Zhou Dan, Shearman Lauren P
Department of Pharmacology, Merck Research Laboratories, RY80Y-150, 126 E. Lincoln Avenue, Rahway, NJ 07065, USA.
Pharmacol Biochem Behav. 2004 Jan;77(1):117-25. doi: 10.1016/j.pbb.2003.10.015.
Cannabinoid CB1 receptor (CB1R) inverse agonists reduce appetite and body weight (BW) gain in various species. Exercise is thought to be a natural reward process and the cannabinoid system is also believed to influence reward. We tested the hypothesis that voluntary exercise would augment the effects of AM251, a CB1R inverse agonist, on food intake (FI) and BW loss in murine genetic models of obesity. ob/ob, agouti yellow (A(y)), and lean C57BL/6J mice were treated via oral gavage with vehicle or AM251 (1, 3, or 10 mg/kg) 1 h before the dark cycle. The suppressive effects of 3 and 10 mg/kg AM251 on overnight FI, BW gain, and water intake (WI) were significant in ob/ob mice. In contrast, in A(y) mice, 10 mg/kg AM251 decreased FI and BW gain while it did not influence WI. Food consumption of ob/ob and A(y) mice, as evidenced by feeding frequency (FF) and feeding duration (FD), was reduced by AM251 for 4-6 h. AM251 at these doses had no impact on the appetitive behavior or BW gain of lean mice. After a 1-week wash-out period, mice were given running wheels in their home cages. With running wheel exercise, lean and obese mice exhibited increased sensitivity to AM251. Low voluntary wheel running activity of ob/ob mice precluded detection of combined effects of AM251 and exercise in this genetic model of obesity. Lean and agouti mice given AM251 combined with exercise lost a greater amount of BW than with AM251 alone. Our data suggest that voluntary exercise can enhance CB1R inverse agonist effects on appetite and BW loss in both lean and agouti obese mice.
大麻素CB1受体（CB1R）反向激动剂可降低多种物种的食欲并抑制体重增加。运动被认为是一种自然的奖赏过程，并且大麻素系统也被认为会影响奖赏。我们测试了这样一个假设：在肥胖小鼠遗传模型中，自愿运动将增强CB1R反向激动剂AM251对食物摄入量（FI）和体重减轻的影响。在黑暗周期前1小时，通过口服灌胃给予ob/ob、刺豚鼠黄色（A(y)）和瘦型C57BL/6J小鼠溶剂或AM251（1、3或10mg/kg）。3mg/kg和10mg/kg的AM251对ob/ob小鼠的过夜食物摄入量、体重增加和水摄入量（WI）具有显著的抑制作用。相比之下，在A(y)小鼠中，10mg/kg的AM251可降低食物摄入量和体重增加，而对水摄入量没有影响。AM251可使ob/ob和A(y)小鼠的食物消耗量（通过进食频率（FF）和进食持续时间（FD）证明）在4 - 6小时内降低。这些剂量的AM251对瘦小鼠的食欲行为或体重增加没有影响。在1周的洗脱期后，在家笼中给小鼠安装跑步轮。通过跑步轮运动，瘦小鼠和肥胖小鼠对AM251的敏感性增加。ob/ob小鼠的低自愿跑步轮活动使得在该肥胖遗传模型中无法检测到AM251与运动的联合作用。给予AM251并结合运动的瘦小鼠和刺豚鼠小鼠比单独给予AM251时体重减轻更多。我们的数据表明，自愿运动可增强CB1R反向激动剂对瘦小鼠和刺豚鼠肥胖小鼠的食欲和体重减轻的作用。
