Research, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Int J Obes (Lond). 2017 Dec;41(12):1790-1797. doi: 10.1038/ijo.2017.176. Epub 2017 Jul 31.
Neuromedin U (NMU) is a neuropeptide with various physiological functions, including regulation of smooth-muscle contraction, blood pressure, stress responses and feeding behaviors. NMU activates two distinct receptors, NMUR1 and NMUR2, which are predominantly expressed in peripheral tissues and the central nervous system (CNS), respectively. It is reported that the NMU signaling system regulates food intake (FI) and body weight (BW) via NMUR2, suggesting that an NMUR2 agonist exhibiting anorectic effects would be a potential therapy for obesity.
Antiobesity effects of NMUR2 activation were assessed using a recently developed, novel NMUR2-selective agonist, NMU-7005 (a polyethylene glycolated octapeptide). Here we assessed cumulative FI and BW loss after peripheral administration of NMU-7005 in NMUR2 knockout and diet-induced obese mice. To gain mechanistic insights, we performed immunohistochemical analysis of c-Fos-like protein expression in the brain.
We found that NMU-7005 was a NMUR2-selective agonist with little activity toward NMUR1. The anorectic effect of NMU-7005 was completely abrogated in NMUR2 knockout mice. Repeated subcutaneous administration of NMU-7005 showed a potent antiobesity effect with FI inhibition (P<0.025) in diet-induced obese mice. NMU-7005 in combination with the glucagon-like peptide-1 receptor (GLP-1R) agonist liraglutide showed an additive antiobesity effect, suggesting that NMUR2-mediated anorectic action is different from that of GLP-1R agonists. NMU-7005 also elicited a minimal conditioned taste-aversive effect, while the effect of liraglutide was significant. As c-Fos expression was upregulated in the hypothalamus and the medulla oblongata in NMU-7005-administered mice, the pharmacological effects of NMU-7005 appeared to be mediated via activation of the CNS.
Our results demonstrated that a novel NMUR2-selective agonist, NMU-7005, is a beneficial tool for the elucidation of NMUR2-mediated physiological functions, which is a promising therapeutic strategy for treating obesity.
神经调节素 U（NMU）是一种具有多种生理功能的神经肽，包括调节平滑肌收缩、血压、应激反应和摄食行为。NMU 激活两种不同的受体，NMUUR1 和 NMUUR2，它们分别主要在周围组织和中枢神经系统（CNS）中表达。据报道，NMU 信号系统通过 NMUUR2 调节食物摄入（FI）和体重（BW），这表明具有厌食作用的 NMUUR2 激动剂将是肥胖治疗的潜在疗法。
使用最近开发的新型 NMUUR2 选择性激动剂 NMU-7005（一种聚乙二醇化八肽）评估 NMUUR2 激活的抗肥胖作用。在这里，我们评估了 NMU-7005 外周给药后 NMUUR2 敲除和饮食诱导肥胖小鼠的累积 FI 和 BW 损失。为了获得机制见解，我们对大脑中 c-Fos 样蛋白表达进行了免疫组织化学分析。
我们发现 NMU-7005 是一种 NMUUR2 选择性激动剂，对 NMUUR1 几乎没有活性。NMU-7005 的厌食作用在 NMUUR2 敲除小鼠中完全被阻断。重复皮下给予 NMU-7005 显示出在饮食诱导肥胖小鼠中具有强大的抗肥胖作用，抑制食物摄入（P<0.025）。NMU-7005 与胰高血糖素样肽-1 受体（GLP-1R）激动剂利拉鲁肽联合使用具有相加的抗肥胖作用，表明 NMUUR2 介导的厌食作用与 GLP-1R 激动剂不同。NMU-7005 还引起最小的条件味觉厌恶效应，而利拉鲁肽的作用则很明显。由于 NMU-7005 给药的小鼠下丘脑和延髓中 c-Fos 表达上调，因此 NMU-7005 的药理作用似乎是通过激活中枢神经系统介导的。
我们的结果表明，新型 NMUUR2 选择性激动剂 NMU-7005 是阐明 NMUUR2 介导的生理功能的有益工具，这是治疗肥胖的有前途的治疗策略。
