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Neuromedin U (NMU) is a hypothalamic peptide involved in energy homeostasis and stress responses. NMU, when administered intracerebroventricularly, decreases food intake and body weight while increasing body temperature and heat production. In addition, NMU, acting via the corticotropin-releasing hormone (CRH) system, induces gross locomotor activity and stress responses. We studied the effect of intracerebroventricularly administered NMU (0.5-4 nmol) in the regulation of gastric functions in conscious rats. Intracerebroventricular administration of NMU significantly decreased gastric acid output to 30-60% and gastric emptying to 35-70% in a dose-dependent manner. Vagotomy did not abolish the inhibitory effect of NMU on pentagastrin-induced gastric acid secretion. Pretreatment with indomethacin (10 mg/kg), an inhibitor of prostaglandin synthesis, also did not affect NMU-induced acid inhibition. Pretreatment with anti-CRH IgG (1 [micro]g/rat), however, completely blocked NMU-induced acid inhibition (P < 0.01). Administration of yohimbine (4 mg/kg), an [[alpha].sub.2]-adrenergic receptor antagonist, also abolished NMU-induced acid inhibition (P < 0.01). These findings suggest that NMU is critical in the central regulation of gastric acid secretion via CRH. hypothalamic peptide; gastric emptying; corticotropin-releasing hormone; central administration

Abstract: Orexin-A and -B (identical to hypocretin-1 and -2) are hypothalamic neuropeptides that regulate appetite and arousal. Orexins-producing neurons project their axons to various brain regions, including the olfactory bulb. In the present study, to understand the relationship between orexins and olfaction, we investigated the distribution of the orexin-A- and -B-immunoreactive (ir) fibers in the rat olfactory bulb and the contents of orexin-A and -B in the rat olfactory bulb after food deprivation for 48h by using immunohistochemistry and radioimmunoassay, respectively. Both orexin-A- and -B-ir fibers are similarly wide spread from the glomerular layer of the olfactory bulb where the terminals of the peripheral olfactory nerves make synapses with the mitral cells or the tufted cells, to the piriform cortex. Dense orexin-A- and -B-ir fibers were observed mainly in the granular cell layer and anterior olfactory nucleus. The contents of orexin-A and -B (pg/10mg wet weight tissue) in fed rats (mean±S.E.M., n =6) were 2.72±0.24 and 6.31±0.63, respectively. Fasting for 48h significantly reduced the contents of orexin-B, but not orexin-A. Orexins in the rat olfactory bulb may be involved in not only olfactory system but also energy balance. [Copyright &y& Elsevier]

Abstract: Neuropeptide W (NPW), a novel endogenous peptide for G protein-coupled receptors GPR7 and GPR8, is expressed in the gastric antral mucosa of rat, mouse, and human stomachs. Here, we studied the ontogeny of NPW in the developing rat stomach. Real-time RT-PCR showed that NPW gene expression was initially detectable in embryonic day 14 (E14) stomach and gradually increased during the progress of age until birth, postnatal day 1 (P1). NPW mRNA level in the stomach increased again from the weaning period (P21) until reaching adulthood. Immunohistochemistry using polyclonal antibodies raised against rat NPW revealed that NPW-positive cells were detected in the P1 antral stomach and gradually increased during the development of age. Furthermore, double immunohistochemistry demonstrated that NPW colocalized with gastrin in P1 rat stomach. These data will provide clues to physiological functions of NPW in the development of rat stomach. [Copyright &y& Elsevier]

Abstract: Ghrelin, an acylated peptide originally identified in rat stomach as the endogenous ligand for the growth hormone secretagogue receptor (GHS-R), stimulates both food intake and growth hormone (GH) secretion. Ghrelin is predominantly synthesized by a subset of endocrine cells in the oxyntic gland of human and rat stomach. Previous studies using immunohistochemistry have shown that ghrelin is also present in the hypothalamic arcuate nucleus, a region critical for the control of feeding and GH secretion, but its expression pattern in this region and the details of its molecular form has yet to be clarified. In this report, we examined the presence of ghrelin in the arcuate nucleus using reverse-phase liquid chromatography combined with radioimmunoassay (RIA) and immunohistochemistry. Neurons in the arcuate nucleus were observed to react positively to ghrelin antibodies. In addition, we confirmed the existence of ghrelin mRNA expression using the reverse-transcription polymerase chain reaction (RT–PCR). We also observed the colocalization of GHS-R with neuropeptide Y (NPY) and growth-hormone-releasing hormone (GHRH) in the arcuate nucleus. The present study clearly indicates that ghrelin is synthesized in the arcuate nucleus, which will further our understanding of ghrelin''s actions in the central nervous system, including feeding behavior and GH secretion. [Copyright &y& Elsevier]

Ghrelin, a brain-gut peptide discovered from the stomach, stimulates growth hormone release, food intake, adiposity, and weight gain. Circulating ghrelin levels are modulated under conditions of positive and negative energy balance, however its effect on macronutrient selection is not known. The present experiment investigates the effect of ghrelin on single and two-diet feeding paradigms in high-carbohydrate (HC) and high-fat (HF) preferring rats. In the macronutrient selection test in which rats were given free access to either high-carbohydrate or high-fat diet, an intracerebroventricular (i.c.v.) administration of ghrelin potently enhanced fat intake over carbohydrate intake in both HC- and HF-preferring rats. In the diet preference test in which rats were given free access to both high-carbohydrate and high-fat diets simultaneously, an i.c.v. administration of ghrelin also preferentially enhanced fat consumption over carbohydrate in both HF- and HC-preferring rats. Intracerebroventricular administrations of galanin and neuropeptide Y enhanced fat and carbohydrate ingestion, respectively. Centrally administered ghrelin enhanced fat ingestion. These results provide further insights for the role of ghrelin in feeding behavior and the development of obesity. [Copyright &y& Elsevier]

Orexins (hypocretins) and the melanin-concentrating hormone (MCH) are neuropeptides localized to the lateral hypothalamic area and are potential regulators of energy homeostasis. Using highly sensitive radioimmunoassay for orexins and MCH, we determined their contents in the lateral hypothalamus (LH) of genetically obese ob/ob and db/db mice and their controls, C57BL/6J and C57BL/KSJ. The orexin contents in the lateral hypothalamus significantly increased in the ob/ob mice, whereas the orexin contents significantly decreased in the db/db mice. Mature orexin-A and -B peptides were the major endogenous orexin molecules in the lateral hypothalamus. Conversely, the MCH contents in the lateral hypothalamus of both obese mice increased compared to the control mice. MCH contents in the lateral hypothalamus were two- to five-fold higher than that of orexin contents. These results suggest that the regulatory mechanism of orexin and MCH may be different in the genetically obese mice. [Copyright &y& Elsevier]

Examines the presence of ghrelin in pancreatic alpha cells of humans and rats. Effects of ghrelin on insulin secretion; Description of growth hormone secretagogues; Cellular source of ghrelin in rat and human pancreas.

Ghrelin is an acylated peptide that stimulates food intake and the secretion of growth hormone. While ghrelin is predominantly synthesized in a subset of endocrine cells in the oxyntic gland of the human and rat stomach, the mechanism regulating ghrelin secretion remains unknown. Somatostatin, a peptide produced in the gastric oxyntic mucosa, is known to suppress secretion of several gastrointestinal peptides in a paracrine fashion. By double immunohistochemistry, we demonstrated that somatostatin-immunoreactive cells contact ghrelin-immunoreactive cells. A single intravenous injection of somatostatin reduced the systemic plasma concentration of ghrelin in rats. Continuous infusion of somatostatin into the gastric artery of the vascularly perfused rat stomach suppressed ghrelin secretion in both dose- and time-dependent manner. These findings indicate that ghrelin secretion from the stomach is regulated by gastric somatostatin. [Copyright &y& Elsevier]

Recent advances in peptidomics have enabled the identification of previously uncharacterized peptides. However, sequence information alone does not allow us to identify candidates for bioactive peptides. To increase an opportunity to discover bio- active peptides, we have focused on C-terminal amidation, a post-translational modification shared by many bioactive peptides. We analyzed peptides secreted from human medullary thyroid carcinoma TT cells that produce amidated peptides, and we identified two novel amidated peptides, designated neuroendocrine regulatory peptide (NERP)-1 and NERP-2. NERPs are derived from distinct regions of the neurosecretory protein that was originally identified as a product of a nerve growth factor-responsive gene in PC12 cells. Mass spectrometric analysis of the immunoprecipitate using specific antibodies as well as reversed phase-high performance liquid chromatography coupled with radioimmunoassay analysis of brain extract demonstrated the endogenous presence of NERP-1 and NERP-2 in the rat. NERPs are abundant in the paraventricular and supraoptic nuclei of the rat hypothalamus and colocalized frequently with vasopressin but rarely with oxytocin. NERPs dose-dependently suppressed vasopressin release induced by intracerebroven-tricular injection of hypertonic NaCI or angiotensin II in vivo. NERPs also suppressed basal and angiotensin II-induced vasopressin secretion from hypothalamic explants in vitro. Bioactivity of NERPs required C-terminal amidation. Anti-NERP IgGs canceled plasma vasopressin reduction in response to water loading, indicating that NERPs could be potent endogenous suppressors of vasopressin release. These findings suggest that NERPs are novel modulators in body fluid homeostasis. [ABSTRACT FROM AUTHOR]

Obestatin is a 23-amino acid peptide, initially isolated from rat stomach as an endogenous ligand for the orphan G-protein-coupled receptor. Obestatin is derived from proteolytic cleavage of a 117-amino acid precursor, preproghrelin. Ghrelin increases food intake, body weight, and gastric emptying, whereas obestatin has the opposite effects. In this study, we characterized obestatin in both rat and human stomach, and investigated the peptide's effect on feeding behavior. Using reversed-phase high-performance liquid chromatography coupled with RIAs specific for rat and human obestatin, we detected a very small amount of obestatin, compared with ghrelin, in the gastric fundi. The ratios of obestatin to ghrelin are 0.0039 and 1.94% respectively in the rat and human gastric fundi. In humans, plasma obestatin accounted for 5.21% of the ghrelin concentration, whereas it was undetectable in rat plasma. Plasma ghrelin concentration decreased after a meal in normal subjects, whereas obestatin concentration did not change. When administered centrally or peripherally, obestatin did not suppress food intake in either free-feeding or fasted rodents. Administration of obestatin did not antagonize ghrelin-induced feeding. These findings indicate that obestatin is present at very low levels compared with ghrelin in both rat and human, and has no acute effect on feeding behavior.

Age-related decreases in energy expenditure have been associated with the loss of skeletal muscle and decline of food intake, possibly through a mechanism involving changes of growth hormone (GH) secretion and feeding behavior. Age-related declines of growth hormone secretion and food intake have been termed the somatopause and anorexia of ageing, respectively. Ghrelin, a 28-amino-acid peptide, was isolated from human and rat stomachs as an endogenous ligand of growth hormone secretagogue receptor. Ghrelin stimulates growth hormone release and food intake when peripherally administered to rodents and humans. Here, we investigate the relationship between age-related decline of growth hormone secretion and/or food intake and ghrelin function. Ghrelin (10 nmol/kg body weight) was administered intravenously to male 3-, 12-, 24-and 27-month-old Long-Evans rats, after which growth hormone concentrations and 2 h food intake were measured. An intravenous administration of ghrelin to rats increased food intake in all generations. In addition, to orexigenic effect by ghrelin, intravenous administration of ghrelin elicited a marked increase in plasma GH levels, with the peak occurring 15 min after administration. These findings suggest that the aged rats maintain the reactivity to administered exogenous ghrelin.