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Obestatin
A New Physiological Opponent of Ghrelin

ghrelin-motilin

The ghrelin-motilin receptor family and their ligands. Each of these gastrointestinal hormones acts on a specific G protein-coupled receptor from the same family to affect food intake and gastrointestinal motility (9-11). Similar dual effects on satiety and gastrointestinal motility are known for glucagon-like peptide 1, cholecystokinine, or peptide YY. Collectively, these peptides may serve to couple meal termination with inhibition of upper gastrointestinal function to prevent ma labsorption and postprandial metabolic disturbances (1, 2, 8).

Ruben Nogueiras and Matthias Tschöp. Science, Vol 310, Issue 5750, 985-986 , 11 November 2005

The ghrelin receptor family

Obestatin/ghrelin ratio: A new activity index in inflammatory bowel diseases.

BACKGROUND:: The aim was to determine obestatin and ghrelin serum levels and their ratio in inflammatory bowel disease (IBD) patients. METHODS:: We measured the ghrelin and obestatin levels of 31 Crohn's disease patients and 22 patients with ulcerative colitis using a radioimmunoassay method. Circulating levels of the 2 hormones and their ratio were correlated with the disease type and activity, disease localization, and treatment. RESULTS:: The mean ghrelin value was statistically significantly higher in patients with active disease (402.4 +/- 462.6 pg/mL) than in patients in remission (148.2 +/- 59.6 pg/mL) P = 0.0290, alpha = 0.05, whereas obestatin mean values were not (217.4 +/- 59.8 pg/mL in active disease and 189.0 +/- 46.8 pg/mL in patients with inactive disease P = 0.0607). When we evaluated the obestatin/ghrelin ratio between active and inactive disease, it was found that the ratio in active disease was statistically significantly lower (0.8 +/- 0.3) than in patients in remission (1.4 +/- 0.3) P < 0.001, alpha = 0.05. There is also a statistically significantly correlation between obestatin/ghrelin ratio and disease activity (P < 0,001). CONCLUSIONS:: Ghrelin and obestatin seem to play a significant role in IBD pathogenesis. Further studies are needed to elucidate the role of these hormones as new biological markers of activity of IBD. Inflamm Bowel Dis 2009.

Alexandridis et al. Inflamm Bowel Dis. 2009 Apr 30. [Epub ahead of print]

Circulating obestatin levels in normal subjects and in patients with impaired glucose regulation and type 2 diabetes mellitus

Background Obestatin is a novel hormone that is encoded by the Ghrelin gene and produced in the gut. Ghrelin is profoundly orexogenic and adipogenic, increasing food intake and body weight. This new ghrelin-associated peptide behaves as a physiological opponent of ghrelin in rodent animals, but its pathophysiological role in humans remains unknown Objective In this study we investigate whether plasma obestatin level is different in patients with impaired glucose regulation (IGR) and type 2 diabetes mellitus (T2DM). Patients and measurements Forty-seven patients with T2DMu, 30 subjects with IGR, and 38 sex- and age-matched normal controls participated in the study. Plasma obestatin levels were measured with a radioimmunoassay (Phoenix Pharmaceuticals, Inc.). The relationship between plasma obestatin levels and anthropometric and metabolic parameters was also analysed. Results Plasma obestatin levels were lower in patients with T2DM and IGR than in controls (37.5 +/- 9.2 ng/l and 39.2 +/- 9.7 ng/l vs. 43.8 +/- 8.0 ng/l, P = 0.002 and P = 0.039, respectively). Decreasing concentrations of obestatin were independently and significantly associated with IGR and T2DM. Multiple logistic regression analysis revealed obestatin to be independently associated with IGR and T2DM. In a multiple linear regression analysis, only waist-to-hip ratio and homeostasis model assessment of insulin resistance (HOMA-IR) were independently associated with plasma obestatin level. Conclusion Our results suggest that obestatin may play a role in appetite regulation in patients with IGR and T2DM.

Qi X, Li L, Yang G, Liu J, Li K, Tang Y, Liou H, Boden G. Clin Endocrinol (Oxf). 2007 Apr;66(4):593-7

Circulating Preprandial Ghrelin to Obestatin Ratio Is Increased in Human Obesity

Context: Obestatin, a sibling of ghrelin derived from preproghrelin, opposes the ghrelin's effects on food intake. Plasma obestatin profiles in relation to ghrelin have not been fully investigated in human obesity. Objective: We hypothesize that obesity might present with imbalance of circulating ghrelin and obestatin levels. Setting: In-patient department of Changhai Hospital, Shanghai, China. Participants: Sixteen obese (8 men, aged 58.8+/-4.9; 8 women, aged 59.9+/-9.6) and fourteen normal weight individuals (7 men, aged 52.7+/-5.9; 7 women, aged 56.1+/-4.9). Main Outcome Measures: Total plasma ghrelin and obestatin levels, one hour before and two hours after breakfast, were measured by radioimmunoassay [from Phoenix Biotech (Beijing)]. Results: Both preprandial plasma ghrelin levels (P < 0.01) and obestatin levels (P < 0.01) were lower in the obese compared with normal weight controls. However, unexpectedly, the ratio of preprandial ghrelin to obestatin was higher in obese compared with normal weight controls (P < 0.01) even after adjustment for gender and age (P < 0.01). The ratio of postprandial ghrelin to obestatin was decreased both in obese (P < 0.05) and controls (P < 0.01) compared with their preprandial levels. There were no significant differences in the ratio of postprandial ghrelin to obestatin between obese and normal weight controls. BMI was positively correlated with and a significantly independent determinant of the preprandial ghrelin to obestatin ratio. Conclusion: Circulating preprandial ghrelin to obestatin ratio is elevated in human obesity. We suggest that high preprandial ghrelin to obestatin ratio may be involved in the etiology and pathophysiology of obesity.

Guo ZF, Zheng X, Qin YW, Hu JQ, Chen SP, Zhang Z. J Clin Endocrinol Metab. 2007 Feb 13; [Epub ahead of print]

Plasma obestatin and ghrelin levels in subjects with Prader-Willi syndrome

Prader-Willi syndrome (PWS) is an obesity syndrome characterized by rapid weight gain and excessive food intake. Food intake is regulated by the hypothalamus but directly influenced by gastrointestinal peptides responding to the nutritional status and body composition of an individual. Ghrelin, derived from preproghrelin, is secreted by the stomach and increases appetite while obestatin, a recently identified peptide derived post-translationally from preproghrelin, works in opposition to ghrelin by decreasing appetite. The objective of this study was to measure fasting obestatin and ghrelin levels in peripheral blood of subjects with PWS and compare to age and gender matched control subjects. Plasma obestatin and ghrelin levels were measured in subjects with PWS (n = 16, mean age = 16.0 +/- 13.3 years; age range 1-44 years) and age and gender matched control subjects (n = 16). Significantly higher obestatin levels were seen in the 16 PWS subjects (398 +/- 102 pg/ml) compared with 16 controls (325 +/- 109 pg/ml; matched t-test, P = 0.04), particularly in 5 young (</=3 years old) PWS subjects (460 +/- 49 pg/ml) compared with 5 young controls (369 +/- 96 pg/ml; matched t-test, P = 0.03). No significant difference in ghrelin levels was seen between the PWS and comparison groups. No significant correlation was observed for either peptide when compared with body mass index but a significant negative correlation was seen for ghrelin and age in PWS subjects. Our observations suggest that obestatin may be higher in infants with PWS compared to comparison infants. The possibility that obestatin may contribute to the failure to thrive which is common in infants with PWS warrants further investigation.

Butler MG, Bittel DC. Am J Med Genet A. 2007 Mar 1;143(5):415-21.

Direct and indirect effects of obestatin peptides on food intake and the regulation of glucose homeostasis and insulin secretion in mice

Obestatin is a recently discovered peptide hormone that appears to be involved in reducing food intake, gut motility and body weight. Obestatin is a product of the preproghrelin gene and appears to oppose several physiological actions of ghrelin. This study investigated the acute effects of obestatin (1-23) and the truncated form, obestatin (11-23), on feeding activity, glucose homeostasis or insulin secretion. Mice received either intraperitoneal obestatin (1-23) or (11-23) (1mumol/kg) 4h prior to an allowed 15min period of feeding. Glucose excursions and insulin responses were lowered by 64-77% and 39-41%, respectively, compared with saline controls. However this was accompanied by 43% and 53% reductions in food intake, respectively. The effects of obestatin peptides were examined under either basal or glucose (18mmol/kg) challenge conditions to establish whether effects were independent of changes in feeding. No alterations in plasma glucose or insulin responses were observed. In addition, obestatin peptides had no effect on insulin sensitivity as revealed by hypoglycaemic response when co-administered with insulin. Our observations support a role for obestatin in regulating metabolism through changes of appetite, but indicate no direct actions on glucose homeostasis or insulin secretion.

Peptides. 2007 Feb 12; [Epub ahead of print]

Distribution and biological activity of obestatin in the rat

Obestatin, a 23 amino acid peptide recently isolated from the rat stomach, is encoded by the same gene that encodes ghrelin. With the use of an antiserum directed against the mouse/rat obestatin, obestatin immunoreactivity (irOBS) was detected in cells of the gastric mucosa, myenteric plexus, and in Leydig cells of the testis in Sprague-awley rats. Double labeling the myenteric plexus with obestatin antiserum and choline acetyltransferase (ChAT) antiserum revealed that nearly all irOBS neurons were ChAT positive and vice versa. For comparative purposes, myenteric ganglion cells, cells in the gastric mucosa, and Leydig cells of the testis were shown to be immunoreactive to preproghrelin. The biological activity of obestatin on rat central neurons was assessed by the calcium microfluorimetric Fura-2 method. Obestatin (100 nM) administered to dissociated and cultured rat cerebral cortical neurons elevated cytosolic calcium concentrations [Ca2C]i in a population of cortical neurons. The result provides the first immunohistochemical evidence that obestatin is expressed in cells of the gastric mucosa and myenteric ganglion cells, and also in Leydig cells of the testis; the peptide is biologically active on central neurons.

Siok L Dun, G Cristina Brailoiu, Eugen Brailoiu, Jun Yang1, Jaw Kang Chang1 and Nae J Dun
Q1 Department of Pharmacology, Temple University School of Medicine, 3420 N. Broad Street, Philadelphia, Pennsylvania 19140, USA
1Phoenix Pharmaceuticals Inc., Belmont, California 94002, USA;
Journal of Endocrinology (2006) 191, 1?0

Obestatin acts in brain to inhibit thirst

Derived from the same prohormone, obestatin has been reported to exert effects on food intake that oppose those of ghrelin. The obestatin receptor, GPR39, is present in brain and pituitary gland. Since the gene encoding those two peptides is expressed also in those tissues, we examined further the possible actions of obestatin in vivo and in vitro. Intracerebroventricular administration of obestatin inhibited water drinking in ad libitum fed and watered rats, and in food and water deprived animals. The effects on water drinking preceded and were more pronounced than any effect on food intake, and did not appear to be the result of altered locomotor/behavioral activity. In addition, obestatin inhibited angiotensin II-induced water drinking in animals provided free access to water and food. Current clamp recordings from cultured, subfornical organ neurons revealed significant effects of the peptide on membrane potential suggesting this as a potential site of action. In pituitary cell cultures, log molar concentrations of obestatin ranging from 1.0 pM to100 nM failed to alter basal growth hormone (GH) secretion. In addition, 100 nM obestatin failed to interfere with the stimulation of GH secretion by GH-releasing hormone or ghrelin, and did not alter the inhibition by somatostatin in vitro. We conclude that obestatin does not act in pituitary gland to regulate GH secretion, but may act in brain to alter thirst mechanisms. Importantly, in rats the effects of obestatin on food intake may be secondary to an action of the peptide to inhibit water drinking. Key words: Ghrelin, Obestatin, Thirst, Appetite, Growth Hormone.

Samson WK, White MM, Price C, Ferguson AV. Am J Physiol Regul Integr Comp Physiol. 2006 Aug 24; [Epub ahead of print]

 

ghrelin

Internalization properties of the ghrelin receptor and of GPR39. Internalization was studied by antibody feeding experiments performed for 45 min with the M2 antibody in HEK293 cells stably transfected with either the FLAG-tagged version of the ghrelin receptor (top three rows), GPR39, or [AsnVI:16Phe]GPR39 (bottom two rows). After fixation and permeabilization, the localization of the M2 antibody was done with an Alexa 488-labeled second antibody (green). Cells were co-exposed to Texas Red-labeled transferrin, which is constitutively internalized by the ubiquitous transferrin receptor. The immunofluorescent analysis was performed on a Zeiss Axiovert 100 microscope, in which out of focus light was deconvoluted from stacks of vertical images and a central 3.0-m z-section was reconstructed using Improvision's Volocity software (see"Experimental Procedures"). These sections, viewed from above, are illustrated for representative single cells from three independent experiments. The ghrelin receptor was exposed to either the agonist, 10-7 M ghrelin (second row), or the inverse agonist, 10-6 M [D-Arg1,D-Phe5,D-Trp7,9,Leu11]-substance P (third row) for the last 15 min of the incubation period.

Holst B, et al. J Biol Chem. 2004 Dec 17;279(51):53806-17. Epub 2004 Sep 21.

Mutational

Mutational analysis of the ghrelin receptor, with focus on the inner faces of the extracellular ends of TMs III, VI, and VII. A, helical wheel diagram of the ghrelin receptor. Residues that could be mutated without eliminating the constitutive activity are indicated in black on gray. Two addition residues (Glu-196 and Arg-198) in extracellular loop 2 located on either side of the Cys residue that forms a disulfide bridge to CysIII:01 were also substituted because they are believed to be located just above the main ligand binding pocket. In white on black are the three Phe residues that were subjected to more elaborate mutagenesis plus the two other residues, GlnIII:05 and ArgVI:20, which were also hits for constitutive activity. B, inositol phosphate accumulation in COS-7 cells transiently transfected with the wild-type (WT) and a series of mutant forms of the ghrelin receptor. Black columns indicate the basal, constitutive signaling activity, and the open bars represent the signaling activity in response to the agonist ghrelin (10-7 M) expressed as percentage of wild-type ghrelin receptor.

Holst B, et al. J Biol Chem. 2004 Dec 17;279(51):53806-17. Epub 2004 Sep 21.

Molecular model

Molecular model of the residues proposed to be part of the structural basis for the high constitutive activity in the ghrelin receptor. A, molecular model of the ghrelin receptor built over the inactive structure of rhodopsin (60, 61). The seven helical bundle is displayed without the loops as viewed from the extra-cellular side. Only the residues on the inner faces of TMs III, VI, and VII, which in the mutational analysis were identified to potentially be involved in the constitutive activity, are shown. The two arrows indicate the proposed inward movement of TM VI and VII toward TM III that occur during activation of 7TM receptors based on metal-ion site engineering between residues: III:08, VI:16, and VII:06. B, the extracellular ends of TMs VI and VII as viewed from between TMs IV and V, showing the close proximity of the three aromatic residues: PheVI:16, PheVII:06, and PheVII:09. These three residues were subject to further mutational analysis, as shown in Fig. 8.

Holst B, et al. J Biol Chem. 2004 Dec 17;279(51):53806-17. Epub 2004 Sep 21.

Obestatin Antibody Staining Immunohistochemistry
Human (H-031-92), Mouse, Rat (H-031-90) & Des (1-10) (Rat, Mouse) (G-031-91)

H-031-92

H-031-90

G-031-92

G-031-91

 

Reseach Publications that use Obestatin Antibodies Rat, Mouse (H-031-90)

rat myenteric ganglion

Obestatin- and preproghrelin-immunoreactive cells in the rat myenteric plexus. (A) Several myenteric ganglia contain clusters of obestatin-immunoreactive cells. (B) Immunoreactivity is not detected in myenteric plexus processed with obestatin antiserum pre-absorbed with the peptide (1 mg/ml) overnight. (C) Several myenteric ganglia contain preproghrelin-immunoreactive cells of varying intensities. (D) A higher magnification of the area shown in C, where several preproghrelin-immunoreactive ganglion cells are clearly seen. Scale bar: A-C, 50 um and D, 25 um.

Dun, S. L. et al. Journal of Endocrinology (2006) 191, 1?0

rat stomach

Confocal images of a rat myenteric ganglion double labeled with choline acetyltransferase- and obestatin antisera. (A) A group of myenteric ganglion cells exhibiting varying intensities of ChAT immunoreactivity. (B) The same group of myenteric neurons labeled with obestatin antiserum. All the ganglion cells shown here contain both ChAT- and obestatin immunoreactivity; several strands of ChAT-immunoreactive fibers (arrows) seem to lack obestatin immunoreactivity. Scale bar: 30 mm.

Dun, S. L. et al. Journal of Endocrinology (2006) 191, 1?0

ghrelin and obestatin

Longitudinal strips of rat stomach labeled with obestatin- or preproghrelin antiserum. (A) Obestatin-immunoreactive cells occur mostly in the glands of gastric mucosa. (B) A higher magnification of the area in A where strongly labeled cells are seen in the glandular base. (C) Preproghrelin-immunoreactive cells are localized near the base of the glands. (D) A higher magnification showing immunoreactive cells localized mainly to the glandular base. MM, muscularis mucosae and SM, submucosa. Scale bar: A and C, 100 mm; B and D, 25 mm.

Dun, S. L. et al. Journal of Endocrinology (2006) 191, 1?0

 

The Yin and Yang personalities of ghrelin and obestatin. Both hormones derive from the same precursor protein and are predominantly secreted by the stomach and released into the blood. Each acts on a different receptor (GPR39 and GHS-R, as shown) and has an opposite effect on food intake, body weight, and gastrointestinal motility.

Ruben Nogueiras and Matthias Tschöp. Science, Vol 310, Issue 5750, 985-986 , 11 November 2005

TR-031-92

Obestatin (Human) Ultrasensitive RIA Kits (RKU-031-92) & RIA Kits (RK-031-92)

RKU-031-92

RK-031-92

Obestatin (Rat, Mouse) Ultrasensitive RIA Kits (RKU-031-90) & RIA Kits (RK-031-90)

RKU-031-90 RK-031-92RK-031-90

Obestatin (Rat, Mouse) Extraction Free EIA Kits (EK-031-90) & Fluorescent EIA Kit (FEK-031-90)

EK-031-90

Minimum Detectable Concentration = 36.6 pg/ml
5.46 times more sensetive than normal EIA Kit

Prepro-Ghrelin

Prepro-Ghrelin Prepro-Ghrelin

The ghrelin receptor family. A, schematic phylogenic tree of the ghrelin receptor family indicating the relative relationship of the receptor. The black dots indicate the three receptors that either previously (the ghrelin receptor and NT-R2 (8, 17)) or in the present study (GPR39) have been demonstrated to display a high degree of constitutive signaling activity. B, serpentine model of GPR39. Residues that are identical among GPR39, the ghrelin receptor, and NT-R2 are highlighted in white on black. The generic numbering system for 7TM receptor residues described by Schwartz (59) is used throughout the article, and the proposed first residues of each transmembrane helix are indicated by 1.

Holst B, et al. J Biol Chem. 2004 Dec 17;279(51):53806-17. Epub 2004 Sep 21.

Effects of obestatin on energy balance and growth hormone secretion in rodents

Nogueiras R, et al. Endocrinology. 2006 Sep 28; [Epub ahead of print]

Obestatin, a new peptide encoded by the Ghrelin Gene, opposes Ghrelin's effects on food intake

Zhang J. V., et al. Science, Vol 310, Issue 5750, 996-999 , 11 November 2005

Separation of Conjoined Hormones Yields Appetite Rivals

Ruben Nogueiras and Matthias Tschöp. Science, Vol 310, Issue 5750, 985-986, 11 November 2005

ghrelin;ghrelin_c_terminal;des_oct_Ghrelin;061-19;MutateGhrelin;Ghrelin in tumor;031-22;ghrelin-receptor;ghrelin-cyto;ghrelin-determination;ghrelin-dap;Ghrelin-Reference-01;

%031-85%;%031-99%;%031-91%;%031-94%;%031-93%;%031-84%;%031-92%;%031-77%;%031-96%;%031-90%;%031-98%


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