Obestatins

Definition
Obestatin is a 23–amino acid amidated peptide, was originally reported to be the ligand for the orphan receptor G-protein– coupled receptor 39 (GPR39)1.

Related Peptides
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, while this ghrelin-associated peptide behaves as a physiological opponent of ghrelin in rodent animals2.

Discovery
Obestatin and its derivative, an 11 amino acid fragment, Ob (11-23) were isolated by Zhang et al., in 20053.

Structural Characteristics
Obestatin and its derivative Ob (11–23) are peptides produced in the rat stomach. Both peptides assume a regular secondary structure in the C-terminal region of the molecule. They show a carboxyl-terminal amide functionality, which is flanked by mono basic residues in the pre-proghrelin sequence in the form of a Gly-extended structure. In this region, structural elements similar to other GPCR binding neuropeptides support the identity of obestatin as a new and functionally autonomous GPCR ligand4. Three overlapping fragments spanning residues 1-13, 6-18, and 11-23 of obestatin where tested upon adult male mice for their ability to reduce feed intake and gain in body weight. The N-terminal peptide (residues 1-13) mimicked obestatin the closest. The middle fragment (residues 6-18) significantly reduced epididymal fat without much altering feed intake or body weight5.

Mode of Action
The G-protein coupled receptor, GPR39, was originally proposed as being an obestatin target receptor, but this remains controversial1.

Functions
Obestatin has been reported to reduce food intake, body weight gain, gastric emptying, and jejunal motility. Moreover, it was found to counteract ghrelin stimulatory effects on these end points and to inhibit ghrelin induced growth hormone secretion in vivo but not in vitro, suggesting that it would serve as a physiological opponent of ghrelin. However, a number of studies failed to confirm obestatin anorexigenic effects. Obestatin has been reported to inhibit thirst and to influence memory, anxiety, and sleep via central activities. At the cellular level, it stimulates proliferation of human retinal cells. Obestatin promotes ß-cell and human islet cell survival and stimulates the expression of main regulatory ß-cell genes1.

References
1.Granata R, Settanni F, Gallo D, Trovato L, Biancone L, Cantaluppi V, Nano R, Annunziata M, Campiglia P, Arnoletti E, Ghè C, Volante M, Papotti M, Muccioli G, Ghigo E (2008). Obestatin Promotes Survival of Pancreatic ß-Cells and Human Islets and Induces Expression of Genes Involved in the Regulation of ß-Cell Mass and Function. Diabetes., 57(4):967–979.
2.Qi X, Li L, Yang G, Liu J, Li K, Tang Y, Liou H, Boden G (2007). Circulating obestatin levels in normal subjects and in patients with impaired glucose regulation and type 2 diabetes mellitus. Clin Endocrinol (Oxf)., 66(4):593-597.
3.Zhang JV, Ren PG, Avsian-Kretchmer O, Luo CW, Rauch R, Klein C, Hsueh AJ (2005). Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science., 310(5750):996-999.
4.Scrima M, Campiglia P, Esposito C, Gomez-Monterrey I, Novellino E, D'Ursi AM (2007). Obestatin conformational features: A strategy to unveil obestatin’s biological role? Biochem Biophys Res Comm.,363(3): 500-505.
5.Nagaraj S, Peddha MS, Manjappara UV (2008). Fragments of obestatin as modulators of feed intake, circulating lipids, and stored fat. Biochem bioys res commun., 366(3):731-737.

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