Probes for INS

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.