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: Lauren P Shearman, Sheng-Ping Wang, Steffen Helmling, D Sloan Stribling, Paul Mazur, Lan Ge, Liyang Wang, Sven Klussmann, D Euan Macintyre, Andrew D Howard, Alison M Strack
• Journal: Endocrinology (Endocrinology) Vol. 147 Issue 3 Pg. 1517-26 (Mar 2006) ISSN: 0013-7227 [Print] United States
• PMID: 16339202 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Ghrelin
• NFATC Transcription Factors
• NOX-B11-2
• Oligonucleotides
• Peptide Hormones
• Peptides
• Polyethylene Glycols
• RNA
• beta-Lactamases

Topics

• Animals
• Anti-Obesity Agents (pharmacology)
• Behavior, Animal
• Body Weight
• CHO Cells
• Cricetinae
• Dose-Response Relationship, Drug
• Enzyme-Linked Immunosorbent Assay
• Feeding Behavior
• Genes, Reporter
• Ghrelin
• Humans
• Inhibitory Concentration 50
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Obese
• NFATC Transcription Factors (metabolism)
• Obesity
• Oligonucleotides (chemistry, pharmacology)
• Peptide Hormones (chemistry, metabolism)
• Peptides (chemistry)
• Polyethylene Glycols (chemistry)
• Protein Binding
• RNA (chemistry)
• Radioimmunoassay
• Time Factors
• beta-Lactamases (metabolism)