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Query: UNIPROT:P06889 (Mol)
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In general, a fish's ability to clear glucose is sluggish in relation to mammals, which has lead to the idea that fish are glucose intolerant. It has been reported that circulating glucose levels do fluctuate in response to environmental challenges. Recent reports suggest that glucose may function as a metabolic signal regulating 'glucosensors' in the brain in fish, as has been reported in mammals. The current study was designed to investigate the effect of glucose on ghrelin and neuropeptide Y (NPY) signaling in the brain, and on the growth hormone/insulin-like growth factor-I (GH/IGF-I) in the tilapia, Oreochromis mossambicus. Glucose treatment significantly increased plasma and stomach mRNA levels of ghrelin. In the brain, mRNA levels of the ghrelin receptor (GRLN-R) were significantly reduced, whereas NPY mRNA levels were significantly elevated; suggesting that NPY containing neurons may be a "glucosensor" as reported in mammals. Glucose treatment resulted in changes in the GH/IGF-I axis. Liver mRNA levels of both GH receptors (GHR1 and GHR2) were significantly elevated, whereas liver IGF-I mRNA were unaltered by glucose treatment. No change in plasma or pituitary mRNA levels of GH was observed. Glucose significantly reduced plasma IGF-I levels. These data show that glucose regulates endocrine factors involved in appetite, growth, and possibly energy homeostasis, and suggests that glucose may be acting as a signal of metabolic status in fish.
Comp Biochem Physiol A Mol Integr Physiol 2009 Dec
PMID:Glucose regulates ghrelin, neuropeptide Y, and the GH/IGF-I axis in the tilapia, Oreochromis mossambicus. 1973 36

This study recorded acute biochemical and subjective measures of satiety, followed by energy intake from a subsequent meal, after varying doses of beta-glucan in extruded breakfast cereals. Molecular weight, solubility and viscosity of beta-glucan products were determined. Seven male and seven female subjects (BMI 25-36 kg/m) consumed five breakfasts (different doses of beta-glucan sourced from two different technological processes) and dietary intake was measured after four hours. Blood was collected to measure glucose, insulin, ghrelin and cholecystokinin, and visual analogue scales measured subjective satiety. Molecular weight, solubility and viscosity indicated products were likely to increase luminal viscosity. beta-Glucan was found to decrease insulin secretion over 2 h (RMANOVA, p = 0.011) in a dose responsive manner from 2.16 to 5.68 g per serving (p = 0.007). Cholecystokinin levels increased linearly over the same range of beta-glucan concentrations (p = 0.002) in women. Subjective satiety was increased at a beta-glucan dose of 2.2 g (p = 0.039). Subsequent meal intake decreased by greater than 400 kJ with higher beta-glucan dose (>5 g). beta-Glucan improves satiety and release of cholecystokinin is likely to be part of the mechanism. Products with different sources of beta-glucan provide similar benefits but each product requires individual testing.
Mol Nutr Food Res 2009 Oct
PMID:Oat beta-glucan increases postprandial cholecystokinin levels, decreases insulin response and extends subjective satiety in overweight subjects. 1975 1

In the terrorist radiation exposure scenario, radiation victims are likely to suffer from additional injuries such as sepsis. Our previous studies have shown that ghrelin is protective in sepsis. However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure. The purpose of this study is to determine whether human ghrelin attenuates organ injury and improves survival in a rat model of radiation combined injury (RCI) and, if so, the potential mechanism responsible for the benefit. To study this, adult male rats were exposed to 5-Gy whole body irradiation followed by cecal ligation and puncture (CLP, a model of sepsis) 48 h thereafter. Human ghrelin (30 nmol/rat) or vehicle (saline) was infused intravenously via an osmotic minipump immediately after radiation exposure. Blood and tissue samples were collected at 20 h after RCI (68 h after irradiation or 20 h after CLP) for various measurements. To determine the longterm effect of human ghrelin after RCI, the gangrenous cecum was removed at 5 h after CLP and 10-d survival was recorded. In addition, vagotomy or sham vagotomy was performed in sham and RCI animals immediately prior to ghrelin administration, and various measurements were performed at 20 h after RCI. Our results showed that serum levels of ghrelin and its gene expression in the stomach were decreased markedly at 20 h after RCI. Administration of human ghrelin attenuated tissue injury markedly, reduced proinflammatory cytokine levels, decreased tissue myeloperoxidase activity, and improved survival after RCI. Furthermore, elevated plasma levels of norepinephrine (NE) after RCI were reduced significantly by ghrelin. However, vagotomy prevented ghrelin's beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to re-balancing the dysregulated sympathetic/parasympathetic nervous systems.
Mol Med
PMID:Human ghrelin ameliorates organ injury and improves survival after radiation injury combined with severe sepsis. 1977 31

Three homology models of the human ghrelin receptor (GHS-R1a) have been generated from the available X-ray structures of rhodopsin (RHO model), opsin (OPS model) and beta-2 adrenergic receptor (B2 model). The latter was used as a starting point for combined molecular dynamics simulation (MDS) and full atom normal modes analysis (NMA). A low-frequency normal mode (mode 16) perfectly reproduced the intracellular motions observed between B2 and RHO models; in the opposite direction along the same mode, the generated structures are closer to the OPS model, suggesting a direct link with GHS-R1a activation. This was in agreement with motions of the seven transmembranous segments, increase of the solvent accessibility of the 140-ERY-142 sequence, and flip of the Trp276 (C WLP) residue, some features related to GPCRs activation. According to our model, His280 was proposed to stabilize Trp276 in the active state; this was verified by site-directed mutagenesis and biochemical characterization of the resulting H280A and H280S mutants, which were fully functional but sharing an important decrease of their basal activities. Docking performed with short ghrelin derivatives Gly-Ser-Ser ([octa])-Phe-NH (2) and Gly-Ser-Ser ([octa])-Phe-Leu-NH (2) allowed the identification of a robust position of these peptides in the active site of the receptor. This model was refined by MDS and validated by docking experiments performed on a set of 55 ghrelin receptor ligands based on the 1,2,4- triazole scaffold. Finally, NMA performed on the obtained peptide-receptor complex suggested stabilization of the Trp276 residue and of the whole receptor in the active state, preventing the motion observed along mode 16 computed for the unbound receptor. Our results show that NMA offers a powerful approach to study the conformational diversity and the activation mechanism of GPCRs.
J Mol Biol 2010 Jan 29
PMID:Activation of the ghrelin receptor is described by a privileged collective motion: a model for constitutive and agonist-induced activation of a sub-class A G-protein coupled receptor (GPCR). 1978 90

Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor. It plays an important role in stimulating growth hormone secretion, food intake, body weight gain and gastric motility. cDNA sequences coding for ghrelin precursor protein (prepro-ghrelin) were isolated from the stomach of a giant panda. Two different mRNA sequences of ghrelin were obtained. The long open reading frame of ghrelin (354 bp) encodes a precursor protein of 117 amino acids with a 23 amino acid signal peptide. The short one (351 bp) encodes a precursor protein of 116 amino acids with the same 23 amino acid signal peptide. The presumed giant panda mature ghrelin proteins also had two forms. Comparative analysis showed that the first and the fourth amino acids (Gly and Phe) were completely conserved and the third amino acid (Ser) was also highly conserved in the mature ghrelin. RT-PCR analysis of giant panda ghrelin mRNA in various tissues revealed high level of expression in stomach, relative lower levels of expression in small intestine, liver and kidney, and no expression in thymus, spleen and heart.
Mol Biol Rep 2010 Jul
PMID:cDNA cloning and expression of ghrelin in giant panda (Ailuropoda melanoleuca). 1982 Oct 57

Ghrelin is a peptide hormone, which has been isolated from the stomach. It is localized mostly in endocrine cells in the oxyntic mucosa of the stomach. Ghrelin receptors are expressed equally in all parts of the gastrointestinal tract, with a similar level of expression in the mucosal and muscle layers. This peptide hormone has several functions, the most widely known is its growth hormone (GH)-releasing effect. Ghrelin plays an important role in regulating appetite, feeding and energy metabolism. It also plays a role in mediating immune response and inflammatory processes. Ghrelin stimulates gastric motility and emptying as well as motility in the small and large intestine. Ghrelin has been reported to be affected in several gastrointestinal diseases/disorders such as inflammatory bowel disease, coeliac disease, infectious diseases, functional disorders and diabetes gastroenteropathy. This indicates that ghrelin is involved in the pathophysiology of gastrointestinal diseases/disorders. Several studies have shown that ghrelin and its antagonist are a promising tool for treatment of several gastrointestinal diseases/disorders.
Int J Mol Med 2009 Dec
PMID:Ghrelin in gastrointestinal diseases and disorders: a possible role in the pathophysiology and clinical implications (review). 1988 11

Hepatocellular dysfunction occurs early in sepsis and this appears to be caused by Kupffer cell-derived TNF-alpha production from the liver as a result of the increased release of the sympathetic neurotransmitter, norepinephrine, from the gut. Ghrelin, a novel stomach-derived peptide, is down-regulated in sepsis and administration of ghrelin into rodents decrease pro-inflammatory cytokines, attenuates hepatic and other organ injuries and improves survival. Ghrelin's beneficial effect in sepsis is mediated by the inhibition of the sympathetic nervous system (SNS), as evidenced by the reduced gut-derived norepineprine (NE) release in sepsis after ghrelin treatment. Recent data suggest that MKP-1, the MAPK phosphatase-1, is involved in the innate immune responses. To determine that the beneficial effect of ghrelin in sepsis is mediated by MKP-1, rats were subjected to sepsis by cecal ligation and puncture (CLP) alone, or treated with ghrelin, beginning at 5-h post-CLP and liver tissues were harvested and examined for MKP-1 mRNA and protein expression. CLP alone produced a significant decrease in MKP-1 gene expression in liver tissues at 20 h after CLP (P<0.05). MKP-1 mRNA was decreased by 30-40% at 2 and 5 h after CLP, but not statistically significant. MKP-1 protein expression was significantly decreased as early as 2 h after CLP and remained low at 5-20 h after CLP. While septic rats treated with vehicle produced significant decreases from sham rats, ghrelin treatment improved both mRNA and protein from vehicle group (0.58+/-0.069 vs. 0.91+/-0.16, P<0.05; 0.14+/-0.027 vs. 0.22+/-0.017, P=0.013), respectively. Since ghrelin's inhibitory effect is mediated by the SNS, we hypothesized that NE treatment in Kupffer cells may downregulate MKP-1. Kupffer cells were treated with NE and examined for MKP-1. Treatment with NE for 60 min showed an average of 46.9% decrease in MKP-1 mRNA expression compared to untreated cells (P<0.001). Likewise, NE treatment in RAW264.7 cells produced significantly lower MKP-1 mRNA than that of control cells. To further confirm the effect of NE on MKP-1, normal rats were infused with NE for 2 h through the portal vein and MKP-1 mRNA from the liver was examined. Infusion with NE produced a significant 73.7% decrease in MKP-1 mRNA. Therefore, ghrelin's inhibitory effect on gut-derived NE release in sepsis leading to the downregulation of pro-inflammatory cytokines is mediated by MKP-1.
Int J Mol Med 2010 Jan
PMID:The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1. 1995 15

Nkx2.2 is an essential regulator of pancreatic endocrine differentiation. Nkx2.2-null mice are completely devoid of beta-ells and have a large reduction of alpha- and PP cells. In the place of these islet populations, there is a corresponding increase in the ghrelin-positive epsilon-cells. Molecular studies have indicated that Nkx2.2 functions as an activator and repressor to regulate islet cell fate decisions. To determine whether Nkx2.2 is solely important for islet cell fate decisions or also has the capability to control ghrelin at the promoter level, we studied the transcriptional regulation of the ghrelin promoter within the pancreas, in vitro and in vivo. These studies demonstrate that both of the previously identified transcriptional start sites in the ghrelin promoter are active within the embryonic pancreas; however, the long transcript is preferentially up-regulated in the Nkx2.2-null pancreas. We also show that the promoter region between -619 and -488 bp upstream of the translational start site is necessary for repression of ghrelin in alphaTC1 and betaTC6 cells. Surprisingly, we also show that Nkx2.2 is able to bind to and activate the ghrelin promoter in several cell lines that do or do not express endogenous ghrelin. Together, these results suggest that the up-regulation of ghrelin expression in the Nkx2.2-null mice is not due to loss of repression of the ghrelin promoter in the nonghrelin islet populations. Furthermore, Nkx2.2 may contribute to the activation of ghrelin in mature islet epsilon-cells.
Mol Endocrinol 2010 Feb
PMID:Nkx2.2 activates the ghrelin promoter in pancreatic islet cells. 1996 28

During the two past decades tremendous effort has been put into uncovering the activation mechanism of 7TM receptors. The majority of such studies have focused on the major binding pocket, comprised of transmembrane segments (TM) -III through -VII, as most non-peptide and peptide ligands, in addition to biogenic amines and retinal a.m.o. bind to residues in this region. Consequently the major helical movements occur here during activation, as described recently in the Global Toggle Switch Model for Family A (also known as rhodopsin-like) members of the 7TM receptors. As a result, the minor binding pocket, comprised of TM-I, -II and, in part, -III and -VII, has received much less attention. With a few exceptions, such as the highly conserved Asp in position II:10/2.50, the residues in this region have generally been considered insignificant with regard to receptor activation. However, accumulating evidence emphasize that this is not the case. In this review, we focus on TM-II with an emphasis on position II:20/2.60, and present data from structure-activity studies on a range of Family A 7TM receptors including chemokine, ghrelin and melanocortin receptors in addition to the orphan EBI2 suggesting that TM-II has important functions for both ligand-dependent and -independent activation of 7TM receptors.
Curr Mol Pharmacol 2009 Jun
PMID:The role of transmembrane segment II in 7TM receptor activation. 2002 54

Puberty, as the end-point of a complex series of maturational events affecting the components of the hypothalamic-pituitary-gonadal (HPG) axis, is gated by the state of body energy reserves and sensitive to different metabolic cues; conditions of severe metabolic stress and energy unbalance (from anorexia to morbid obesity) being commonly linked to perturbation of the onset of puberty. In the last two decades, the neuroendocrine mechanisms responsible for the tight coupling between energy homeostasis and puberty onset have begun to be deciphered. These seemingly involve a plethora of metabolic hormones and neuropeptides, which impinge and integrate (mostly) at the hypothalamic centers governing reproduction. Yet, characterization of the mechanisms of action of such regulators (and even their nature and physiological relevance) still remains incomplete. In this review, we will summarize some recent developments in our knowledge of the effects and mechanisms of action of two key metabolic hormones, leptin and ghrelin, in the control of puberty onset. In addition, the roles of the hypothalamic Kiss1 system in the metabolic gating of puberty will be reviewed, with special attention to its regulation by leptin and the recent identification of the putative roles of Crtc1 and mTOR signaling as molecular conduits for the metabolic control of Kiss1 expression. Elucidation of these novel players and regulatory mechanisms will help for a better understanding of the determinants of the timing of puberty, and its eventual alterations in adverse metabolic conditions.
Mol Cell Endocrinol 2010 Aug 05
PMID:Metabolic control of puberty onset: new players, new mechanisms. 2002 41


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