinology, 151, 2009) on hypothalamic GHS-R1a gene expression, as well as the effect of coadministration of a GHS-R1a antagonist on decreased food intake. Results: Compared to vehicle controls, ICV ghrelininjected rats (2 nmol/head) that were treated with cisplatin failed to reduce the decrease in food intake. Hypothalamic GHS-R1a gene expression was significantly enhanced during the 48-h fasting but was reduced after treatment with cisplatin or mCPP, a 5-HT2C receptor agonist (saline; 1.0 ± 0.08 vs. mCPP; 0.77 ± 0.06 relative mRNA, p = 0.0157, Steel's test), but not with 1B/2B receptor agonist treatment. The induced decrease was reversed by a 5HT2C receptor antagonist (cisplatin plus saline; 0.83 ± 0.06, and vs. relative mRNA level in cisplatin plus SB242084HCl, 1.2 ± 0.06, p = 0.026) or RKT (0.71 ± 0.06; cisplatin plus 500 mg/kg, 1.12 ± 0.09, p = 0.009; cisplatin plus 1000 mg/kg, 1.06 ± 0.09, p = 0.03), but not by granisetron or ondansetron, which are 5-HT3 receptor antagonists. The suppressive effect of cisplatin and mCPP on the decrease in food intake was abolished by coadministration of the GHS-R1a antagonist. Conclusion: Cisplatin-induced anorexia may worsen because of decreased hypothalamic GHS-R1a gene expression. Activation of the cerebral 5-HT2C receptor partially contributed to the decrease in GHS-R1a gene expression after cisplatin treatment.

Effect of food restriction on ghrelin in adult male rats and its relation to male reproductive hormones

Ghrelin is an endogenous ligand for growth hormone secretagogue (GHS) receptor (GHS-R). It has recently emerged as an orexigenic food intake controlling signal acting upon hypothalamic centres. To study the effect of food restriction on ghrelin level and its relation to male reproductive hormones, 32 adult male albino rats divided into two groups: Group I (8 rats as a control group) fed ad libitum for 21 days and 24 rats as Group II (food-restricted group) fed 30% of ad libitum intake of food consumed by the control group. Rats were weighed every 3 days. Group II rats were further subdivided into three subgroups: IIa, IIb and IIc that were killed at days 8, 16 and 21 from the start of food restriction respectively. Ghrelin level was assayed by ELISA technique in serum samples and tissue homogenates prepared from the stomach and hypothalamus. In addition, male reproductive hormones: testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assayed in serum by chemiluminescence. Mean body weight of food restricted rats was observed to decrease during the period of the experiment. Food restriction produced a significant increase of serum ghrelin and a significant decrease of both gastric and hypothalamic ghrelin in group II when compared with group I. The changes in ghrelin level varied with the duration of food restriction. Significant inverse correlation was found between serum ghrelin and each of gastric and hypothalamic ghrelin in group II. A significant decrease of testosterone, FSH and LH were found in food restricted rats compared with controls. The decrease was significantly related to the duration of food restriction. Significant inverse correlation was detected between serum ghrelin and each of the male reproductive hormones in food restricted group II rats. Thus ghrelin could be one of the hormones responsible for the suppression of male reproductive axis in case of negative energy balance.

Rikkunshito and 5-HT2C receptor antagonist improve cisplatin-induced anorexia via hypothalamic ghrelin interaction

Circulating ghrelin concentration regulates appetite behavior, but no study thus far has focused on the role of central ghrelin in anorexia after chemotherapy. To clarify the action mechanisms of rikkunshito (RKT), a traditional Japanese medicine, on cisplatin-induced anorexia, we attempted to elucidate its effect on hypothalamic ghrelin receptor expression in cisplatin-induced anorexia. We first examined the effects of an intracerebroventricular (ICV) injection of exogenous ghrelin on food intake with or without cisplatin treatment, and the effects of cisplatin or m-chlorophenylpiperazine (mCPP), a 5-HT2C receptor agonist, on hypothalamic growth hormone secretagogue receptor 1a (GHS-R1a) mRNA expression. To identify the mechanism of cisplatin-induced decrease in hypothalamic GHS-R1a mRNA expression, we evaluated the effects of SB242084HCl, a 5-HT2C receptor antagonist, and RKT on hypothalamic GHS-R1a gene expression, along with the effect of coadministration of a GHS-R1a antagonist on decreased food intake. Compared to vehicle controls, an ICV-injected rat ghrelin failed to inhibit the decrease in food intake in cisplatin-treated rats. Hypothalamic GHS-R1a gene expression was significantly reduced after cisplatin or mCPP treatment, and the induced decrease was reversed by SB242084HCl or RKT, but not granisetron or ondansetron, both of which are 5-HT3 receptor antagonists. Their suppressive effect on the decrease in food intake was abolished by coadministration of the GHS-R1a antagonist. Administration of RKT or SB242084HCl reversed the decrease in food intake induced by mCPP injection. The improvement by RKT on decreased food intake after cisplatin treatment was partly mediated by hesperidin and isoliquiritigenin, components of RKT. Cisplatin-induced anorexia may worsen because of decreased hypothalamic GHS-R1a gene expression. A 5-HT2C receptor antagonist and RKT suppressed cisplatin-induced anorexia by inhibiting reduction of GHS-R1a signal transduction in the hypothalamus.

Hypothalamic Ghrelin Suppresses Pulsatile Secretion of Luteinizing Hormone via β-Endorphin in Ovariectomized Rats

Objectives: Ghrelin, an endogenous growth hormone secretagogue, is a known accelerator of feeding behavior and suppresses pulsatile secretion of luteinizing hormone (LH) in ovariectomized rats. However, the mechanisms underlying this action remain unclear. We examined the effects of naloxone (NAL), a specific opioid antagonist, on the suppression of pulsatile LH secretion by ghrelin to determine whether β-endorphin (β-END) is involved in this suppressive effect. Methods: Ghrelin was administered intracerebroventricularly, and NAL was injected intravenously in ovariectomized rats; then, serum LH concentrations were measured by radioimmunoassay in blood samples drawn every 6 min for 2 h to analyze pulsatile secretion. Results: Administration of ghrelin significantly reduced mean LH concentration and pulse frequency. Coadministration of NAL with ghrelin significantly restored mean LH concentration and pulse frequency. Conclusion: Suppressive effect of intracerebroventricular injection of ghrelin on pulsatile LH secretion was mediated by β-END, suggesting that hypothalamic ghrelin suppressed pulsatile gonadotropin-releasing hormone secretion via β-END in female rats.

Effect of reducing hypothalamic ghrelin receptor gene expression on energy balance

Central and peripheral injections of fghrelin potently stimulates food intake via its receptor, GHSR1a expressed in the brain. In this study, we explored the role of GHSR1a in the paraventricular nucleus of the hypothalamus (PVN) by reducing their gene expression using the RNA interference (RNAi). pSUPER plasmids inserted with sh (short hairpin)-GHSR1a were injected into the PVN to reduce its expression. The transfected rats were monitored daily for their food intake and body weight throughout the experimental period lasting 8 days. We found that knockdown of GHSR1a did not affect daily food intake but significantly reduced body weight and blood ghrelin levels. This suggests that the central ghrelin system could selectively regulate body weight without affecting energy intake.

Plasma Ghrelin Modulation in Gastric Band Operation and Sleeve Gastrectomy

Gastric band operation and sleeve gastrectomy are increasingly popular bariatric surgeries for weight loss. The purpose of this study is to investigate the changes in plasma ghrelin levels and hypothalamic ghrelin receptor expression with weight loss achieved through these surgeries. Twenty-four high fat diet-induced obese rats were used to investigate the effects of gastric band and sleeve operation on Body Mass Index, fat mass, plasma ghrelin levels, and hypothalamic growth hormone secretagogue receptor 1a (GHS-R 1a) protein expression in hypothalamus. In comparison, data of patients who received laparoscopic adjustable gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG) in our hospital in 2005 were also summarized. Body weights and fat mass decreased significantly in rats that received operation. Plasma ghrelin concentrations in the sleeve group were 0.4-fold of control rats and about 2-fold of control in the gastric band group. GHS-R1a protein expression in hypothalamus was 1.5-fold in the sleeve group compared with control group, while it was only 0.9-fold in the gastric band group. Clinical data showed that patients in the LSG group lost 60% excess body weights in 2 years follow-up. After operation, fasting plasma ghrelin concentrations in LAGB was significantly higher than the LSG group. Both LAGB and LSG can decrease patients' excess body weights and fat mass. Plasma ghrelin levels are down-regulated with LSG operation but up-regulated with LAGB operation. Hypothalamic GHS-R1a expression is elevated in sleeve gastrectomy.

Expression of Genes Involved in the Somatotropic, Thyrotropic, and Corticotropic Axes During Development of Langshan and Arbor Acres Chickens

We investigated changes in mRNA expression of the somatotropic, thyrotropic, and corticotropic axes of Langshan (LS) and Arbor Acres (AA) broiler chickens during embryonic and postnatal development. We found an inverse expression profile between pituitary growth hormone (GH) and hepatic GH receptor mRNA [postnatal d (P)28 to P42], insulin-like growth factor (IGF)-I, and IGF-IR (P0 to P42), respectively. Hepatic IGF-I was a major point of control in the GH-IGF axis from P0 to P28. Pituitary GH-releasing hormone receptor may serve an autocrine-paracrine function from P0 to P28, and hypothalamic ghrelin may affect growth by stimulating the release of hepatic IGF-I from embryonic d (E)8 to P28. Hypothalamic ghrelin might interact with corticotropin-releasing hormone (CRH) from P0 to P28. Hepatic IGF-binding protein-2 regulated growth by regulating hepatic IGF-II bioavailability from P0 to P42. Hepatic IGF-binding protein-5 was an important IGF mediator. A coexpression profile was found between hypothalamic GH-releasing hormone (E10 to E16 and P0 to P42), somatostatin (SS; P0 to P28), thyrotropin-releasing hormone (E10 to E16 and P0 to P28), ghrelin (P0 to P42), and pituitary GH mRNA, hypothalamic SS (P0 to P28), corticotropin-releasing hormone (P0 to P42), thyrotropin-releasing hormone (E10 to E18 and P0-P42), and thyroid-stimulating hormone-β mRNA, respectively. Moreover, AA chickens were fed a nutrient-rich AA diet (as a control group) and LS chickens were fed either a less nutritious LS diet or the AA diet. Langshan and AA chickens fed the same AA diet showed no differences in pituitary GH, hypothalamic SS, ghrelin, hepatic IGF-I, or GH receptor mRNA. Our data indicate that select genes may show parallel expression during certain periods of development, and that differences in BW and gene expression respond differently to nutrient intake in LS and AA chickens. Our findings may help improve the molecular breeding of chickens.

Anxiogenic, orexigenic and metabolic effects of hypothalamic ghrelin

Anxiogenic, orexigenic and metabolic effects of hypothalamic ghrelin

Adaptive upregulation of gastric and hypothalamic ghrelin receptors and increased plasma ghrelin in a model of cancer chemotherapy-induced dyspepsia

Chemotherapy treatment can lead to delayed gastric emptying, early satiety, anorexia, nausea and vomiting, described collectively as the cancer-associated dyspepsia syndrome (CADS). Administration of ghrelin (GHRL), an endogenous orexigenic peptide known to stimulate gastric motility, has been shown to reduce the symptoms of CADS induced in relevant animal models with the potent chemotherapeutic agent, cisplatin. We examined the effects in the rat of cisplatin (6 mg/kg i.p.) treatment on the expression of GHRL and ghrelin receptor (GHSR) mRNAs in the hypothalamus and the stomach at a time-point (2 days) when the effects of cisplatin are pronounced. In addition, plasma levels of GHRL (acylated and total including des-acyl GHRL) were measured and the effect on these levels of treatment with the synthetic glucocorticoid dexamethasone (2 mg/kg s.c. bd.) was investigated. Cisplatin increased GHSR mRNA expression in the stomach (67%) and hypothalamus (52%) but not GHRL mRNA expression and increased the percentage of acylated GHRL (7.03 ±1.35% vs. 11.38 ± 2.40%) in the plasma. Dexamethasone reduced the plasma level of acylated GHRL and the percentage of acylated GHRL to values below those in animals treated with saline alone (7.03 ± 1.35% vs. 2.60 ±0.49%). Our findings support the hypothesis that an adaptive upregulation of the ghrelin receptor may occur during cancer chemotherapy-associated dyspepsia. This may have a role in defensive responses to toxic challenges to the gut. In addition, our results provide preliminary evidence for glucocorticoid modulation of plasma ghrelin levels.

Mice lacking the ghrelin receptor (GHS-R -/-) exhibit impaired hippocampal-dependent learning.

Ghrelin is a 28 amino acid peptide produced by epithelial cells in the stomach which increases food intake. Hypothalamic ghrelin receptors are thought to play an important role in the regulation of energy balance. However, ghrelin receptors are also expressed in several extra-hypothalamic brain regions, including the hippocampal formation. Previous work from our lab and others suggest that ghrelin is important for learning and memory. Specifically, intra-hippocampal ghrelin administration increases memory retention in a Step-Down Passive Avoidance test and ghrelin-deficient mice exhibit attenuated performance of the Novel Object Recognition task. In the current study, we utilized ghrelin receptor-deficient mice (GHS-R -/-) to confirm that ghrelin-signaling is necessary for the acquisition of a hippocampal-dependent spatial memory task. Consistent with previous reports, GHS-R -/- mice weigh less and have reduced average food intake relative to wild-type (WT) controls. GHS-R -/- and WT mice ( n 's=8/group) were trained in a Morris water maze task. GHS-R -/- mice exhibited significantly increased escape latencies relative to their WT controls, supporting the conclusion that ghrelin receptor signaling is required for the acquisition of a truly hippocampal-dependent task. Additional studies examine the role of GSH-R in the acquisition of non-hippocampal dependent tasks including learned meal-initiation and conditioned fear. Overall, these data confirm and extend out previous findings that ghrelin is a key mediator of hippocampal-dependent learning processes.