Kask A, Rägo L, Korrovits P, Wikberg J E, Schiöth H B
Department of Pharmacology, University of Tartu, Ulikooli 18, Tartu, EE-2400, Estonia.
Biochem Biophys Res Commun. 1998 Jul 20;248(2):245-9. doi: 10.1006/bbrc.1998.8961.
Recent studies using melanocortin-4 receptor (MC4R) knockout mice and MC4R antagonists have shown that weakening of MC4R-ergic tone increases food intake and causes obesity. In this study, we used the newly discovered selective MC4R antagonist HS014 for increasing food intake in free-feeding rats and evaluated the effects of the NPY Y1 receptor antagonist 1229U91 and the selective serotonin uptake inhibitor fluoxetine on this increased feeding behavior. 1229U91 (12 nmol, i.c.v.), which alone does not affect food intake, significantly attenuated the orexigenic effects of HS014, whereas 1 and 3 nmol doses of 1229U91 were ineffective. Fluoxetine, which has been shown to inhibit NPY release, inhibited spontaneous food intake and completely blocked the stimulation of food intake by HS014. These data suggest that feeding induced by weakening of the MC4R-ergic tone may be mediated through activation of the NPY-ergic system. This is the first report showing that physiological feeding response evoked by MC4R blockage is influenced by NPY signalling.
最近使用促黑素皮质素-4受体（MC4R）基因敲除小鼠和MC4R拮抗剂的研究表明，MC4R信号减弱会增加食物摄入量并导致肥胖。在本研究中，我们使用新发现的选择性MC4R拮抗剂HS014来增加自由进食大鼠的食物摄入量，并评估NPY Y1受体拮抗剂1229U91和选择性5-羟色胺摄取抑制剂氟西汀对这种增加的进食行为的影响。单独使用时不影响食物摄入量的1229U91（12 nmol，脑室内注射）可显著减弱HS014的促食欲作用，而1和3 nmol剂量的1229U91则无效。已证明可抑制NPY释放的氟西汀可抑制自发食物摄入，并完全阻断HS014对食物摄入的刺激。这些数据表明，MC4R信号减弱诱导的进食可能通过NPY能系统的激活介导。这是第一份表明MC4R阻断引起的生理性进食反应受NPY信号影响的报告。
