Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.
Research and Preclinical Development Department, Helsinn SA, Lugano, Switzerland.
Diabetes Obes Metab. 2017 Dec;19(12):1740-1750. doi: 10.1111/dom.13020. Epub 2017 Jul 13.
Ghrelin is implicated in the control of energy balance and glucose homeostasis. The ghrelin receptor exhibits ligand-independent constitutive activity, which can be pharmacologically exploited to induce inverse ghrelin actions. Because ghrelin receptor inverse agonists (GHSR-IA) might be effective for the treatment of obesity-related metabolic disease, we tested 2 novel synthetic compounds GHSR-IA1 and GHSR-IA2.
In functional cell assays, electrophysiogical and immunohistochemical experiments, we demonstrated inverse agonist activity for GHSR-IA1 and GHSR-IA2. We used healthy mice, Zucker diabetic fatty (ZDF) rats and diet-induced obese (DIO) mice to explore effects on food intake (FI), body weight (BW), conditioned taste aversion (CTA), oral glucose tolerance (OGT), pancreatic islet morphology, hepatic steatosis (HS), and blood lipids.
Both compounds acutely reduced FI in mice without inducing CTA. Chronic GHSR-IA1 increased metabolic rate in chow-fed mice, suppressed FI, and improved OGT in ZDF rats. Moreover, the progression of islet hyperplasia to fibrosis in ZDF rats slowed down. GHSR-IA2 reduced FI and BW in DIO mice, and reduced fasting and stimulated glucose levels compared with pair-fed and vehicle-treated mice. GHSR-IA2-treated DIO mice showed decreased blood lipids. GHSR-IA1 treatment markedly decreased HS in DIO mice.
Our study demonstrates therapeutic actions of novel ghrelin receptor inverse agonists, suggesting a potential to treat obesity-related metabolic disorders including diabetes mellitus.
Ghrelin 参与能量平衡和葡萄糖稳态的控制。Ghrelin 受体表现出配体非依赖性组成型活性，这可以通过药理学方法加以利用，从而诱导反向 ghrelin 作用。由于 ghrelin 受体反向激动剂（GHSR-IA）可能对治疗肥胖相关代谢疾病有效，我们测试了 2 种新型合成化合物 GHSR-IA1 和 GHSR-IA2。
在功能细胞测定、电生理和免疫组织化学实验中，我们证明了 GHSR-IA1 和 GHSR-IA2 具有反向激动剂活性。我们使用健康小鼠、Zucker 糖尿病肥胖（ZDF）大鼠和饮食诱导肥胖（DIO）小鼠来探索它们对食物摄入（FI）、体重（BW）、条件味觉厌恶（CTA）、口服葡萄糖耐量（OGT）、胰岛形态、肝脂肪变性（HS）和血脂的影响。
这两种化合物都能在不引起 CTA 的情况下急性降低小鼠的 FI。慢性 GHSR-IA1 增加了正常饮食喂养小鼠的代谢率，抑制了 FI，并改善了 ZDF 大鼠的 OGT。此外，ZDF 大鼠胰岛增生向纤维化的进展速度减慢。GHSR-IA2 降低了 DIO 小鼠的 FI 和 BW，并降低了禁食和刺激的血糖水平，与配对喂养和用载体治疗的小鼠相比。GHSR-IA2 治疗的 DIO 小鼠血脂降低。GHSR-IA1 治疗明显降低了 DIO 小鼠的 HS。
我们的研究证明了新型 ghrelin 受体反向激动剂的治疗作用，表明其有可能治疗肥胖相关的代谢紊乱，包括糖尿病。
