3 years ago

Differential effects of selective agonists of neuromedin U1 and 2 receptors in obese and diabetic mice

Shiro Takekawa, Tomoko Asakawa, Kouta Matsumiya, Kotaro Yokoyama, Tetsuya Ohtaki, Hiroshi Inooka, Jiro Noguchi, Hisashi Fujita, Kazue Tsuchimori, Taiji Asami, Katsuko Dote, Naoki Nishizawa, Tomoko Kaisho, Jun-ichi Sakamoto, Hiroaki Nagai, Yoko Kanematsu-Yamaki
BACKGROUND AND PURPOSE Neuromedin U (NMU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both responsible for the NMU-mediated anti-obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor-selective agonists. EXPERIMENTAL APPROACH Efficacy and safety were assessed in mice with diet-induced obesity (DIO) and those with leptin-deficient diabetes (ob/ob) through repeated peripheral administration of selective agonists to NMU1 (NMU-6102) and NMU2 (NMU-2084), along with NMU1/2 non-selective agonists (NMU-0002 and NMU-6014). We also performed immunohistochemistry for c-Fos protein expression in the brain to probe their mechanisms of action. KEY RESULTS Although both NMU1/2 non-selective agonists and the NMU2-selective agonist had high efficacy compared to the NMU1-selective agonist, only the NMU2-selective agonist led to relatively low adverse effects, such as diarrhoea, in DIO mice. However, the NMU1/2 non-selective agonist and the NMU1-selective agonist, but not the NMU2-selective agonist, were effective in diabetic ob/ob mice. Mechanistically, NMU2-selective agonists preferentially activate pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus, but not in the paraventricular nucleus. CONCLUSION AND IMPLICATIONS These results suggest that an NMU2 receptor-selective agonist may be a well-balanced drug for the treatment of obesity, and that an NMU1 receptor-selective agonist may also be beneficial for treating obesity and diabetes once its side effects are minimized.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1111/bph.14077

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