Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Gottingen Minipigs
Long-acting CCK analogue NN9056 lowers food intake and body weight in obese Gottingen Minipigs
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DOI：
10.1038/s41366-019-0386-0
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发表时间：
2020-02-01
影响因子：
4.9
通讯作者：
Clausen, Trine Ryberg
中科院分区：
文献类型：
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作者：
Christoffersen, Berit O.;Skyggebjerg, Rikke Bjerring;Clausen, Trine Ryberg
背景/目的胆囊收缩素（CCK）是人类食欲和能量摄入的调节因子。本研究旨在研究长效CCK-1受体选择性CCK类似物NN9056对肥胖哥廷根迷你猪摄食量和体重的影响。研究对象/方法以100 nmol/kg （n = 3-4）为剂量，评估NN9056对瘦肉家猪的耐受性以及对摄食量、胰腺组织学、淀粉酶和脂肪酶水平的急性影响。随后，肥胖的哥廷根小型猪每天皮下注射1次（s.c.），连续13周，用NN9056低剂量（5至2 nmol/kg）或NN9056高剂量（10 nmol/kg） （n = 7-8）。每日测量食物摄取量，每周测量体重2次。在治疗期结束时，进行静脉葡萄糖耐量试验（IVGTT）和24小时暴露谱。数据为平均值+/- SD。结果家猪急性试验显示，NN9056对猪的摄食量、耐受性有显著的剂量依赖性，且无胰腺炎的病理表现。肥胖哥廷根小猪的亚慢性治疗耐受良好，与对照组相比，两组的累积食物摄入量均显著降低，NN9056剂量水平之间无显著差异（高剂量组、低剂量组和对照组分别为41.8 +/- 12.6、51.5 +/- 13.8和86.5 +/- 19.5 kg，低剂量组和高剂量组分别为p = 0.012和p < 0.0001）。因此，治疗组和药物组的体重均下降，而药物组的体重均增加（高剂量、低剂量和药物组的体重分别为-7.2 +/- 4.6%、-2.3 +/- 3.2%和12.3 +/- 3.9%,p < 0.0001）。各组IVGTT数据差异无统计学意义。结论NN9056是一种长效CCK-1受体选择性CCK类似物，每天给药1次，连续13周显著降低肥胖哥廷根迷你猪的摄食量和体重。
Background/Objectives Cholecystokinin (CCK) is a regulator of appetite and energy intake in man. The aim of this study was to determine the effect of NN9056, a long-acting CCK-1 receptor-selective CCK analogue, on food intake and body weight (BW) in obese Gottingen Minipigs. Subjects/Methods Tolerability of NN9056 and acute effects on food intake, pancreas histology, amylase and lipase levels were assessed in lean domestic pigs in doses up to 100 nmol/kg (n = 3-4). Subsequently, obese Gottingen Minipigs were treated subcutaneously (s.c.) once daily for 13 weeks with vehicle, NN9056 low dose (regulated from 5 to 2 nmol/kg) or NN9056 high dose (10 nmol/kg) (n = 7-8). Food intake was measured daily and BW twice weekly. At the end of the treatment period, an intravenous glucose tolerance test (IVGTT) and a 24-h exposure profile was obtained. Data are mean +/- SD. Results The acute studies in domestic pigs showed significant and dose-dependent effect of NN9056 on food intake, acceptable tolerability and no histopathological signs of pancreatitis. Sub-chronic treatment in obese Gottingen Minipigs was also well tolerated and accumulated food intake was significantly lower in both treated groups compared to vehicle, with no significant difference between the dose levels of NN9056 (41.8 +/- 12.6, 51.5 +/- 13.8 and 86.5 +/- 19.5 kg in high-dose, low-dose and vehicle groups, respectively, p = 0.012 and p < 0.0001 for low and high dose vs. vehicle, respectively). Accordingly, there was a weight loss in both treated groups vs. a weight gain in the vehicle group (-7.2 +/- 4.6%, -2.3 +/- 3.2% and 12.3 +/- 3.9% in the high-dose, low-dose and vehicle groups, respectively, p < 0.0001 for both vs. vehicle). IVGTT data were not significantly different between groups. Conclusion NN9056, a long-acting CCK-1 receptor-selective CCK analogue, significantly reduced food intake and BW in obese Gottingen Minipigs after once daily s.c. dosing for 13 weeks.