title: Ghrelin neutralization by a ribonucleic acid-SPM ameliorates obesity in diet-induced obese mice.
abstract: Ghrelin, an acylated peptide secreted from the stomach, acts as a short-term signal of nutrient depletion. Ghrelin is an endogenous ligand for the GH secretagogue receptor 1a, a G protein-coupled receptor expressed in the hypothalamus and pituitary. We used a synthetic oligonucleotide, NOX-B11-2, capable of specific high-affinity binding to bioactive ghrelin to determine whether ghrelin neutralization would alter indices of energy balance in vivo. This novel type of ghrelin-blocking agent, called an RNA Spiegelmer (SPM), is a polyethylene glycol-modified l-RNA oligonucleotide, the nonnatural configuration of which confers in vivo stability. NOX-B11-2 blocked ghrelin mediated activation of GH secretagogue receptor 1a in cell culture (IC50 approximately 5 nm). We explored the effects of acute NOX-B11-2 administration on ghrelin-induced feeding in mice. NOX-B11-2 (66 mg/kg, sc) blocked ghrelin-induced feeding and was without effect on feeding evoked by an orally active nonpeptide ghrelin receptor agonist. We demonstrated that selective ghrelin blockade effectively promoted weight loss in diet-induced obese (DIO) mice. Chronic infusion of NOX-B11-2 (33 mg/kg.d, sc) to DIO mice evoked body weight loss for 13 d and reduced food intake and fat mass relative to control SPM-infused mice. In a 7-d study, DIO mice infused with NOX-B11-2 (33 mg/kg.d, sc) showed body weight loss, compared with animals receiving control SPM. This effect was directly mediated by SPM neutralization of ghrelin because NOX-B11-2 administration to ghrelin-deficient mice resulted in no weight loss. The decreased obesity observed in SPM-treated DIO mice provides validation for ghrelin neutralization as a potential antiobesity therapy.
authors.affiliation: Department of Pharmacology, Merck Research Laboratories, P.O. Box 2000, RY80Y-150, Rahway, New Jersey 07065, USA. lauren_shearman@merck.com
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Shearman
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Wang
authors.forename: Steffen
authors.initials: S
authors.lastname: Helmling
authors.forename: D Sloan
authors.initials: DS
authors.lastname: Stribling
authors.forename: Paul
authors.initials: P
authors.lastname: Mazur
authors.forename: Lan
authors.initials: L
authors.lastname: Ge
authors.forename: Liyang
authors.initials: L
authors.lastname: Wang
authors.forename: Sven
authors.initials: S
authors.lastname: Klussmann
authors.forename: D Euan
authors.initials: DE
authors.lastname: Macintyre
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Howard
authors.forename: Alison M
authors.initials: AM
authors.lastname: Strack
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology; D001522:Behavior, Animal; D001835:Body Weight; D016466:CHO Cells; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005247:Feeding Behavior; D017930:Genes, Reporter; D054439:Ghrelin; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D050778:NFATC Transcription Factors / Q000378:metabolism; D009765:Obesity; D009841:Oligonucleotides / Q000737:chemistry / Q000494:pharmacology*; D036361:Peptide Hormones / Q000737:chemistry / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011485:Protein Binding; D012313:RNA / Q000737:chemistry; D011863:Radioimmunoassay; D013997:Time Factors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D019440:Anti-Obesity Agents; D054439:Ghrelin; D050778:NFATC Transcription Factors; C509286:NOX-B11-2; D009841:Oligonucleotides; D036361:Peptide Hormones; D010455:Peptides; D011092:Polyethylene Glycols; D012313:RNA; D001618:beta-Lactamases