title: Ghrelin gene products and the regulation of food intake and gut motility.
abstract: A breakthrough using "reverse pharmacology" identified and characterized acyl ghrelin from the stomach as the endogenous cognate ligand for the growth hormone (GH) secretagogue receptor (GHS-R) 1a. The unique post-translational modification of O-n-octanoylation at serine 3 is the first in peptide discovery history and is essential for GH-releasing ability. Des-acyl ghrelin, lacking O-n-octanoylation at serine 3, is also produced in the stomach and remains the major molecular form secreted into the circulation. The third ghrelin gene product, obestatin, a novel 23-amino acid peptide identified from rat stomach, was found by comparative genomic analysis. Three ghrelin gene products actively participate in modulating appetite, adipogenesis, gut motility, glucose metabolism, cell proliferation, immune, sleep, memory, anxiety, cognition, and stress. Knockdown or knockout of acyl ghrelin and/or GHS-R1a, and overexpression of des-acyl ghrelin show benefits in the therapy of obesity and metabolic syndrome. By contrast, agonism of acyl ghrelin and/or GHS-R1a could combat human anorexia-cachexia, including anorexia nervosa, chronic heart failure, chronic obstructive pulmonary disease, liver cirrhosis, chronic kidney disease, burn, and postsurgery recovery, as well as restore gut dysmotility, such as diabetic or neurogenic gastroparesis, and postoperative ileus. The ghrelin acyl-modifying enzyme, ghrelin O-Acyltransferase (GOAT), which attaches octanoate to serine-3 of ghrelin, has been identified and characterized also from the stomach. To date, ghrelin is the only protein to be octanylated, and inhibition of GOAT may have effects only on the stomach and is unlikely to affect the synthesis of other proteins. GOAT may provide a critical molecular target in developing novel therapeutics for obesity and type 2 diabetes.
authors.affiliation: Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Japan.
authors.forename: Chih-Yen
authors.initials: CY
authors.lastname: Chen
authors.forename: Akihiro
authors.initials: A
authors.lastname: Asakawa
authors.forename: Mineko
authors.initials: M
authors.lastname: Fujimiya
authors.forename: Shou-Dong
authors.initials: SD
authors.lastname: Lee
authors.forename: Akio
authors.initials: A
authors.lastname: Inui
mesh_terms: D000217:Acyltransferases / Q000502:physiology; D000818:Animals; D001069:Appetite Regulation / Q000187:drug effects / Q000502:physiology*; D001835:Body Weight; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000502:physiology*; D054439:Ghrelin / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D036361:Peptide Hormones / Q000502:physiology; D054440:Receptors, Ghrelin / Q000502:physiology
chemical_list: D054439:Ghrelin; D036361:Peptide Hormones; D054440:Receptors, Ghrelin; C422650:ghrelin, des-n-octanoyl; C505799:obestatin, human; D000217:Acyltransferases; C542776:MBOAT4 protein, human