White C L, Ishii Y, Mendoza T, Upton N, Stasi L P, Bray G A, York D A
Pennington Biomedical Research Center, Experimental Obesity laboratory, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
Peptides. 2005 Nov;26(11):2331-8. doi: 10.1016/j.peptides.2005.03.042.
An orexin-1 receptor antagonist decreases food intake whereas orexin-A selectively induces hyperphagia to a high-fat diet. In the present study, we evaluated the effect of an orexin antagonist in two strains of rats that differ in their sensitivity to becoming obese while eating a high-fat diet. Male Osborne-Mendel (OM) and S5B/Pl (S5B) rats were treated acutely with an orexin-1 receptor antagonist (SB-334867), after adaptation to either a high-fat (56% fat energy) diet or a low-fat (10% fat energy) diet that were equicaloric for protein (24% energy). Ad libitum fed rats were injected intraperitoneally with SB-334867 at doses of 3, 10 or 30 mg/kg, or vehicle at the beginning of the dark cycle, and food intake and body weight were measured. Hypothalamic prepro-orexin and orexin-1 receptor mRNA expression were analyzed in OM and S5B rats fed at a high-fat or low-fat diet for two weeks. SB-334867 significantly decreased food intake in both strains of rats eating the high-fat diet but only in the OM rats eating the low fat diet. The effect was greatest at 12 and 24 h. Body weight was also reduced in OM rats 1d after injection of SB-334867 but not in the S5B rats. Prepro-orexin and orexin-1 receptor expression levels did not differ between strains or diets. These experiments demonstrate that an orexin antagonist (SB-334867) reduces food intake and has a greater effect in a rat strain that is susceptible to dietary-induced obesity, than in a resistant strain.
食欲素-1受体拮抗剂可减少食物摄入量，而食欲素-A则选择性地诱导对高脂饮食的食欲亢进。在本研究中，我们评估了一种食欲素拮抗剂对两种在高脂饮食时肥胖易感性不同的大鼠品系的作用。雄性奥斯本-孟德尔（OM）大鼠和S5B/Pl（S5B）大鼠在适应等热量蛋白质（能量的24%）的高脂（56%脂肪能量）或低脂（10%脂肪能量）饮食后，用食欲素-1受体拮抗剂（SB-334867）进行急性处理。自由进食的大鼠在黑暗周期开始时腹腔注射剂量为3、10或30 mg/kg的SB-334867或赋形剂，并测量食物摄入量和体重。对喂食高脂或低脂饮食两周的OM和S5B大鼠的下丘脑前食欲素原和食欲素-1受体mRNA表达进行分析。SB-334867显著降低了两种高脂饮食大鼠的食物摄入量，但仅降低了低脂饮食的OM大鼠的食物摄入量。在12小时和24小时时效果最明显。注射SB-334867后1天，OM大鼠体重也减轻，但S5B大鼠体重未减轻。前食欲素原和食欲素-1受体表达水平在品系或饮食之间没有差异。这些实验表明，一种食欲素拮抗剂（SB-334867）可减少食物摄入量，并且在易患饮食诱导性肥胖的大鼠品系中比在抗性品系中具有更大的作用。
