Erratum: GSK1614343, a Novel Ghrelin Receptor Antagonist, Produces an Unexpected Increase of Food Intake and Body Weight in Rodents and Dogs

Ghrelin is a 28-amino-acid polypeptide expressed in the stomach and hypothalamus that stimulates GH secretion, increases food intake (FI) and promotes body weight (BW) gain most likely via activation of the growth hormone secretagogue receptor type 1a (GHSR1a). GSK1614343 is a novel selective and potent GHSR antagonist with no partial agonist properties, recently characterized as GH secretion inhibitor by Sabbatini et al. [Chem Med Chem 2010;5:1450–1455]. In the present study, GSK1614343 (10 mg/kg) was not able to antagonize ghrelin-induced food consumption in rat, but unexpectedly stimulated FI and BW gain in both rats and dogs, a profile associated with decreased ghrelin plasma level. Interestingly, GSK1614343 selectively reduced the pro-opiomelanocortin mRNA levels in rat hypothalami chronically treated with the compound. To better understand the observed effects, we administered GSK1614343 (30 mg/kg) to Ghsr null mice and measured body mass components (fat, lean and free fluid) by using a NMR spectrometer. The increases of FI and BW were abolished in Ghsr null mice, while fat and lean masses increased in wild-type mice. Taken together, these results indicate that the orexigenic effect of GSK1614343 is mediated by GHSR1a and that the weight gain could be attributed to the increase of both adiposity and muscle mass, but not to fluid retention. The observed dissociation between effects on GH secretion and effects on FI/BW is inconsistent with a simple hormone-receptor model, suggesting unknown underlying regulations of the ghrelin system whose understanding require further investigation.

饥饿素（ghrelin）是一种由28个氨基酸组成的多肽，可在胃与下丘脑中表达，能够刺激生长激素（growth hormone, GH）分泌、增加食物摄入量（food intake, FI）并促进体重（body weight, BW）增加，其作用机制大概率是通过激活生长激素促分泌素受体1a型（growth hormone secretagogue receptor type 1a, GHSR1a）实现。GSK1614343是一种新型选择性强效GHSR拮抗剂，无部分激动剂活性，萨巴蒂尼（Sabbatini）等人于2010年在《Chem Med Chem》期刊（5卷：1450–1455页）中对其进行了表征，证实其可抑制生长激素分泌。在本研究中，给予10 mg/kg剂量的GSK1614343无法拮抗饥饿素诱导的大鼠摄食行为，但出乎意料的是，该化合物可同时刺激大鼠与犬的食物摄入量增加及体重上升，该作用特征伴随血浆饥饿素水平降低。有趣的是，对大鼠下丘脑进行慢性给药处理后，GSK1614343可选择性降低阿黑皮素原mRNA（pro-opiomelanocortin mRNA）的表达水平。为进一步阐明上述观测到的效应，我们给予30 mg/kg剂量的GSK1614343至Ghsr基因敲除小鼠（Ghsr null mice）中，并通过核磁共振波谱仪（NMR spectrometer）检测其身体组成成分（脂肪量、瘦体重与游离体液）。结果显示，Ghsr基因敲除小鼠的食物摄入量与体重增加现象被完全消除，而野生型小鼠的脂肪量与瘦体重均出现上升。综合上述结果可知，GSK1614343的促食欲效应由GHSR1a介导，其诱导的体重增加可归因于脂肪蓄积与肌肉量的同时提升，而非体液潴留。本研究观测到的生长激素分泌抑制效应与摄食/体重调控效应之间的解离现象，与简单的激素-受体模型不符，提示饥饿素系统存在尚未阐明的潜在调控机制，相关机制的解析仍需进一步研究。