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We compared the central mechanisms of feeding suppression by the anorexigenic hormones neuromedin U (NMU) and neuromedin S (NMS) in rats. I.c.v. injection of either NMU or NMS dose dependently decreased 3-h food intake during the first quarter of a dark period. Pretreatment involving i.c.v. injection of a specific anti-NMS IgG blocked the suppression of food intake induced by i.c.v.- and i.p.-injected leptin, but anti-NMU IgG elicited no blockade. Quantitative PCR analysis revealed that i.c.v. injection of NMU or NMS caused a dose-dependent increase in CRH and proopiomelanocortin mRNA expression in the paraventricular nucleus (PVN) and arcuate nucleus (Arc) respectively. In tissue cultures of the Arc, secretion of α-melanocyte-stimulating hormone was stimulated by NMU and NMS, with more potent stimulation by NMS. The time-course curves of the increase in neuronal firing rate in Arc slices in response to NMU and NMS showed almost the same pattern, with a peak 10–15 min after treatment, whereas the time-course curves for the PVN slices differed between NMU and NMS. These results suggest that NMS and NMU may share anorexigenic effects, depending on physiological conditions.
Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Department of Biochemistry, National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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It has been shown that the ghrelin receptor, GH secretagogue receptor (GHS-R), is synthesized in neurons of the nodose ganglion and then transmitted to axon terminals, where it binds to ghrelin. The orexigenic signal of ghrelin secreted from the stomach is transmitted to the brain via the vagal afferent nerve. To explore the regulation of GHS-R synthesis in the nodose ganglion, we examined whether or not GHS-R type a mRNA expression shows circadian rhythm, and is affected by starvation, vagotomy, or i.v. administration of gastrointestinal peptides. Nodose ganglion GHS-R mRNA levels showed a diurnal rhythm, being high during periods of light and low during darkness. Although starvation tended to increase the level of GHS-R mRNA, a more significant increase was observed upon re-feeding. Vagotomy decreased the level of GHS-R mRNA significantly in comparison with animals that underwent a sham procedure. Cholecystokinin and gastrin increased the level of GHS-R mRNA after 2 h, but after 4 h, the level decreased. These results suggest that GHS-R synthesis in the nodose ganglion is regulated centrally and peripherally by neuronal and humoral information, and that these dynamic changes of GHS-R mRNA expression may be involved in the regulation of feeding by ghrelin.
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We examined which factors suppress the rise of ghrelin secretion under hunger in 16-h-starved rats, and compared the responses of plasma ghrelin and leptin levels to various exogenous and endogenous stimuli in intact rats. Although an acute expansion of the stomach by infusion of 6 ml air or 3 ml water in rats starved for 16 h did not change the level of plasma acyl-ghrelin 3 ml corn starch solution, corn oil, or 20% ethanol significantly decreased it. Vagotomy inhibited suppression by nutrients but not by ethanol. Chronic infusion of ethanol into the stomach for 3 weeks in free-feeding rats caused widespread injury of the stomach mucosa, and increased both plasma ghrelin levels and the number of ghrelin cells. In intact rats, low temperature did not change ghrelin levels, but increased leptin levels. On the other hand, restriction stress decreased plasma ghrelin levels, but had the reverse effect on plasma leptin levels. Although insulin decreased and 20% glucose increased plasma glucose levels, they both decreased plasma ghrelin levels. Insulin elevated plasma leptin levels, but glucose had no effect. These results indicate that 1) acyl-ghrelin secretion from the stomach under fasting condition is suppressed by nutrients but not by mechanical expansion of the stomach; 2) high and low environmental temperature, stress, or administration of insulin reciprocally affect plasma levels of ghrelin and leptin; and 3) an increase of stomach ghrelin cell number and plasma ghrelin levels after chronic ethanol treatment may be involved in restoration of gastric mucosae.
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Ghrelin is a natural GH secretagogue first identified in the stomach. The ghrelin peptide is 28 amino acids long with an octanoic acid attached to Ser3 near the N-terminus. This lipid modification is essential for the interaction between ghrelin and the ghrelin-specific receptor GH secretagogue receptor type 1a (GHSR1a), whereas the five or more residues of the N-terminus seem to be sufficient to activate GHSR1a to the same level as those of full-length ghrelin. In this study, we found that ghrelin was converted into smaller fragments during incubation with animal plasma in vitro and in a mouse model. Mass spectrometric analysis revealed that both acyl and desacyl ghrelin were hydrolyzed at the peptide bond between Arg15 and Lys16, generating an N-terminal peptide consisting of the first 15 residues. Next, we partially purified a ghrelin endopeptidase from bovine plasma and identified the enzyme as an anticoagulant serine protease-activated protein C. Octanoyl-truncated ghrelin(1–15) activated GHSR1a-dependent signaling similar to the full-length peptide, as assayed using the cell-based early-growth factor 1 reporter system. Moreover, administration of the protein C-activating agent, ProTac, to mice enhanced the production of octanoyl ghrelin(1–15) in circulation. These results indicate that ghrelin is processed into shorter peptides in circulation under thrombotic and inflammatory conditions, although high doses of the short-form or full-length ghrelin did not have any obvious effects on thromboplastin time or platelet aggregation in human plasma. Truncation of ghrelin might be responsible for altering structural characteristics such as stability, hydrophobicity, and affinity with circulating macromolecules.
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Ghrelin, an endogenous ligand for the GH secretagog receptor, is predominantly produced in the stomach. It has been reported that endogenous ghrelin levels are increased by fasting and decreased after refeeding. It has also been reported that estrogen upregulates ghrelin expression and production and that somatostatin inhibits ghrelin secretion, whereas leptin has a paradoxical effect. Recently, several studies have shown that estrogen, somatostatin, and leptin are produced in the stomach, but the direct effects of these gastric hormones on ghrelin expression in a fasting state remain obscure. In this study, we examined the mRNA expression levels of gastric ghrelin, aromatase (estrogen synthetase), leptin and somatostatin, and concentrations of stomach leptin and portal vein 17β-estradiol in fasted male rats. After 48 h of fasting, although gastric ghrelin mRNA level was significantly increased, both gastric leptin mRNA level and leptin content were decreased. Further, refeeding of fasted rats resulted in a decrease in ghrelin expression level and an increase in leptin expression level. On the other hand, gastric estrogen and somatostatin levels did not change after fasting. In vitro studies revealed that leptin dose-dependently inhibited ghrelin expression and also inhibited estrogen-stimulated ghrelin expression. Moreover, ghrelin cells were found to be tightly surrounded by leptin cells. RT-PCR analysis clearly showed that long and short forms of the leptin receptor are expressed in the rat stomach. These results strongly suggest that an elevated gastric ghrelin expression level in a fasting state is regulated by attenuated restraint from decreased gastric leptin level.
Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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Graduate School of Biosphere Science, Hiroshima University, Higashi-Hiroshima-shi, Hiroshima 739-8528, Japan
National Cardiovascular Center Research Institute, Osaka 565-8565, Japan
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The present study was conducted to investigate roles of ghrelin in glucose-induced insulin secretion in fasting- and meal-fed state in sheep. Castrated Suffolk rams were fed a maintenance diet of alfalfa hay cubes once a day. Hyperglycemic clamp (HGC) was carried out to examine glucose-induced insulin response from 48 to 53 h (fasting state) and from 3 to 8 h (meal-fed state) after feeding in Experiment 1 and 2 respectively. Total dose of 70 nmol/kg body weight of d-Lys3-GHRP6, a GH secretagogue receptor 1a (GHS-R1a) antagonist, was intravenously administered at 0, 60, and 120 min after the commencement of HGC. In the fasting state, the ghrelin antagonist significantly (P < 0.01) enhanced glucose-induced insulin secretion. In the meal-fed state, i.v. administration of synthetic ovine ghrelin (0.04 μ g/kg body weight per min during HGC) significantly (P < 0.05) enhanced glucose-induced insulin secretion. d-Lys3-GHRP6 treatment suppressed ghrelin-induced enhancement of the insulin secretion. In conclusion, ghrelin has an inhibitory and stimulatory role in glucose-induced insulin secretion via GHS-R1a in fasting- and meal-fed state respectively.
