Shearman Lauren P, Wang Sheng-Ping, Helmling Steffen, Stribling D Sloan, Mazur Paul, Ge Lan, Wang Liyang, Klussmann Sven, Macintyre D Euan, Howard Andrew D, Strack Alison M
Department of Pharmacology, Merck Research Laboratories, P.O. Box 2000, RY80Y-150, Rahway, New Jersey 07065, USA.
Endocrinology. 2006 Mar;147(3):1517-26. doi: 10.1210/en.2005-0993. Epub 2005 Dec 8.
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.
胃饥饿素是一种由胃分泌的酰化肽，作为营养物质消耗的短期信号。胃饥饿素是生长激素促分泌素受体1a的内源性配体，该受体是一种在下丘脑和垂体中表达的G蛋白偶联受体。我们使用了一种能够与生物活性胃饥饿素特异性高亲和力结合的合成寡核苷酸NOX-B11-2，来确定胃饥饿素中和是否会改变体内能量平衡指标。这种新型的胃饥饿素阻断剂，称为RNA Spiegelmer（SPM），是一种聚乙二醇修饰的l-RNA寡核苷酸，其非天然构型赋予了体内稳定性。NOX-B11-2在细胞培养中阻断了胃饥饿素介导的生长激素促分泌素受体1a的激活（IC50约为5 nM）。我们探讨了急性给予NOX-B11-2对小鼠胃饥饿素诱导进食的影响。NOX-B11-2（66 mg/kg，皮下注射）阻断了胃饥饿素诱导的进食，对口服活性非肽胃饥饿素受体激动剂诱发的进食没有影响。我们证明选择性胃饥饿素阻断有效地促进了饮食诱导肥胖（DIO）小鼠的体重减轻。向DIO小鼠慢性输注NOX-B11-2（33 mg/kg·d，皮下注射），持续13天引起体重减轻，与输注对照SPM的小鼠相比，食物摄入量和脂肪量减少。在一项为期7天的研究中，与接受对照SPM的动物相比，输注NOX-B11-2（33 mg/kg·d，皮下注射）的DIO小鼠体重减轻。这种作用是由SPM对胃饥饿素的中和直接介导的，因为向胃饥饿素缺乏的小鼠给予NOX-B11-2不会导致体重减轻。在SPM处理的DIO小鼠中观察到的肥胖减轻为胃饥饿素中和作为一种潜在的抗肥胖疗法提供了验证。
