Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Orexin-A and -B are neuropeptides that are implicated in the regulation of vigilance states and energy homeostasis. Orexins are specifically produced by neurons located within the lateral hypothalamic area (LHA), a region implicated in the regulation of feeding behavior. Here, we examined the functional interactions between orexins and anorectic factors [leptin, alpha-melanocyte-stimulating hormone (alpha-MSH) and glucagon-like peptide-1 (GLP-1)] in rats. Intracerebroventricular injection of orexin-A (10 nmol) potently augmented food intake in rats. Neuropeptide Y (NPY) (0.3 nmol) and galanin (3 nmol) also induced a transient increase in food intake. Both NPY- and galanin-induced feeding behaviors were completely inhibited by preadministration of leptin (3 microg), while the same or a higher dose (10 microg) of leptin only partially inhibited orexin-A or -B-induced increase of food intake. Preadministration of anorectic peptides (alpha-MSH and GLP-1), which are shown to be regulated by leptin, abolished NPY-induced feeding; however, orexin-induced feeding was only partially inhibited by these anorectic peptides. These observations suggest that NPY- and galanin-induced increases of feeding involve a leptin-sensitive pathway, while orexin-induced feeding involves both leptin-sensitive and -insensitive pathways.
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PMID:Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive pathways. 1241 1

Orexins (hypocretins) are novel neuropeptides that appear to play a role in the regulation of energy balances. Orexin-A (OXA) increases food intake in rodents, and fasting activates OXA neurons in both the lateral hypothalamic area and gut. OXA is also found in the endocrine pancreas; however, little is known about its release or functional significance. In this study, we show that depolarizing stimuli evoke the release of OXA from rat pancreatic islets in a calcium-dependent manner. Moreover, OXA release is stimulated by low glucose (2.8 mmol/l), similar to glucagon secretion, and inhibited by high glucose (16.7 mmol/l). Fasting increases plasma OXA, supporting the idea that orexin is released in response to hypoglycemia. Cells that secrete glucagon and insulin contain OXA and both cell types express orexin receptors. OXA increases glucagon secretion and decreases glucose-stimulated insulin release from isolated islets. OXA infusion increases plasma glucagon and glucose levels and decreases plasma insulin in fasted rats. We conclude that orexin-containing islet cells, like those in the brain and gut, are glucosensitive and part of a network of glucose "sensing" cells that becomes activated when blood glucose levels fall. OXA may modulate islet hormone secretion to maintain blood glucose levels during fasting.
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PMID:Glucose regulates the release of orexin-a from the endocrine pancreas. 1250

Orexin A (OXA) is found in the central nervous system (CNS) and in the gut. Peripheral administration of OXA to rats results in an inhibition of fasting motility. Plasma OXA increases during fasting and central administration of OXA increases food intake. The aim of the present study was to assess the pharmacokinetic profile of OXA and the effect of intravenously (i.v.) administered OXA on plasma concentrations of insulin and glucagon concentrations. Rats were given OXA i.v. (100 pmol kg(-1) min(-1)) for time periods of 0, 10, 20, 30 min and for 10, 20, 30 min after ceasing a 30-min infusion. After each time period, rats were then sacrificed and blood obtained. OXA was also administered at increasing doses (0, 100, 300 and 500 pmol kg(-1) min(-1)) for 30 min and blood was obtained. Plasma OXA, insulin and glucagon levels were measured using commercially available radioimmunoassay (RIA) kits. The plasma half-life of OXA was 27.1+/-9.5 min. Stepwise increasing infusion rates of OXA confirmed a linear concentration-time curve and thus first-order kinetics. Its volume of distribution indicated no binding to peripheral tissues. Plasma glucagon decreased during infusion of OXA, while insulin was unaffected. Plasma OXA was raised fourfold after food intake. Thus, OXA has a longer plasma half-life than many other peptides found in the gut. This needs to be taken into account when assessing effects of OXA on biological parameters after peripheral administration.
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PMID:Pharmacokinetic profile of orexin A and effects on plasma insulin and glucagon in the rat. 1512 Apr 82

Orexin-expressing neurons in the hypothalamus project throughout the neuraxis and are involved in regulation of the sleep/wake cycle, food intake, and autonomic functions. Here we specifically analyze the anatomical organization of orexin projections to the dorsal vagal complex (DVC) and raphe pallidus and effects on ingestive behavior and autonomic functions of local orexin-A administration in nonanesthetized rats. Retrograde tracing experiments revealed that as many as 20% of hypothalamic orexin neurons project to the DVC, where they form straight varicose axon profiles, some of which are in close anatomical apposition with tyrosine hydroxylase (TH)-, glucagon-like peptide-1-, gamma-aminobutyric acid-, and nitric oxide synthase-immunoreactive neurons in a nonselective manner. Similar contacts were frequently observed with neurons of the nucleus of the solitary tract whose activation by gastrointestinal food stimuli was demonstrated by the expression of nuclear c-Fos immunoreactivity. Orexin-A administration to the fourth ventricle induced significant Fos-expression throughout the DVC compared with saline control injections, with about 20-25% of TH-ir neurons among the stimulated ones. Fourth ventricular orexin injections also significantly stimulated chow and water intake in nonfood-deprived rats. Direct bilateral injections of orexin into the DVC increased intake of palatable high-fat pellets. Orexin-ir fibers also innervated raphe pallidus. Fourth ventricular orexin-A (1 nmol) activated Fos expression in the raphe pallidus and C1/A1 catecholaminergic neurons in the ventral medulla and increased body temperature, heart rate, and locomotor activity. The results confirm that hypothalamomedullary orexin projections are involved in a variety of physiological functions, including ingestive behavior and sympathetic outflow.
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PMID:Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function. 1577 47

Orexin A (OXA) increases food intake and inhibits fasting small bowel motility in rats. The aim of this study was to examine the effect of exogenous OXA and endogenous OXA on gastric emptying, acid secretion, glucose metabolism and distribution of orexin immunoreactivity in the stomach. Rats equipped with a gastric fistula were subjected to intravenous (IV) infusion of OXA or the selective orexin-1 receptor (OX1R) antagonist SB-334867-A during saline or pentagastrin infusion. Gastric emptying was studied with a liquid non-nutrient or nutrient, using 51Cr as radioactive marker. Gastric retention was measured after a 20-min infusion of OXA or SB-334867-A. Plasma concentrations of OXA, insulin, glucagon, glucose and gastrin were studied. Immunohistochemistry against OXA, OX1R and gastrin in gastric tissue was performed. OXA alone had no effect on either acid secretion or gastric emptying. SB-334867-A inhibited both basal and pentagastrin-induced gastric acid secretion and increased gastric retention of the liquid nutrient, but not PEG 4000. Plasma gastrin levels were unchanged by IV OXA or SB-334867-A. Plasma OXA levels decreased after intake of the nutrient meal and infusion of the OX1R antagonist. Only weak effects were seen on plasma glucose and insulin by OXA. Immunoreactivity to OXA and OX1R were found in the mucosa, myenteric cells bodies and varicose nerve fibers in ganglia and circular muscle of the stomach. In conclusion, endogenous OXA influences gastric emptying of a nutrient liquid and gastric acid secretion independent of gastrin. This indicates a role for endogenous OXA, not only in metabolic homeostasis, but also in the pre-absorptive processing of nutrients in the gut.
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PMID:Stimulatory effect of endogenous orexin A on gastric emptying and acid secretion independent of gastrin. 1612 3

A CNS component of glucose counterregulatory collapse is supported by evidence for nonuniform genomic responsiveness of neurons in characterized central autonomic loci during recurring insulin-induced hypoglycemia (IIH). We have reported that exacerbated hypoglycemia and attenuated patterns of glucagon and epinephrine secretion in rats treated by daily sc injection of the intermediate-acting insulin formulation, Humulin NPH (NPH), are correlated with diminished immunodemonstrability of the AP-1 transcription factor, Fos, in several components of the central metabolic regulatory circuitry, including the lateral hypothalamic area (LHA). Neurons that synthesize the potent orexigenic peptide neurotransmitter, orexin-A, are restricted to the LHA and adjacent hypothalamic loci, and project throughout the central neuroaxis to structures that govern autonomic and behavioral motor output. Dual-label immunocytochemical and real-time RT-PCR techniques were utilized here to evaluate the functional status of this LHA phenotype during a single versus repetitive exposure to prolonged IIH. Tissue sections were collected at predetermined rostrocaudal levels of the LHA after acute or repeated NPH administration, and processed for nuclear Fos- and cytoplasmic orexin-A-immunoreactivity (-ir). Mean numbers of orexin-A-ir neurons were not different between treatment groups. Colabeling of these cells for Fos was increased relative to controls following a single injection of insulin, but numbers of Fos-ir-positive orexin-A neurons were significantly reduced after treatment with four versus one dose of insulin. Prepro-orexin mRNA levels in microdissected LHA tissue were upregulated during acute hypoglycemia, but were returned to control levels by repeated IIH. These data corroborate previous evidence that IIH is an activational stimulus for orexin-A-synthesizing neurons in the LHA, and further demonstrate that induction of cfos and prepro-orexin gene expression by acute hypoglycemia is attenuated by precedent exposure to hypoglycemia. The current results thus provide unique evidence for neurotransmitter-specific habituation of LHA neuronal sensitivity to IIH.
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PMID:Habituation of insulin-induced hypoglycemic transcription activation of lateral hypothalamic orexin-A-containing neurons to recurring exposure. 1667 83

The potent orexigenic neuropeptide, orexin-A (ORX-A), acts at multiple sites within the central neuroaxis to control autonomic responses to energy imbalance, including the dorsal vagal motor nucleus (DMV), where it regulates pancreatic efferent nerve firing. Recent evidence that recurrent insulin-induced hypoglycemia (RIIH) attenuates lateral hypothalamic ORX-A-ergic neuronal transcriptional activation and prepro-orexin gene expression suggests that this phenotype undergoes functional adaptation to repeated glucoprivation. We examined the hypothesis that RIIH-associated patterns of ORX-A neurotransmission and/or orexin-receptor-1 (OR-1) expression within the DMV may be correlated with exacerbated hypoglycemic and impaired pancreatic counterregulatory responses to repeated insulin administration. Male rats were pretreated by bilateral intra-DMV infusion of the OR-1 antagonist, SB-334867, or vehicle prior to s.c. injection of Humulin NPH (NPH), or diluent alone. Other animals were injected with one or four doses of NPH, on as many days, or diluent alone, and pretreated by bilateral intra-DMV administration of graded doses of ORX-A or vehicle on the final day of the study. Effects of acute versus repeated insulin administration on ORX-A and OR-1 protein levels in the microdissected dorsal vagal complex (DVC) were evaluated by radioimmunoassay and Western blot analyses, respectively. SB-334867 treatment prior to acute NPH administration decreased plasma glucose and suppressed peak glucagon secretion, whereas exogenous ORX-A administration prior to RIIH did not reverse amplified patterns of hypoglycemia. RIIH did not alter intra-DVC ORX-A tissue concentrations, but diminished OR-1 levels in that site. These results show that DMV OR-1 function is critical for optimal glucagon secretory responsiveness to acute hypoglycemia, and that RIIH-associated downregulation of receptor expression in that brain site may contribute to impaired restoration of euglycemia. The current data provide unique evidence that ORX-A acts via OR-1-dependent mechanisms within DMV to regulate glucagon counterregulatory function during hypoglycemia, and that decreased receptor-mediated signaling during RIIH may underlie characteristic intensification of hypoglycemia.
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PMID:Role of dorsal vagal motor nucleus orexin-receptor-1 in glycemic responses to acute versus repeated insulin administration. 1727 8

Orexin-A (OXA) regulates food intake and energy homeostasis. It increases insulin secretion in vivo and in vitro, although controversial effects of OXA on plasma glucagon are reported. We characterized the effects of OXA on glucagon secretion and identify intracellular target molecules in glucagon-producing cells. Glucagon secretion from in situ perfused rat pancreas, isolated rat pancreatic islets, and clonal pancreatic A-cells (InR1-G9) were measured by RIA. The expression of orexin receptor 1 (OXR1) was detected by Western blot and immunofluorescence. The effects of OXA on cAMP, adenylate-cyclase-kinase (AKT), phosphoinositide-dependent kinase (PDK)-1, forkhead box O-1 (Foxo1), and cAMP response element-binding protein were measured by ELISA and Western blot. Intracellular calcium (Ca(2+)(i)) concentration was detected by fura-2and glucagon expression by real-time PCR. Foxo1 was silenced in InR1-G9 cells by transfecting cells with short interfering RNA. OXR1 was expressed on pancreatic A and InR1-G9 cells. OXA reduced glucagon secretion from perfused rat pancreas, isolated rat pancreatic islets, and InR1-G9 cells. OXA inhibited proglucagon gene expression via the phosphatidylinositol 3-kinase-dependent pathway. OXA decreased cAMP and Ca(2+)(i) concentration and increased AKT, PDK-1, and Foxo1 phosphorylation. Silencing of Foxo1 caused a reversal of the inhibitory effect of OXA on proglucagon gene expression. Our study provides the first in vitro evidence for the interaction of OXA with pancreatic A cells. OXA inhibits glucagon secretion and reduces intracellular cAMP and Ca(2+)(i) concentration. OXA increases AKT/PDK-1 phosphorylation and inhibits proglucagon expression via phosphatidylinositol 3-kinase- and Foxo-1-dependent pathways. As a physiological inhibitor of glucagon secretion, OXA may have a therapeutic potential to reduce hyperglucagonemia in type 2 diabetes.
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PMID:Orexin-A inhibits glucagon secretion and gene expression through a Foxo1-dependent pathway. 1816 14

In 1998, Orexin A was added to the long list of orexigenic neuropeptides of the brain's physiology. Orexin A is involved in the central control of appetite and in energy homeostasis, as well as in the regulation of many other physiological functions. It is produced by a small cluster of the brain's neurons, located mainly in and around the lateral hypothalamic area. This site is known to be involved in regulating feeding in mammals. An intracerebroventricular injection of Orexin A into the rat's brain causes an impressive increase in the consumption of food, while an intravenous injection induces changes on glucagon plasma concentrations in rats. In addition, there are signs of changes on glucagon plasma concentrations when Orexin A acts on individual pancreatic islets of rats. In this study, we investigated the potential effects of the central administration of porcine Orexin A on glucagon plasma concentrations in pigs, and examined whether these changes are associated with the possible effect of the neuropeptide on the enteroinsular axis.
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PMID:Impact of porcine Orexin A on glucagon plasma concentrations in pigs. 1883 20

Several pieces of evidence support that sleep duration plays a role in body weight control. Nevertheless, it has been assumed that, after the identification of orexins (hypocretins), the molecular basis of the interaction between sleep and energy homeostasis has been provided. However, no study has verified the relationship between neuropeptide Y (NPY) and orexin changes during hyperphagia induced by sleep deprivation. In the current study we aimed to establish the time course of changes in metabolite, endocrine, and hypothalamic neuropeptide expression of Wistar rats sleep deprived by the platform method for a distinct period (from 24 to 96 h) or sleep restricted for 21 days (SR-21d). Despite changes in the stress hormones, we found no changes in food intake and body weight in the SR-21d group. However, sleep-deprived rats had a 25-35% increase in their food intake from 72 h accompanied by slight weight loss. Such changes were associated with increased hypothalamus mRNA levels of prepro-orexin (PPO) at 24 h followed by NPY at 48 h of sleep deprivation. Conversely, sleep recovery reduced the expression of both PPO and NPY, which rapidly brought the animals to a hypophagic condition. Our data also support that sleep deprivation rapidly increases energy expenditure and therefore leads to a negative energy balance and a reduction in liver glycogen and serum triacylglycerol levels despite the hyperphagia. Interestingly, such changes were associated with increased serum levels of glucagon, corticosterone, and norepinephrine, but no effects on leptin, insulin, or ghrelin were observed. In conclusion, orexin activation accounts for the myriad changes induced by sleep deprivation, especially the hyperphagia induced under stress and a negative energy balance.
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PMID:Orexin activation precedes increased NPY expression, hyperphagia, and metabolic changes in response to sleep deprivation. 2005 29


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