Herling Andreas W, Kilp Susanne, Elvert Ralf, Haschke Guido, Kramer Werner
Therapeutic Department Metabolism, Pharmacology, H 821, Sanofi-Aventis Deutschland GmbH, Industriepark Hoechst, 65926 Frankfurt/Main, Germany.
Endocrinology. 2008 May;149(5):2557-66. doi: 10.1210/en.2007-1515. Epub 2008 Feb 14.
The CB1 receptor antagonist, rimonabant, affects the endocannabinoid system and causes a sustained reduction in body weight (BW) despite the transient nature of the reduction in food intake. Therefore, in a multiple-dose study, female candy-fed Wistar rats were treated with rimonabant (10 mg/kg) and matched with pair-fed rats to distinguish between hypophagic action and hypothesized effects on energy expenditure. Within the first week of treatment, rimonabant reduced BW nearly to levels of standard rat chow-fed rats. Evaluation of energy balance (energy expenditure measured by indirect calorimetry in relation to metabolizable energy intake calculated by bomb calorimetry) revealed that increased energy expenditure based on increased fat oxidation contributed more to sustained BW reduction than reduced food intake. A mere food reduction through pair feeding did not result in comparable effects because animals reduced their energy expenditure to save energy stores. Because fat oxidation measured by indirect calorimetry increased immediately after dosing in the postprandial state, the acute effect of rimonabant on lipolysis was investigated in postprandial male rats. Rimonabant elevated free fatty acids postprandially, demonstrating an inherent pharmacological activity of rimonabant to induce lipolysis and not secondarily postabsorptively due to reduced food intake. We conclude that the weight-reducing effect of rimonabant was due to continuously elevated energy expenditure based on increased fat oxidation driven by lipolysis from fat tissue as long as fat stores were elevated. When the amount of endogenous fat stores declined, rimonabant-induced increased energy expenditure was maintained by a re-increase in food intake.
CB1受体拮抗剂利莫那班可影响内源性大麻素系统，尽管食物摄入量的减少是短暂的，但它能使体重持续下降。因此，在一项多剂量研究中，给喂食糖果的雌性Wistar大鼠服用利莫那班（10毫克/千克），并与配对喂食的大鼠进行匹配，以区分其抑制食欲的作用和对能量消耗的假定影响。在治疗的第一周内，利莫那班使体重几乎降至标准大鼠饲料喂养的大鼠的水平。能量平衡评估（通过间接量热法测量的能量消耗与通过弹式量热法计算的可代谢能量摄入量相关）表明，基于脂肪氧化增加的能量消耗增加对体重的持续下降贡献更大，而不是食物摄入量的减少。单纯通过配对喂食减少食物摄入量并没有产生类似的效果，因为动物会减少能量消耗以节省能量储备。由于在餐后状态给药后通过间接量热法测量的脂肪氧化立即增加，因此在餐后雄性大鼠中研究了利莫那班对脂肪分解的急性作用。利莫那班在餐后可提高游离脂肪酸水平，表明利莫那班具有诱导脂肪分解的内在药理活性，而不是由于食物摄入量减少而在吸收后继发产生的。我们得出结论，只要脂肪储备增加，利莫那班的减肥效果是由于脂肪组织中的脂肪分解驱动脂肪氧化增加，从而使能量消耗持续升高。当内源性脂肪储备量下降时，利莫那班诱导的能量消耗增加通过食物摄入量的再次增加得以维持。
