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Gastrin releasing peptide-induced satiety is associated with hypothalamic and brainstem changes in chicks
Abstract
Gastrin releasing peptide (GRP) is involved in the stimulation of gastric acid release from the stomach. It also mediates effects on feeding behavior. It is associated with anorexigenic effects in both mammalian and avian species, but the mechanism of action is unknown in any species. The aim of the present study was thus to investigate the hypothalamic and brainstem mechanisms mediating GRP-induced satiety in chicks. In Experiment 1, chicks that received intracerebroventricular (ICV) injection of GRP reduced food intake for up to 150 min following injection and reduced water intake up to 120 min following injection. In Experiment 2, chicks that were food restricted following GRP injection did not reduce water intake. Alimentary canal transit time was not affected by GRP in Experiment 3. A behavior analysis was conducted in Experiment 4, revealing that GRP-treated chicks reduced feeding pecks. In Experiment 5, GRP-treated chicks had increased c-Fos immunoreactivity in the lateral hypothalamus, paraventricular nucleus, and arcuate nucleus of the hypothalamus, and the nucleus of the solitary tract. Collectively, these results demonstrate that central GRP causes anorexigenic effects that are associated with hypothalamic changes without affecting other behaviors.
... A new GRP variant of 6 amino acids (GRP 6 ) was isolated from turkeys but it showed no activity in inducing either acid or pancreatic enzymes secretion (Campbell, et al., 1990). In the studies by Cline's research group (Bohler, et al., 2019;Tachibana, et al., 2010), cGRP 27 was also reported to be involved in feeding and satiety control. cGRP 27 and cGRP 10 both can specifically activate its receptor cGRPR with potency while the cGRP 27 showed a signtificantly higher affinity than cGRP 10 in our previous study (Mo, et al., 2017). ...
... Present study enriches the role of GRP among the chicken tissues. In addition to be involved in acid induction, gastrin release, pancreatic juice secretion and satiety control in chicken tissues (Bohler, et al., 2019;Campbell, et al., 1991Campbell, et al., , 1994Tachibana, et al., 2010), GRP may be involved in the more physiological activities such as follicular development. ...
The gastrin-releasing peptide (GRP) is reported to be mainly produced by the pituitary in chickens, with its receptor (GRPR) highly expressed in the ovaries, indicating its regulatory role in ovarian function. Present study aims to verify the role of GRP and GRPR in regulating the growth of ovarian follicles in chickens in vitro. GRPR was found to be highly expressed in granulosa cells of early follicles (1-6 mm), but shows barely detectable expression in theca cells. Moreover, in cultured granulosa cells isolated from early ovarian follicles, GRP peptide can activate the intracellular MAPK/ERK signaling pathway, thereby promoting granulosa cell proliferation. It was demonstrated that GRP enhanced the expression of Heparin-Binding EGF-like growth factor (HB-EGF), a local ovarian mediator that stimulates granulosa cell proliferation. The finding that GRPR is predominantly expressed in early follicles granulosa cells (1-6 mm), contrasts that of follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR) being mainly abundantly expressed in granulosa cells of late follicles (F5 and F1). The present study supports the notion of coordination between GRP peptide and gonadotropins (LH and FSH) in promoting chicken follicular development.
... Particularly, we found an upregulated ttr, and downregulated cart (coding for cocaine-and amphetamine-regulated transcript) and grp (coding for gastrin releasing peptide) expressions in photosensitive, compared to photorefractory birds, consistent with photoperiodic initiation of physiological processes. Whereas increased ttr gene expression might indicate enhanced activity of the photostimulated thyroid hormone responsive pathway, the decreased cart and grp gene expressions probably suggest the activation of processes associated with the hyperphagia and consequently the body fattening and weight gain in photosensitive birds exposed to stimulatory long days [50][51][52] . Further, there seems to be changes in genes associated with metabolic processes, as suggested by downregulated expression of coa6 and uqcrc1 genes in the photosensitive state. ...
We investigated time course of photoperiodically driven transcriptional responses in physiologically contrasting seasonal life-history states in migratory blackheaded buntings. Birds exhibiting unstimulated winter phenotype (photosensitive state; responsive to photostimulation) under 6-h short days, and regressed summer phenotype (photorefractory state; unresponsiveness to photostimulation) under 16-h long days, were released into an extended light period up to 22 h of the day. Increased tshβ and dio2 , and decreased dio3 mRNA levels in hypothalamus, and low prdx4 and high il1β mRNA levels in blood confirmed photoperiodic induction by hour 18 in photosensitive birds. Further, at hours 10, 14, 18 and 22 of light exposure, the comparison of hypothalamus RNA-Seq results revealed transcriptional differences within and between states. Particularly, we found reduced expression at hour 14 of transthyretin and proopiomelanocortin receptor , and increased expression at hour 18 of apolipoprotein A1 and carbon metabolism related genes in the photosensitive state. Similarly, valine, leucine and isoleucine degradation pathway genes and superoxide dismutase 1 were upregulated, and cocaine- and amphetamine-regulated transcript and gastrin-releasing peptide were downregulated in the photosensitive state. These results show life-history-dependent activation of hypothalamic molecular pathways involved in initiation and maintenance of key biological processes as early as on the first long day.
... Considering the documented links between high GRP level and both neutrophil chemotaxis and infiltration as well as reduction in food and water intake [243], it is not surprising to detect high neutrophil count [244] and anorexia in severe COVID-19 patients [245]. ...
... Considering the documented links between high GRP level and both neutrophil chemotaxis and infiltration as well as reduction in food and water intake [243], it is not surprising to detect high neutrophil count [244] and anorexia in severe COVID-19 patients [245]. ...
COVID-19 is an ongoing viral pandemic disease that is caused by SARS-CoV2, inducing severe pneumonia in humans. However, several classes of repurposed drugs have been recommended, no specific vaccines or effective therapeutic interventions for COVID-19 are developed till now. Viral dependence on ACE-2, as entry receptors, drove the researchers into RAS impact on COVID-19 pathogenesis. Several evidences have pointed at Neprilysin (NEP) as one of pulmonary RAS components. Considering the protective effect of NEP against pulmonary inflammatory reactions and fibrosis, it is suggested to direct the future efforts towards its potential role in COVID-19 pathophysiology. Thus, the review aimed to shed light on the potential beneficial effects of NEP pathways as a novel target for COVID-19 therapy by summarizing its possible molecular mechanisms. Additional experimental and clinical studies explaining more the relationships between NEP and COVID-19 will greatly benefit in designing the future treatment approaches.
The avian endocrine system includes the hypothalamus, pituitary gland, thyroid gland, ultimobranchial glands, adrenal glands, endocrine cells in the digestive system, endocrine cells in the pancreas, the testes of males, and the ovaries of females. In this chapter, I discuss the respective functions of hormones produced by these glands and cells. The hypothalamus produces and secretes hormones that help regulate the actions of the anterior pituitary and produces hormones that are stored in and released from the posterior pituitary. The anterior pituitary produces and secretes hormones that target specific organs, such as the gonads, or have body-wide effects. The specific functions of these hormones are described in this chapter, as are the hormones released by the posterior pituitary. Also discussed in this chapter are the functions of hormones produced and secreted by the thyroid gland, parathyroid gland, ultimobranchial glands, adrenal glands, and the pancreas. The specific roles of thyroid hormones in reproduction, embryonic development and hatching, and migration are also discussed. The respective functions of hormones that play important roles in regulating bird appetites and digestion are also explained.
The objectives were to evaluate the effects of standardized ileal digestible (SID) His:Lys ratio above the current NRC requirement on growth performance, intestinal health, and mobilization of His-containing proteins, including hemoglobin, carnosine, and trypsinogen, in nursery pigs from 7 to 11 kg body weight (BW). Forty pigs (26 d of age; initial BW of 7.1 ± 0.5 kg) were allotted to 5 dietary treatments based on a randomized block design with sex and initial BW as blocks. Dietary treatments were supplemented with varying SID His to Lys levels of 26, 32, 38, 43, and 49% and fed to pigs for 14 d (SID Lys = 1.22%). Feed intake and BW were recorded at d 0, 7, and 14 to measure growth performance. Blood samples were collected on d 12. Pigs were euthanized on d 14 to collect pancreas, longissimus dorsi muscles, mid-jejunum, and jejunal mucosa. Data were analyzed using the Proc Mixed of SAS. Growth performance was not affected, whereas varying SID His to Lys ratio affected hemoglobin (P < 0.05, max: 12 g/dL at 36%), immunoglobulin A (IgA, P < 0.05, min: 1.25 μg/mg at 35%) in jejunal mucosa, villus height (P = 0.065, max: 536 μm at 40%) in jejunum, trypsinogen (P = 0.083, max: 242 pg/mg at 41%) in pancreas, and carnosine (P = 0.051, max: 4.7 ng/mg at 38%) in muscles. Varying SID His to Lys ratios linearly increased (P < 0.05, from 1.95 to 2.80 nmol/mg) protein carbonyl in muscles and decreased (P < 0.05, from 29.1 to 26.9%) enterocyte proliferation. In conclusion, SID His to Lys ratio between 35 and 41% in diets fed to nursery pigs at 7 to 11 kg enhanced intestinal health and maximized concentrations of His-containing proteins, indicating that His-containing proteins are effective response criteria when determining His requirement.
DNA methylation is an epigenetic modification that influences gene transcription; however, the effects of methylation-influencing chemicals on appetite are unknown. We evaluated the effects of single administration of a methyl donor, S-Adenosylmethionine (SAM), or methylation inhibitor, 5-Azacytidine (AZA), on immediate and later-age food intake in an anorexic chick model. The doses of intracerebroventricularly-injected SAM were 0 (vehicle), 0.1, 1, and 10 μg, and of AZA were 0 (vehicle), 1, 5, and 25 μg. When injected on day 5 posthatch, there was no effect of SAM on food intake in either fed or fasted chicks, whereas AZA increased food consumption in the fasted state but decreased it in fed chicks. We then performed a single injection (same doses) at hatch and measured food intake on day 5 in response to neuropeptide Y (NPY; 0.2 μg) injection. Irrespective of NPY, chicks injected with 1 μg of SAM ate more than others on day 5. In contrast, chicks injected with AZA (5 and 25 μg doses) consumed less on day 5. In conclusion, we identified DNA methylation-regulating chemicals as regulators of food intake. AZA but not SAM affected food intake in the short-term, feeding state dependently. Later, both chemicals injected on the day of hatch were associated with food intake changes at a later age, suggesting that feeding pathways might be altered through changes in methylation.
Meeting the challenge of optimizing productive efficiency, product quality and animal health and well-being requires a thorough understanding of the mechanisms that regulate and coordinate feed intake and energy metabolism. The regulation of feed intake consists of several overlapping neural and endocrine pathways involved in negative and positive feedback mechanisms. This chapter focuses on the central and peripheral molecular mechanisms involved in the regulation of feed intake in avian species. Although chickens have several similarities in their mechanisms of the regulation of feed intake, some peculiarities exist where some feeding-related peptides have different effects compared to that in mammalian species.
The two structurally and functionally related peptides, gastrin-releasing peptide (GRP) and neuromedin B (NMB) play critical roles in many physiological/pathological processes in mammals. However, the information regarding the expression and functionality of avian NMB, GRP, and their receptors is limited. Here, we characterized cNMB, cGRP and their receptors (cNMBR, cGRPR, cBRS3) in chickens. Our results showed that: 1) cNMBR and cGRPR expressed in CHO cells could be potently activated by cNMB and cGRP respectively, as monitored by cell-based luciferase reporter assays, indicating that cNMBR and cGRPR are cNMB- and cGRP-specific receptors; Strikingly, BRS3 of chickens (/spotted gars), which is orthologous to mouse bombesin receptor subtype-3 (BRS3), could be potently activated by GRP and NMB, demonstrating that both peptides are the endogenous ligands for chicken(/spotted gar) BRS3; 2) Quantitative real-time PCR revealed that cGRPR is widely expressed in chicken tissues with abundant expression in the ovary, pancreas, proventriculus, spinal cord and brain, whereas cNMB, cNMBR and cBRS3 are mainly expressed in the brain and testes; 3) Interestingly, qPCR, Western blot, and immuno-staining revealed that cGRP is predominantly expressed in the anterior pituitary and mainly localized to LH-cells, suggesting that cGRP is likely a novel pituitary hormone in chickens. In summary, our data helps to uncover the roles of GRP, NMB and their receptors in birds, and provides the first persuasive evidence from an evolutionary prospective that in vertebrates, GRP and NMB are the endogenous ligands for BRS3, an orphan receptor which has puzzled endocrinologists for more than two decades.
The gastrin-releasing peptide receptor (GRP-R) is one of three members of the mammalian bombesin subfamily of seven-transmembrane G protein-coupled receptors that mediate diverse biological responses including secretion, neuromodulation, chemotaxis, and growth. The X chromosome-linked GRP-R gene is expressed widely during embryonic development and predominantly in gastrointestinal, neuronal, and neuroendocrine systems in the adult. Surprisingly, gene-targeted mice lacking a functional GRP-R gene develop and reproduce normally and show no gross phenotypic abnormalities. However, peripheral administration of bombesin at dosages up to 32 nmol/kg to such mice had no effect on the suppression of glucose intake, whereas normal mice showed a dose-dependent suppression of glucose intake. These data suggest that selective agonists for the GRP-R may be useful in inducing satiety.
Neuropeptide Y (NPY) is one of the most widespread neuropeptides in the brain. Transgenic mice were generated that expressed bright Renilla green fluorescent protein (GFP) in most or all of the known NPY cells in the brain, which otherwise were not identifiable. GFP expression in NPY cells was confirmed with immunocytochemistry and single-cell reverse transcription-PCR. NPY neurons in the hypothalamic arcuate nucleus play an important role in energy homeostasis and endocrine control. Whole-cell patch clamp recording was used to study identified arcuate NPY cells. Primary agents that regulate energy balance include melanocortin receptor agonists, AgRP, and cannabinoids; none of these substances substantially influenced electrical properties of NPY neurons. In striking contrast, neuropeptides of the bombesin family, including gastrin-releasing peptide and neuromedin B, which are found in axons in the mediobasal hypothalamus and may also be released from the gut to signal the brain, showed strong direct excitatory actions at nanomolar levels on the NPY neurons, stronger than the actions of ghrelin and hypocretin/orexin. Bombesin-related peptides reduced input resistance and depolarized the membrane potential. The depolarization was attenuated by several factors: substitution of choline for sodium, extracellular Ni(2+), inclusion of BAPTA in the pipette, KB-R7943, and SKF96365. Reduced extracellular calcium enhanced the current, which reversed around -20 mV. Together, these data suggest two mechanisms, activation of nonselective cation channels and the sodium/calcium exchanger. Since both NPY and POMC neurons, which we also studied, are similarly directly excited by bombesin-like peptides, the peptides may function to initiate broad activation, rather than the cell-type selective activation or inhibition reported for many other compounds that modulate energy homeostasis.
This paper presents evidence for the existence in extracts from porcine non-antral gastric tissue of a peptide capable of causing substantial rises of plasma immunoreactive gastrin levels in a dose dependent manner and of stimulation of gastric acid and pepsin secretion. Obtained data show that the peptide is basic and that its gastrin releasing properties are at least partially resistant to atropinisation and beta-receptor blockade. Antrectomy almost eliminates the rise in plasma IRGa when the peptide is administered. The possible relationship of this peptide to amphibian bombesin is discussed.
New information regarding neuronal circuits that control food intake and their hormonal regulation has extended our understanding of energy homeostasis, the process whereby energy intake is matched to energy expenditure over time. The profound obesity that results in rodents (and in the rare human case as well) from mutation of key signalling molecules involved in this regulatory system highlights its importance to human health. Although each new signalling pathway discovered in the hypothalamus is a potential target for drug development in the treatment of obesity, the growing number of such signalling molecules indicates that food intake is controlled by a highly complex process. To better understand how energy homeostasis can be achieved, we describe a model that delineates the roles of individual hormonal and neuropeptide signalling pathways in the control of food intake and the means by which obesity can arise from inherited or acquired defects in their function.
Amphibian bombesin and its related peptides consist a family of neuropeptides in many vertebrate species. Bombesin and two major bombesin-like peptide in mammals, gastrin-releasing peptide (GRP) and neuromedin B (NMB), have been shown to elicit various physiological effects. These include inhibition of feeding, smooth muscle contraction, exocrine and endocrine secretions, thermoregulation, blood pressure and sucrose regulations and cell growth. Receptors for GRP and NMB (GRP-R and NMB-R), as well as third subtype of bombesin-like peptide receptor (BRS-3) have been cloned. These receptors are G-protein-coupled receptors and are expressed in various brain regions and in the digestive tract. In this paper, we will summarize studies on these peptides and their receptors, with special reference to research using gene-knockout mice. These studies clearly demonstrated the role of three receptors in vivo and in vitro. We will also discuss the phylogeny of these receptors.
This confirmatory work is aimed to test that the hypothesis that the gastrin releasing peptide (GRP) receptor – the BB2 receptor – is necessary for reduction of meal size (MS) and prolongation of the intermeal interval (IMI) by the small and the large forms of GRP in the rat, GRP-10 and GRP-29, and to confirm the sites of action regulating such responses – the vascular bed of the celiac artery (CA, supplying stomach and upper duodenum). To pursue these aims we measured first MS and IMI length in response to GRP-10 and GRP-29 (0, 0.5 nmol/kg) infused in the CA (n = 8 rats) and the cranial mesenteric artery (CMA, supplying the small and part of the large intestine, n = 8 rats) in near spontaneously free feeding rats pretreated with the BB2 receptor antagonist BW2258U89 (0.1 mg/kg) in the same arteries prior to the onset of the dark cycle. We found that GRP-29, but not GRP-10, infused by the CA reduced MS and prolonged the IMI by decreasing meal latency and meal duration and the BB2 receptor antagonist BW2258U89 infused in the same artery attenuated these responses. These results suggest that the BB2 receptor is necessary for reduction of MS and prolongation of the IMI by exogenous GRP-29, and the vascular bed of the CA, stomach and upper duodenum, contains sites of action regulating these feeding responses.
Bombesin (BN) interacts with two mammalian receptor subtypes termed gastrin-releasing peptide (GRP)-preferring (GRP-R) and neuromedin B (NMB)-preferring (NMB-R) that may mediate the satiety action of BN. We examined the feeding behavior of mice that were deficient in the GRP-R (GRP-R KO) to assess the overall contribution of this receptor subtype in the feeding actions of BN-related peptides. GRP-R KO mice failed to suppress glucose intake in response to systemically administered BN and GRP(18-27), whereas both peptides elicited a potent reduction of intake in wild-type (WT) mice. Neither GRP-R KO nor WT mice suppressed glucose intake following NMB administration. Unlike the impaired responses to BN-like peptides, the feeding inhibitory action of cholecystokinin was enhanced in GRP-R KO mice. Consistent with behavioral results, GRP-R KO mice also exhibited a reduction in c-Fos immunoreactivity in the nucleus of the solitary tract (NTS) and paraventricular nucleus (PVN) following peripheral administration of BN. An evaluation of meal patterns showed that GRP-R KO mice ate significantly more at each meal than WT mice, although total 24 h food consumption was equivalent. A long-term analysis of body weight revealed a significant elevation in GRP-R KO mice compared with WT littermates beginning at 45 weeks of age. These data suggest that the GRP-R mediates the feeding effects of BN-like peptides and participates in the termination of meals in mice.
The effects of gastrin-releasing peptide (GRP) on the circadian clock in the suprachiasmatic nucleus (SCN) are dependent on the activation of N-methyl-d-aspartate (NMDA) receptors in the SCN. In this study, the interaction between GRP, glutamate and serotonin in the regulation of circadian phase in Syrian hamsters was evaluated. Microinjection of GRP into the third ventricle induced c-fos and p-ERK expression throughout the SCN. Coadministration of an NMDA antagonist or 8-hydroxy-2-di-n-propylamino-tetralin [a serotonin (5-HT)1A,7 agonist, DPAT] with GRP limited c-fos expression in the SCN to a region dorsal to GRP cell bodies. Similar to the effects of NMDA antagonists, DPAT attenuated GRP-induced phase shifts in the early night, suggesting that the actions of serotonin on the photic phase shifting mechanism occur downstream from retinorecipient cells. c-fos and p-ERK immunoreactivity in the supraoptic (SON) and paraventricular hypothalamic nuclei also increased following ventricular microinjection of GRP. Because of this finding, a second set of experiments was designed to test a potential role for the SON in the regulation of clock function. Syrian hamsters were given microinjections of GRP into the peri-SON during the early night. GRP-induced c-fos activity in the SCN was similar to that following ventricular administration of GRP. GRP or bicuculline (a γ-aminobutyric acidA antagonist) administered near the SON during the early night elicited phase delays of circadian activity rhythms. These data suggest that GRP-induced phase-resetting is dependent on levels of glutamatergic and serotonergic neurotransmission in the SCN and implicate activity in the SON as a potential regulator of photic signaling in the SCN.
The satiety-eliciting effect of gastrin-releasing peptide (GRP), a putative mammalian counterpart of bombesin (BBS), was examined in mildly food-deprived rats. Intraperitoneal injections of GRP resulted in a significant decrease of 30-minute food intake at 2, 4, 8 and 16 μg/kg, while 1 μg/kg had no reliable effect. Intraperitoneal GRP at 4 and 8 μg/kg did not suppress 30-minute water consumption by thirsty rats. When the dose-effect curves of GRP and BBS are compared on a molar scale, GRP is approximately 30% less potent than BBS in suppressing food intake. The two dose-effect curves are similar in shape and their regression lines have parallel slopes. These data lend further support to the hypothesis that GRP is a mammalian counterpart of BBS and strengthen the argument that they may function as endogenous satiety factors.
While neuropeptide Y (NPY) has been studied extensively per its pronounced role in food intake stimulation as well as its role in central pathways governing eating disorders, it has to our knowledge not been studied in polygenic models of hypo- and hyperphagia. Thus, the present study was designed to measure central NPY-associated food intake in lines of chickens that have undergone long-term genetic selection for low (LWS) or high (HWS) body weight and exhibit hypo- and hyperphagia, respectively. LWS chicks did not respond with any magnitude of altered food intake to any dose of NPY tested, while HWS chicks responded to all doses of NPY at similar magnitudes throughout the duration of observation. Both lines responded with similar increases in c-Fos immunoreactivity in the lateral hypothalamus and both divisions of the paraventricular nucleus; there were no significant line or line by treatment interactions. These data support the hypothesis that differences exist in the central NPY system of chicks from LWS and HWS lines and may provide novel insight for understanding NPY control of appetite.
Regulating food intake is complicated in animals including domestic birds. Just after hatching, neonatal chicks find their food by themselves and they can control food intake, since domestic chicken belongs to the precocial type of avian species. Thus, domestic chickens have relatively well-developed mechanisms of food-intake control at hatching. While many aspects of food-intake regulation in chickens appear similar to that in mammals, there are some responses that are unique to chickens. For instance, some neurotransmitters such as neuropeptide Y (NPY), orexin-A, orexin-B, motilin, melanin-concentrating hormone (MCH), galanin, growth hormone releasing factor (GRF) and ghrelin stimulate feeding in mammals. Only NPY strongly stimulates food intake in birds similar to that observed in mammals; however, both orexins, motilin, MCH and galanin failed to alter food intake of the chick. Moreover, GRF and ghrelin suppressed feeding of chicks. On the other hand, cholecystokinin (CCK), gastrin, glucagon-like peptide-1 (GLP-1), corticotropin-releasing factor (CRF), histamine, α-melanocyte stimulating hormone (α-MSH), leptin and bombesin are known to suppress feeding in mammals. These responses are similar to those of mammals except for leptin. Therefore, the inhibitory mechanisms for feeding are well conserved in chicks.
Domestic chickens are precocial and therefore have relatively well-developed processes at hatch. As a result, neonatal chicks grow well at hatch with no parental care. The regulation of food intake in animals, including domestic birds, is complicated. Just after hatching, neonatal chicks find their food by themselves and they can control their food intake. Recently, prolactin releasing peptide and gonadotropin-inhibitory hormone were confirmed as central orexigenic factors in the neonatal chick. Both peptides have a common structure as RFamide peptides. On the other hand, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide, both belonging to the glucagon superfamily, were recognized as inhibitory. Broiler chicks have either a greater capability to acclimatize to novel environments, or a blunted hypothalamus-pituitary-adrenal axis compared with layer chicks. These differences are explained by higher melatonin concentrations in the pineal gland and other parts of the brain of broiler chicks since melatonin attenuates the stress response. Stressful behavior in chicks can be attenuated by neurotransmitters or by nutrients such as creatine, phosphatidylserine, L-serine and (-)-epigallocatechin gallate. It is suggested that the regulation of behavior is somewhat specific and can be attenuated by some manipulation in neonatal chicks.
We and others have shown that gastrin-releasing peptide (GRP) reduces food intake. In this study, we determined the activation of the gastrointestinal and dorsal vagal complex (DVC) neurons by various forms of GRP to determine the pathway involved in this reduction. We found the following: (1) GRP-10, -27 and -29 (2.1 nmol/kg, i.p.) increased the Fos-like immunoreactivity (Fos-LI, a marker for neuronal activation) in the myenteric neurons of the stomach and the area postrema (AP) of the DVC; (2) GRP-27 and GRP-29 increased the Fos-LI in the myenteric plexus of the duodenum; and (3) only GRP-29 increased the Fos-LI in the submucosal plexus of the duodenum. In conclusion, GRP may reduce food intake by activating the area postrema. The enteric neurons may have a potential role in this reduction through the direct activation of the AP or exerting local gut actions, such as the stimulation of gut motility or secretions.
In mammals, gastrin releasing peptide (GRP) 10 and 27 reduce food intake. In the current work, we test the hypothesis that GRP-29, the large molecular form of GRP in the rat, also evokes feeding responses consistent with a possible role in satiety. Here, we measured three feeding responses, size of first meal, intermeal interval (IMI, time between first and second meal) and satiety ratio (SR, satiation period for every unit of food consumed in the first meal), in overnight food deprived rats following GRP-10, 27 or 29 (0, 0.3, 1.0, 2.1, 4.1, 10.3, 17.2nmol/kg) intraperitoneally and presentation of a 10% sucrose test diet. GRP-29 and GRP-27 reduced the size of the first meal, prolonged IMI and increased SR, but GRP-10 failed to exhibit similar feeding responses. The order of potency was GRP-29=GRP-27>GRP-10. The current data support a role for GRP-29 in the short-term regulation of food intake.
Gastrin-releasing peptide (GRP) and neuromedin B (NMB) have been isolated as homologues of bombesin. Central administration of bombesin inhibits feeding behavior in chicks (Gallus gallus) while the effects of GRP and NMB have not been reported. The purpose of the present study was to investigate whether intracerebroventricular (ICV) injection of GRP, NMB and neuromedin C (NMC, the C-terminus decapeptide of GRP) affected feeding and drinking behavior in chicks. Injection of GRP, NMC and NMB (0.2-5 nmol) decreased feeding behavior in chicks while drinking behavior was not affected. ICV injection of 5 nmol GRP and NMC decreased voluntary locomotion while NMB did not. It is therefore possible that GRP- and NMC-associated hypoactivity is related to the peptides' anorexigenic effects. GRP, NMC and NMB did not affect plasma corticosterone concentration, suggesting that hypothalamus-pituitary-adrenal axis might not be related to the anorexigenic action of these peptides. All these findings support the hypothesis that GRP, NMC and NMB function as anorexigenic factors in the brain of chicks.
Rat maternal behavior is a complex social behavior. Most antipsychotic drugs disrupt active maternal responses (e.g., pup retrieval, pup licking and nest building). Our previous work shows that typical antipsychotic haloperidol disrupts maternal behavior by blocking dopamine D(2) receptors, whereas atypical clozapine works by blocking 5-HT(2A/2C) receptors. The present study used c-Fos immunohistochemistry technique, together with pharmacological tools and behavioral observations, and delineated the neuroanatomical bases of the disruptive effects of haloperidol and clozapine. Postpartum female rats were treated with haloperidol (0.2 mg/kg sc) or clozapine (10.0 mg/kg sc), with or without pretreatment of quinpirole (a selective dopamine D(2)/D(3) agonist, 1.0 mg/kg sc) or 2,5-dimethoxy-4-iodo-amphetamine (DOI, a selective 5-HT(2A/2C) agonist, 2.5 mg/kg sc). They were then sacrificed 2 h later after a maternal behavior test was conducted. Brain regions that have been previously implicated in the regulation of rat maternal behavior and/or in the antipsychotic action were examined. Behaviorally, both haloperidol and clozapine disrupted pup retrieval, pup licking and nest building. Pretreatment of quinpirole, but not DOI, reversed the haloperidol-induced disruptions. In contrast, pretreatment of DOI, but not quinpirole, reversed the clozapine-induced deficits. Neuroanatomically, the nucleus accumbens (both the shell and core), dorsolateral striatum and lateral septum showed increased c-Fos expression to the treatment of haloperidol. In contrast, the nucleus accumbens shell showed increased expression of c-Fos to the treatment of clozapine. More importantly, pretreatment of quinpirole and DOI produced opposite response profiles in the brain regions where haloperidol and clozapine had an effect. Based on these findings, we concluded that haloperidol disrupts active maternal behavior primarily by blocking dopamine D(2) receptors in a neural circuitry involving the nucleus accumbens, dorsolateral striatum and lateral septum. In contrast, clozapine appears to disrupt maternal behavior mainly by blocking serotonin 5-HT(2A/2C) receptors in the nucleus accumbens shell.
Gastrin-releasing peptide (GRP) is a bombesin-like peptide widely distributed in the gastrointestinal tract and central nervous system. In the brain, GRP mRNA is located in the hypothalamic paraventricular nucleus (PVN), a region that receives neural input from the arcuate nucleus and plays a critical role in food intake and energy balance. Because GRP neurons are localized in the vicinity of projection sites in the PVN for peptides that participate in energy homeostasis, we investigated whether GRP mRNA expression in the PVN may be sensitive to challenges imposed by either 38 h food deprivation or stimulation of the melanocortin system by the melanocortin 3/4 receptor agonist, melanotan II (MTII). We found that food deprivation significantly decreased GRP mRNA expression, whereas lateral ventricular MTII administration increased GRP mRNA expression in ad libitum-fed rats 4 h after administration. Furthermore, administration of MTII at a dose that reduces 24 h food intake and body weight prevented the decrease in GRP mRNA expression observed in animals that were pair fed to the amount of food consumed by those injected with MTII. These results demonstrate that food deprivation and stimulation of the melanocortin system produce opposing changes in GRP gene expression in the PVN, suggesting that GRP-containing neurons in the PVN may be part of the hypothalamic signaling pathway controlling food intake and energy balance.
Gastrin-releasing peptide gene expression in the hypothalamic paraventricular nucleus is responsive to signals related to energy balance.
This chapter discusses the endocrine cells of the gastric mucosa. On ultrastructural and histochemical grounds, non-enterochromaffin (EC) endocrine cells of the gastrointestinal mucosa were classified as four or six independent cell types. Six distinct types of endocrine cells were added to the well-known EC cells. Staining patterns in light and electron microscopy amine histochemistry, and/or immunohistochemistry confirm the existence of this manifold population of endocrine cells. So far, biochemical and functional studies support the existence of four endocrine products, namely, 5-hydroxytryptamine (5HT), gastrin, histamine, and gastro glucagon. Thus, based on morphological evidence, more hormones than those presently reported are to be expected from the gastric mucosa. The interaction between endocrine cells and stimuli coming from the lumen or from blood and the nervous system; both the hypothesis of a direct interaction of luminal stimuli with the endocrine cell and a more complex mechanism involves specialized receptors and local or long central reflexes must be considered. The close dependence of most digestive functions on gastrointestinal hormones, the behavior of gastrointestinal endocrine cells in some digestive diseases associated with severe functional derangements such as peptic ulcer, malabsorption, pancreatitis, and the sequelae of surgical procedures affecting the alimentary canal—should be extensively investigated.
A heptacosapeptide with potent gastrin releasing activity has been isolated from porcine non-antral gastric and intestinal tissue. The amino acid sequence suggested from a preliminary study on the gastric peptide is: Ala-Pro-Val-Ser-Val-Gly-Gly-Gly-Thr-Val-Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH2. Striking homology in the C-terminal region is seen with bombesin, accounting for the similar bioactivities of the two peptides. Some structural resemblance with porcine cholecystokinin in the N-terminal region is noted.
Intraoral intakes of sucrose (SI; 0.1 M) and distilled water (WI) were measured in tube-fed neurologically intact and tube-fed chronic supracollicular decerebrate (CD) rats after intraperitoneal injections of saline and bombesin (BN) and gastrin-releasing peptide (GRP) in concentrations of 1, 2.5, 5, and 10 micrograms/kg. Also, to determine whether BN and GRP administration interacted with taste processing, oral motor responses during the 1st min of the intraoral infusion were videotaped and subsequently analyzed to determine the number of ingestive and aversive taste reactivity (TR) responses. Injections of greater than or equal to 2.5 micrograms/kg BN reliably suppressed SI similarly in both control and CD rats. In response to GRP, the only group difference was that injections of 1 microgram/kg GRP reliably suppressed SI in control but not CD rats. Administration of greater than or equal to 2.5 micrograms/kg GRP suppressed SI similarly in both control and CD rats. Although SI was suppressed by peripheral administration of BN and GRP, these treatments had no effect on the TR responses elicited by sucrose in either group. To determine whether the effects of BN and GRP were selective for sweet nutritive stimuli, intraoral WI was also measured in control rats after the same treatments. Injections of 5 and 10 micrograms/kg BN and 10 micrograms/kg GRP reliably suppressed WI, but lower doses had no effect. BN and GRP had no reliable effect on the pattern of TR responses elicited by water. Intraoral WI by CD rats was minimal (less than 1 ml) after injections of saline, BN, and GRP, and hence peptide effects could not be reliably assessed.(ABSTRACT TRUNCATED AT 250 WORDS)
Endocrine cells in the acid-secreting part of the avian stomach, the proventriculus, contain two forms of gastrin-releasing peptide (GRP) of 27 and 6 residues, respectively. We have examined the actions of exogenous GRP-27 and GRP-6 and endogenously released GRP in the control of pancreatic secretion in urethan-anesthetized turkeys. Chicken GRP-27 and the structurally related amphibian peptide bombesin were potent stimulants of fluid and protein output from the pancreas (at 6-100 pmol/kg, iv). GRP-6 had no significant effect at doses up to 1,000 times higher. A bombesin antagonist, (CH3)2-CHCO-[D-Ala24]GRP-20--26-NHCH3, inhibited the action of exogenous chicken GRP-27 but did not inhibit intravenous cholecystokinin octapeptide (CCK-8). Distension of the proventriculus with a solution of peptone produced an increase in the flow of pancreatic juice and an increase in protein output, which was not reduced by atropine. The bombesin antagonist produced a reversible inhibition of this response. A CCK-gastrin antagonist, BOC-beta-Ala-Trp-Leu-Asp-O(CH2)2- phenyl(4F), which inhibited the action of exogenous CCK, had no effect on the pancreatic response to exogenous GRP-27 or to distension of the proventriculus with peptone. We suggest that protein-rich solutions in the proventriculus release GRP, which in turn acts directly on the pancreas to stimulate enzyme secretion.
Gastrin has two principal biological effects: stimulation of acid secretion from gastric parietal cells and stimulation of mucosal growth in the acid-secreting part of the stomach. Circulating gastrin regulates the increase in acid secretion that occurs during the after meals. Gastrin also stimulates mucosal growth in the stomach. Exogenously administered gastrin causes increased cell division in the proliferative zone that lies between the surface cells and the gastric glands in the acid-secreting mucosa. The newly formed cells undergo differentiation into surface epithelial cells, parietal cells and gastric enterochromaffin-like cells. Furthermore, the increased mucosal proliferation that occurs with refeeding after a period of fasting may be mediated by gastrin since refeeding stimulates gastrin production and a parallel increase in mucosal DNA synthesis. Both food and gastrin cause a rapid increase in cell division and an increase in gastric ornithine decarboxylase mRNA in fasting rats. In preliminary immunoneutralization experiments, the stimulation of ornithine decarboxylase produced by food was inhibited by gastrin antibody. The sustained inhibition of gastric acid secretion obtained by surgery or with antisecretory drug therapy results in hypergastrinaemia associated with increased gastric mucosal cell proliferation. A good correlation between gastric enterochromaffin-like cell density and circulating gastrin concentrations has been found under these conditions as well as during infusions of exogenous gastrin. Trophic effects of gastrin have also been reported for the colon, duodenum and pancreas, but chronic hypergastrinaemia does not appear to produce hyperplasia of these organs.(ABSTRACT TRUNCATED AT 250 WORDS)
In an attempt to identify potential target sites for the satiety action of bombesin (BN), the distribution and pharmacological specificity of bombesin binding sites were examined in the rat gastrointestinal tract by in vitro autoradiography utilizing (125I-Tyr4) bombesin. Specific BN binding was localized to the circular muscle level of the gastric fundus and antrum, submucosal layer of the small intestine and longitudinal and circular muscle and submucosal layers of the colon. Pharmacological studies indicated that gastrin releasing peptide (GRP), Ac-GRP20-27 and BN-like compounds, litorin and ranatensin, inhibited the binding of (125I-Tyr4)BN with high affinity while compounds which lacked COOH-terminal homology with BN demonstrated a low affinity for BN binding sites. The wide distribution of BN binding sites in the gastrointestinal tract provides a number of potential sites for the mediation of the satiety action of BN.
The proto-oncogene c-fos is expressed in neurons in response to direct stimulation by growth factors and neurotransmitters.
In order to determine whether the c-fos protein (Fos) and Fos-related proteins can be induced in response to polysynaptic
activation, rat hindlimb motor/sensory cortex was stimulated electrically and Fos expression examined immunohistochemically.
Three hours after the onset of stimulation, focal nuclear Fos staining was seen in motor and sensory thalamus, pontine nuclei,
globus pallidus, and cerebellum. Moreover, 24-hour water deprivation resulted in Fos expression in paraventricular and supraoptic
nuclei. Fos immunohistochemistry therefore provides a cellular method to label polysynaptically activated neurons and thereby
map functional pathways.
Peptides of diverse structure stimulate grooming in rodents and other mammals. Peptide-induced grooming may be observed in several motivational contexts, with or without strong alternative response tendencies. Bombesin-like peptides elicit grooming route dependently in the rat and hamster, independently of, or concomitantly with, changes in ingestive behaviors or resting. The pattern of body surfaces groomed after i.c.v. BBS is in proportion to the representation of body surfaces in somatosensory but not motor cortex of rat. A bombesin-like peptide may be a neurotransmitter in somatosensory afferent processing, and grooming after i.c.v. BBS may reflect a response to alteration of cutaneous sensation. Bombesin is a putative satiety signal in the control of feeding and ethanol intake, but the satiation effects of systemic BBS can be dissociated from the grooming effect of central BBS. Thus, bombesin may perform independent and site-specific functions in the control of behavior. Grooming produced by BBS is not affected by naloxone, involves a different proportion of motor acts than is observed in normal or ACTH-induced grooming, and no cross-tolerance has been reported between ACTH and BBS in the rat. These properties of bombesin-induced grooming indicate multiple, separable mechanisms of peptide-induced grooming and scratching. Cholecystokinin-like peptide-induced grooming is observed after central injection in the rat and is unaccompanied by changes in feeding or resting. The well-documented satiety action of systemic CCK-like peptides is not accompanied by excessive grooming, so multiple, site-specific behavioral roles are also indicated for CCK-like peptides in control of behavior. CCK-8 exhibits short-term cross-tolerance with ACTH in elicitation of grooming, and central CCK-8 is co-localized with CRF and stimulates ACTH and corticosterone release in the rat. Thus, CCK-8 may induce grooming by increasing CRF or ACTH activity. These properties of CCK-like peptide-induced grooming indicate convergent neuroendocrine mechanisms that may explain some, but not all, peptide-induced grooming syndromes. Further characterization of the qualitative topographic, neuropharmacological, and neuroanatomical differences and species specificities of peptide-induced excessive grooming should provide a basis for understanding how brains coordinate grooming. Knowledge of the processes of neuropeptide control of grooming may provide potential peptide-based controls of grooming-related clinical disorders such as pruritus and allergic reactions.(ABSTRACT TRUNCATED AT 400 WORDS)
Neuropeptide Y (NPY) and peptide YY (PYY) were injected intracerebroventricularly (ICV) in broiler chicks. Both NPY and PYY markedly increased food intake during the first hour post-injection compared to saline (SAL) controls. Food intake doubled in chicks given 5 micrograms NPY. A response surface analysis suggested that following ICV injection of NPY, maximum food intake occurred, using a dose of 9 micrograms. In contrast, an estimated dose between one and 5 micrograms PYY resulted in maximum food intake, giving the latter a slightly higher potency. Time spent drinking was not significantly different among NPY, PYY and SAL groups. Chicks given NPY or PYY also spent significantly less time standing while those given PYY spent significantly less time preening compared to controls.
Intraperitoneal injections of tetradecapeptide bombesin (BBS) produced large, dose-related suppressions of liquid and solid food intake in rats, with threshold doses of 1--2 micrograms-kg-1. The feeding-associated behaviors of rats receiving BBS by this route at a test meal were normally sequenced, and several other observations suggested that the effect of BBS was specific and not due to malaise. The structurally related amphibian peptide litorin and the structurally related mammalian gastrin-releasing peptide (GRP) produced similar suppressions of food intake. The satiety effect of BBS administered intraperitoneally did not require the accumulation of food in the gut, the presence of intact adrenals, the abdominal vagus, or the release of cholecystokinin. When BBS and cholecystokinin were administered simultaneous, the suppressive effects on food intake were additive. Lateral cerebroventricular injections of BBS also produced large, dose-related suppressions of food intake, with a threshold dose of 100 ng per rat. The effect by this route, however, was not behaviorally specific: BBS produced equivalent inhibitions of food and water intake at every point on the dose-response curve, and produced a marked increase in grooming which dominated the behavioral display. Thus, (1) peripheral BBS is a putative satiety signal in the rat; (2) the class (endocrine, paracrine, or neural) and mechanism of this satiety action is not established; and (3) the differences in specificity and behavior following intraperitoneal and cerebroventricular routes indicate that peripheral BBS does not act solely via the cerebrospinal fluid to elicity satiety.
Stimulation of fibroblasts with serum or purified growth factors leads to a dramatic induction of expression of both c-fos mRNA and protein within a few minutes, followed by activation of c-myc. This suggests that c-fos induction is a primary event and the earliest known effect on gene expression by growth factors.
Immunoreactive gastrin releasing peptide (GRP) was demonstrated in neuronal elements in the porcine pancreas and in the gut of several mammals. Immunoreactive endocrine cells could not be detected. The results of radioimmunochemical analysis agreed well with those of immunocytochemistry. The occurrence of gastrin-releasing peptide-containing nerve cell bodies in the myenteric ganglia all along the gut indicates that gastrin-releasing peptide fibers are intramural in origin. The distribution of gastrin-releasing peptide fibers in all layers of the gut wall suggests multiple functions of gastrin-releasing peptide, including a role in the regulation of intramural neuronal activities, smooth muscle tone and in secretory and absorptive processes.
Using a newly developed radioimmunoassay for porcine gastrin-releasing peptide in plasma, we studied the pharmacokinetics of this peptide after infusing it into pigs at two dose levels. The disappearance of the peptide from plasma was characterized by two components, a fast one (t 1/2 1.4 min) and a slow one (t 1/2 6.6 min). With the same assay the release of gastrin releasing-peptide from the stomachs of 8 pigs that had been catheterized for selective sampling of fundic and antral blood was studied during vagal and splanchnic stimulation with or without acute adrenalectomy at neutral, acidic, and alkaline intragastric pH. Electrical stimulation of the vagal nerves resulted in a marked increase in both antral and fundic gastrin-releasing peptide release, whereas splanchnic stimulation was without effect. The effects of nerve stimulation were neither influenced by intragastric pH nor by adrenalectomy. Because of its presence in nerves in all layers of the gastric wall, its potent effect on gastrin release, and its release after vagal stimulation, gastrin-releasing peptide is likely to play a role in the vagal control of gastrin release, gastric motility, and acid secretion.
Five anti-gastrin releasing peptide (GRP) sera have been characterized against GRP, bombesin and related polypeptides spotted on cellulose acetate discs. Antibodies reacting with the C-terminal G-14 sequence of bombesin and the 19-27 sequence of GRP, were detected in all sera. Antibodies directed exclusively against the bombesin unrelated 1-17 sequence of GRP were found only in one serum (R-6902). With parallel immunohistochemical tests only the C-terminal immunoreactivity was detected in endocrine-paracrine cells of the chicken proventriculus, while both immunoreactivities were present in nerve fibres and a few nerve cell bodies of the mammalian gut. The distribution of GRP- and bombesin-like immunoreactive nerves in the gastric mucosa of both pyloric and oxyntic type the submucosal and myenteric plexus along the whole gastrointestinal wall and at sphincter regions is detailed.
The mechanisms of action of gastrin and gastrin releasing peptide (GRP) in stimulating gastric acid secretion were examined in the anaesthetized turkey. Gastrin and GRP produced dose-dependent increases in acid secretion that were inhibited by the gastrin/CCK-B antagonist CI988. The antagonist did not affect the acid secretory responses to histamine or carbachol. A GRP antagonist (M216140) inhibited the acid response to GRP, but not gastrin. The results suggest that in birds, GRP stimulates acid secretion by release of gastrin, which acts in turn on classical gastrin/CCK-B receptors in the proventriculus.
The development of the blood-brain barrier was microscopically examined in the optic tectum of the chick. The permeability of neural vessels to Evans blue and horseradish peroxidase decreases progressively during the period of incubation. Diffusion is massive on the 6th and 10th days of incubation and is reduced on the 14th day; on the 18th-21st day of incubation the vascular walls still allow Evans blue to diffuse but prevent extravasation of horseradish peroxidase completely. In one month old chickens the nervous substrate is free of both tracers.
Bombesin (BN)-like peptides injected peripherally or centrally suppress food intake in rats. The relationship between the central and peripheral actions of BN is unknown. However, experimental evidence supports a critical role for the caudal hindbrain in mediating the feeding effects of BN. To investigate this relationship further, we examined the ability of fourth ventricular infusion of a specific gastrin-releasing peptide (GRP) antagonist, [D-F5, Phe6, D-Ala11]BN-(6-13) methyl ester (BN-ME), to block suppression of glucose intake (0.5 kcal/ml) produced by intraperitoneal administration of GRP-(18-27) in 5-h food-deprived male Sprague-Dawley rats (n = 10). We found that fourth ventricular administration of 10, 32, and 100 ng BN-ME blocked the suppression of glucose intake produced by peripherally administered 10 nmol/kg GRP-(18-27). The most effective dose of BN-ME (100 ng) blocked the ability of peripheral injection of GRP-(18-27) to inhibit glucose intake but had no effect on intake when given alone. These results demonstrate that the availability of caudal hindbrain GRP receptors is necessary for peripherally administered GRP-(18-27) to reduce food intake in rats.
The brain-gut peptides cholecystokinin (CCK) and the mammalian bombesin-like peptide gastrin-releasing peptide (GRP) suppress food intake. Vagotomy blocks CCK- but not bombesin (BN)-induced feeding suppression, demonstrating differential vagal contributions. We examined the relationship between the ability of CCK and the active fragment of GRP, GRP-(18-27), to stimulate gastric vagal afferent activity and their ability to elicit changes in gastric motility. We also examined ligated cervical vagal segments and revealed specific 125I-CCK vagal binding without evidence of radiolabeled BN binding sites. Both close arterial and intraperitoneal CCK and GRP-(18-27) produced dose-dependent increases in activity in gastric vagal mechanoreceptive afferents. CCK dose dependently decreased gastric pressure without altering antral wall tension, whereas GRP-(18-27) dose dependently increased both gastric pressure and peak antral wall muscle tension. These results suggest that GRP-(18-27) activates gastric vagal afferents secondary to its stimulation of gastric motor effects. CCK activates this same population of vagal afferents independent of changes in gastric tension, suggesting a direct action of CCK at functional vagal CCK receptors.
This study was designed to investigate the contribution of the hypothalamus, anterior pituitary and adrenal gland in the increase of adrenocorticotropin (ACTH) and corticosterone secretion induced by gastrin-releasing peptide (GRP) on in vitro isolated hypothalamus, pituitary and adrenal gland. Furthermore, we have examined in dispersed anterior pituitary cells whether the ACTH release induced by GRP is a Ca2+-dependent process. Moderate concentrations of GRP (1 and 10 nM) were able to increase the release of corticotropin-releasing factor (CRF)-like material in the medium of isolated hypothalami, whereas higher concentrations (100 and 1000 nM) were needed to elevate ACTH and corticosterone secretion in pituitary and adrenal quarters, respectively. The competitive and specific GRP receptor antagonist (Leu13-psi-CH2NH-Leu14) bombesin (10, 100 and 1000 nM) was without effect on basal secretion of CRF-like material, ACTH and corticosterone in isolated hypothalami, pituitary and adrenal quarters respectively. However, this antagonist (100 nM) completely blocked the stimulatory effects of GRP (100 nM) on bioactive CRF, ACTH and corticosterone release. In addition, in dispersed anterior pituitary cells which medium contained Ca2+ (1.5 mM), GRP stimulated the secretion of ACTH, but was without effect when the concentration of Ca2+ in the medium was lower (200 nM). These results suggest that: (1) the hypothalamus, anterior pituitary and adrenal gland seem to contribute to the elevation of ACTH and corticosterone secretion induced by GRP by a mechanism mediated through GRP receptors and (2) the stimulation of ACTH by GRP in the anterior pituitary appears to be dependent upon the presence of physiological concentrations of extracellular Ca2+.
In 1970, Erspamer et al.(1,14)isolated and characterized the tetradecapeptide bombesin (BN) from the skin of amphibian frog Bombina bombina. Subsequently, several BN-like peptides have been identified in mammals, consisting of various forms of gastrin-releasing peptide (GRP) and/or neuromedin B (NMB), together with their distinct receptor subtypes. It has been proposed that BN-related peptides may be released from the gastrointestinal (GI)-tract in response to ingested food, and that they bridge the gut and brain (through neurocrine means) to inhibit further food intake. Conversely, the suppression of release of BN-like peptides at relevant brain nuclei may signal the initiation of a feeding episode. The present review will describe recent pharmacological, molecular, behavioral and physiological experiments, supporting the contention that endogenous BN-related peptides do indeed influence ingestive behaviors. Particular attention is focused on the relationship between these peptides in the peripheral compartment and their impact on central circuits using GRP and/or NMB as transmitters. In addition, however, we will point out various caveats and conundrums that preclude unequivocal conclusions about the precise role(s) of these peptides and their mechanism(s) of action. We conclude that BN-related peptides play an important role in the control of food intake, and may contribute to ingestive disruptions associated with anorexia (anorexia nervosa, AIDS and cancer anorexia), bulimia, obesity and depression. Hence, pharmacological targeting of these systems may be of therapeutic value.
The dorsal vagal complex in the medulla oblongata is the hub of the central nervous system network that produces vagal cephalic-phase reflexes. The preganglionic motor neurons controlling these cephalic responses of digestion and metabolism are organized topographically in longitudinal columnar subnuclei in the dorsal motor nucleus of the vagus. Gustatory and other visceral afferent inputs project into different subnuclei of the nucleus of the solitary tract capping the dorsal motor nucleus. Descending projections from more rostral stations of the neuroaxis project to the nuclei of the dorsal vagal complex, providing input both from exteroceptive senses, such as olfaction and vision, and from forebrain areas that modulate reflex strength. Recent structural analyses of the dorsal vagal complex, as well as characterizations of the region's inputs and neurochemistry, have provided a more complete understanding of the neural basis of cephalic-phase responses.
The current view of the control of food intake involves a central feeding system in the hypothalamus receiving input from peripheral systems. The presence of food in the gut stimulates the release of several regulatory peptides that control gut motility and secretion. Some of these peptides also act as feedback satiety signals, responsible for termination of a meal. Among the regulatory peptides suggested as peripheral satiety signals are cholecystokinin and gastrin releasing peptide. A more long-term peripheral regulation of food intake has also been postulated and leptin has been suggested as a regulator of food intake. Several regulatory peptides mediate orexigenic or anorexigenic effects in the central feeding system. Neuropeptide Y and galanin both act centrally and stimulate the intake of food, while corticotropin releasing factor reduces food intake. At present, most information about the regulation of food intake is gained from mammalian studies and these findings are used as a base for a discussion on the current knowledge of how regulatory peptides control appetite in non-mammalian vertebrates.
As we commemorate the 25th anniversary of the journal Peptides, it is timely to review the functional significance of the bombesin (BB)-like peptides and receptors in the CNS. Over two decades ago we published an article in the journal Peptides demonstrating that BB-like peptides are present in high densities in certain rat brain regions (such as the paraventricular nucleus of the hypothalamus). Subsequently, one of the mammalian forms of BB, gastrin-releasing peptide (GRP) containing cell bodies were found in the suprachiasmatic nucleus of the hypothalamus and nucleus of the solitary tract of the hindbrain. Another related peptide, namely neuromedin (NM)B, was detected in the olfactory bulb and dentate gyrus. BB and GRP bind with high affinity to BB(2) receptors, whereas NMB binds with high affinity to BB(1) receptors. The actions of BB or GRP are blocked by BB(2) receptor antagonists such as (Psi(13,14)-Leu(14))BB whereas PD168368 is a BB(1) receptor antagonist. Exogenous administration of BB into the rat brain causes hypothermia, hyperglycemia, grooming and satiety. BB-like peptides activate the sympathetic nervous system and appear to modulate stress, fear and anxiety responses. GRP and NMB modulate distinct biological processes through discrete brain regions or circuits, and globally these peptidergic systems may serve in an integrative or homeostatic function.
Intracerebroventricular (i.c.v.) injections of bombesin (BN) and gastrin-releasing peptide (GRP) dose-dependently decreased food intake in male Wistar rats fasted for 17 h. Neuromedin B (NMB) did not show any effect on food intake. After BN administration, locomotor activity did not significantly change, compared with a vehicle-injected group. The anorexia induced by BN (0.3 microg) was perfectly inhibited by pretreatment with a GRP-receptor antagonist, [D-Tyr(6)]BN(6-13) methyl ester (10 microg), an NO synthase inhibitor, L-nitro-arginine (30 microg), and a PKG inhibitor, H-9 (2 microg). The cGMP concentration in the hypothalamus increased 1 h after administration when compared with the vehicle-injected group. On the other hand, an NMB-receptor antagonist, BIM23127 (10 microg), and the protein kinase (PK) C inhibitors, chelerythrine (2 microg) and Go6983 (2 microg), inhibited only the late phase of the anorexia. A PKC activator, phorbol 12, 13-dibutyrate (3 microg), injected into the ventricle decreased food intake. These findings suggest that BN suppresses food intake mainly mediated through the GRP receptor and NO-cGMP-PKG pathway, and NMB receptor and PKC is partly involved in the late phase of the anorexia.
Obesity represents the most prevalent nutritional problem worldwide which in the long run predisposes to development of diabetes mellitus, hypertension, endometrial carcinoma, osteoarthritis, gall stones and cardiovascular diseases. Despite significant reductions in dietary fat consumption, the prevalence of obesity is on a rise and is taking on pandemic proportions. Obesity develops when energy intake exceeds energy expenditure over time. Recently, a close evolutionary relationship between the peripheral and hypothalamic neuropeptides has become apparent. The hypothalamus being the central feeding organ mediates regulation of short-term and long-term dietary intake via synthesis of various orexigenic and anorectic neuropeptides. The structure and function of many hypothalamic peptides (neuropeptide Y (NPY), melanocortins, agouti-related peptide (AGRP), cocaine and amphetamine regulated transcript (CART), melanin concentrating hormone (MCH), orexins have been characterized in rodent models The peripheral neuropeptides such as cholecystokinin (CCK), ghrelin, peptide YY (PYY3-36), amylin, bombesin regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. The pharmacological potential of several endogenous peripheral peptides released prior to, during and/or after feeding are being explored. Long-term regulation is provided by the main circulating hormones leptin and insulin. These systems implicated in hypothalamic appetite regulation provide potential targets for treatment of obesity which could potentially pass into clinical development in the next 5 years. This review summarizes various effects and interrelationship of these central and peripheral neuropeptides in metabolism, obesity and their potential role as targets for treatment of obesity.