Objective

Combination therapies with gut hormone analogs represent promising treatment strategies for obesity. This pilot study investigates the therapeutic potential of modulators of the glucagon-like peptide 1 (GLP-1) and neuropeptide Y (NPY) system using GLP-1 receptor agonists (semaglutide) and antagonists (exendin 9-39), as well as non-selective and NPY-Y2-receptor selective peptide tyrosine tyrosine (PYY) analogs (PYY3-36/NNC0165-0020 and NNC0165-1273) and an NPY-Y2 receptor antagonist (JNJ31020028).

Methods

High-fat diet (HFD)-induced obese rats were randomized into following treatment groups: group 1, nonselective PYY analog + semaglutide (n = 4); group 2, non-selective and NPY-Y2 receptor selective PYY analog + semaglutide (n = 2); group 3, GLP-1 receptor antagonist + NPY-Y2 receptor antagonist (n = 3); group 4, semaglutide (n = 5); and group 5, control (n = 5). Animals had free access to HFD and low-fat diet. Food intake, HFD preference and body weight were measured daily.

Results

A combinatory treatment with a non-selective PYY analog and semaglutide led to a maximum body weight loss of 14.0 ± 4.9% vs 9.9 ± 1.5% with semaglutide alone. Group 2 showed a maximum weight loss of 20.5 ± 2.4%. While HFD preference was decreased in group 2, a strong increase in HFD preference was detected in group 3.

Conclusions

PYY analogs (especially NPY-Y2 selective receptor agonists) could represent a promising therapeutic approach for obesity in combination with GLP-1 receptor agonists. Additionally, combined GLP-1 and PYY3-36 receptor agonists might have beneficial effects on food preference.

中文翻译：

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GLP-1 和 PYY 治疗肥胖：在饮食诱导的大鼠中使用激动剂和拮抗剂的初步研究

客观的

与肠道激素类似物的联合疗法代表了有前景的肥胖治疗策略。该初步研究使用 GLP-1 受体激动剂（索马鲁肽）和拮抗剂（exendin 9-39）以及非药物，研究胰高血糖素样肽 1 (GLP-1) 和神经肽 Y (NPY) 系统调节剂的治疗潜力。 -选择性和NPY-Y2-受体选择性肽酪氨酸酪氨酸(PYY)类似物(PYY3-36/NNC0165-0020和NNC0165-1273)和NPY-Y2受体拮抗剂(JNJ31020028)。

方法

高脂饮食（HFD）诱导的肥胖大鼠被随机分为以下治疗组：第1组，非选择性PYY类似物+索马鲁肽（n = 4）；第1组，非选择性PYY类似物+索马鲁肽（n  = 4）；第2组，非选择性和NPY-Y2受体选择性PYY类似物+索马鲁肽（n  = 2）；第3组，GLP-1受体拮抗剂+NPY-Y2受体拮抗剂（n  =3）；第 4 组，索马鲁肽（n  = 5）；第 5 组，对照组（n  = 5）。动物可以自由摄入高脂饮食和低脂饮食。每天测量食物摄入量、HFD 偏好和体重。

结果

非选择性 PYY 类似物和索马鲁肽联合治疗导致最大体重减轻 14.0 ± 4.9%，而单独使用索马鲁肽则为 9.9 ± 1.5%。第 2 组的最大体重减轻为 20.5 ± 2.4%。虽然第 2 组中的 HFD 偏好有所下降，但第 3 组中的 HFD 偏好却大幅增加。

结论

PYY 类似物（尤其是 NPY-Y2 选择性受体激动剂）与 GLP-1 受体激动剂联合使用可能代表一种有前景的肥胖治疗方法。此外，联合使用 GLP-1 和 PYY3-36 受体激动剂可能对食物偏好产生有益影响。