Dalbøge Louise S, Pedersen Søren L, Secher Thomas, Holst Birgitte, Vrang Niels, Jelsing Jacob
Gubra ApS, Agern Alle 1, 2970 Hørsholm, Denmark; University of Copenhagen, The Novo Nordisk Foundation Center for Basic Metabolic Research, Blegdamsvej 3B, 2200 Copenhagen N, Denmark.
Gubra ApS, Agern Alle 1, 2970 Hørsholm, Denmark.
Peptides. 2015 Jul;69:56-65. doi: 10.1016/j.peptides.2015.04.010. Epub 2015 Apr 18.
Neuromedin U (NMU) is a gut-brain peptide, implicated in energy and glucose homeostasis via the peripherally expressed NMU receptor 1 (NMUR1) and the central NMUR2. We investigated the effects of a lipidated NMU analog on gastric emptying (GE), glucose homeostasis and food intake to evaluate the use of a NMU analog as drug candidate for treatment of obesity and diabetes. Finally mRNA expression of NMU and NMUR1 in the gut and NMUR2 in the hypothalamus was investigated using a novel chromogen-based in situ hybridization (ISH) assay. Effects on food intake (6 and 18 h post dosing) were addressed in both mice and rats. The effects on GE and glycaemic control were assessed in mice, immediately after the first dose and after seven days of bidaily (BID) dosing. The lipidated NMU analog exerted robust reductions in GE and food intake in mice and improved glycaemic control when measured immediately after the first dose. No effects were observed after seven days BID. In rats, the analog induced only a minor effect on food intake. NMU mRNA was detected in the enteric nervous system throughout the gut, whereas NMUR1 was confined to the lamina propria. NMUR2 was detected in the paraventricular (PVN) and arcuate nuclei (ARC) in mice, with a reduced expression in ARC in rats. In summary, the anorectic effect of the lipidated NMU is partly mediated by a decrease in gastric emptying which is subject to tachyphylaxis after continuous dosing. Susceptibility to NMU appears to be species specific.
神经介素U（NMU）是一种肠脑肽，通过外周表达的NMU受体1（NMUR1）和中枢的NMUR2参与能量和葡萄糖稳态调节。我们研究了一种脂化NMU类似物对胃排空（GE）、葡萄糖稳态和食物摄取的影响，以评估该NMU类似物作为治疗肥胖症和糖尿病候选药物的适用性。最后，我们使用一种基于新型显色原位杂交（ISH）检测方法，研究了肠道中NMU和NMUR1以及下丘脑NMUR2的mRNA表达。在小鼠和大鼠中均研究了给药后6小时和18小时对食物摄取的影响。在小鼠中，首次给药后及每日两次（BID）给药7天后，评估了对胃排空和血糖控制的影响。脂化NMU类似物在首次给药后立即测量时，可显著降低小鼠的胃排空和食物摄取，并改善血糖控制。每日两次给药7天后未观察到影响。在大鼠中，该类似物仅对食物摄取产生轻微影响。在整个肠道的肠神经系统中均检测到NMU mRNA，而NMUR1局限于固有层。在小鼠的室旁核（PVN）和弓状核（ARC）中检测到NMUR2，在大鼠的ARC中表达降低。总之，脂化NMU的厌食作用部分是由胃排空减少介导的，连续给药后会出现快速耐受性。对NMU的敏感性似乎具有物种特异性。
