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A New Physiological Opponent of Ghrelin

ghrelin and obestatin schematics
rat prepro ghrelinhuman 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.
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.

Alexandridis E, Zisimopoulos A, Liratzopoulos N, Katsos I, Manolas K, Kouklakis G. Obestatin/ghrelin ratio: a new activity index in inflammatory bowel diseases. Inflamm Bowel Dis. 2009;15(10):1557-61. 

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, et al. Circulating obestatin levels in normal subjects and in patients with impaired glucose regulation and type 2 diabetes mellitus. Clin Endocrinol (Oxf). 2007;66(4):593-7.

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. Circulating preprandial ghrelin to obestatin ratio is increased in human obesity. J Clin Endocrinol Metab. 2007;92(5):1875-80.

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 (

Butler MG, Bittel DC. Plasma obestatin and ghrelin levels in subjects with Prader-Willi syndrome. Am J Med Genet A. 2007;143A(5):415-21.

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.

Green BD, Irwin N, Flatt PR. Direct and indirect effects of obestatin peptides on food intake and the regulation of glucose homeostasis and insulin secretion in mice. Peptides. 2007;28(5):981-7.

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.

Dun SL, Brailoiu GC, Brailoiu E, Yang J, Chang JK, Dun NJ. Distribution and biological activity of obestatin in the rat. J Endocrinol. 2006;191(2):481-9.

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. Obestatin acts in brain to inhibit thirst. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R637-43.

Ghrelin stimulates food intake and adiposity and thereby increases body weight (BW) in rodents after central as well as peripheral administration. Recently, it was discovered that the gene precursor of ghrelin encoded another secreted and bioactive peptide named obestatin. First reports appeared to demonstrate that this peptide requires an amidation for its biological activity and acts through the orphan receptor, GPR-39. Obestatin was shown to have actions opposite to ghrelin on food intake, BW, and gastric emptying. In the present study, we failed to observe any effect of obestatin on food intake, BW, body composition, energy expenditure, locomotor activity, respiratory quotient, or hypothalamic neuropeptides involved in energy balance regulation. In agreement with the first report, we were unable to find any effect of obestatin on GH secretion in vivo. Moreover, we were unable to find mRNA expression of GPR-39, the putative obestatin receptor, in the hypothalamus of rats. Therefore, the results presented here do not support a role of the obestatin/GPR-39 system in the regulation of energy balance.

Nogueiras R, Pfluger P, Tovar S, et al. Effects of obestatin on energy balance and growth hormone secretion in rodents. Endocrinology. 2007;148(1):21-6.

Ghrelin, a circulating appetite-inducing hormone, is derived from a prohormone by posttranslational processing. On the basis of the bioinformatic prediction that another peptide also derived from proghrelin exists, we isolated a hormone from rat stomach and named it obestatin-a contraction of obese, from the Latin "obedere," meaning to devour, and "statin," denoting suppression. Contrary to the appetite-stimulating effects of ghrelin, treatment of rats with obestatin suppressed food intake, inhibited jejunal contraction, and decreased body-weight gain. Obestatin bound to the orphan G protein-coupled receptor GPR39. Thus, two peptide hormones with opposing action in weight regulation are derived from the same ghrelin gene. After differential modification, these hormones activate distinct receptors.

Zhang JV, Ren PG, Avsian-kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science. 2005;310(5750):996-9.

The ghrelin-motilin receptor family and their ligands. 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

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