Department of Physiology, Monash University, Clayton, Victoria, Australia.
Int J Obes (Lond). 2013 Feb;37(2):279-87. doi: 10.1038/ijo.2012.35. Epub 2012 Apr 3.
Current anti-obesity monotherapies have proven only marginally effective and are often accompanied by adverse side effects. The cannabinoid 1 (CB1) receptor antagonist rimonabant, while effective at producing weight loss, has been discontinued from clinical use owing to increased incidence of depression. This study investigates the interaction between the cannabinoid and melanin-concentrating hormone (MCH) systems in food intake, body weight control, and mood.
Lean male C57BL/6 mice were injected i.p. with rimonabant (0.0, 0.03, 0.3 and 3.0 mg kg(-1)) or the MCH1-R antagonist SNAP-94847 (0.0, 1.0, 5.0 and 10.0 mg kg(-1)) to establish dose response parameters for each drug. Diet-induced obese (DIO) mice were given either vehicle, sub-threshold dose of rimonabant and SNAP-94847 alone or in combination. Impact on behavioral outcomes, food intake, body weight, plasma metabolites and expression of key metabolic proteins in the brown adipose tissue (BAT) and white adipose tissue (WAT) were measured.
The high doses of rimonabant and SNAP-94847 produced a reduction in food intake after 2 and 24 h. Combining sub-threshold doses of rimonabant and SNAP-94847 produced a significantly greater loss of body weight in DIO mice compared with vehicle and monotherapies. In addition, combining sub effective doses of these drugs led to a shift in markers of thermogenesis in BAT and lipid metabolism in WAT consistent with increased energy expenditure and lipolysis. Furthermore, co-administration of rimonabant and SNAP-94847 produced a transient reduction in food intake, and significantly reduced fat mass and adipocyte size. Importantly, SNAP-94847 significantly attenuated the ability of rimonabant to reduced immobility time in the forced swim test.
These results provide proof of principle that combination of rimonabant and a MCH1 receptor antagonist is highly effective in reducing body weight below that achieved by rimonabant and SNAP-94847 monotherapies. In addition, the combination therapy normalizes the rimonabant-induced behavioral changes seen in the forced swim test.
目前的抗肥胖单药治疗仅证明有一定效果，且常伴有不良反应。大麻素 1（CB1）受体拮抗剂利莫那班虽然能有效减肥，但由于抑郁发生率增加，已从临床应用中停用。本研究探讨了大麻素和黑色素浓缩激素（MCH）系统在食物摄入、体重控制和情绪方面的相互作用。
向 lean 雄性 C57BL/6 小鼠腹腔注射利莫那班（0.0、0.03、0.3 和 3.0mg/kg）或 MCH1-R 拮抗剂 SNAP-94847（0.0、1.0、5.0 和 10.0mg/kg），以建立每种药物的剂量反应参数。给予饮食诱导肥胖（DIO）小鼠单独或联合使用载体、利莫那班和 SNAP-94847 的亚阈值剂量。测量行为结果、食物摄入、体重、血浆代谢物以及棕色脂肪组织（BAT）和白色脂肪组织（WAT）中关键代谢蛋白的表达。
利莫那班和 SNAP-94847 的高剂量在 2 和 24 小时后导致食物摄入量减少。与载体和单药治疗相比，联合使用亚阈值剂量的利莫那班和 SNAP-94847 可显著减轻 DIO 小鼠的体重。此外，这些药物的亚有效剂量联合使用可导致 BAT 产热标志物和 WAT 脂质代谢的变化，与能量消耗和脂肪分解增加一致。此外，利莫那班和 SNAP-94847 的联合给药可导致食物摄入量短暂减少，并显著降低脂肪质量和脂肪细胞大小。重要的是，SNAP-94847 显著减弱了利莫那班降低强迫游泳试验中不动时间的能力。
这些结果提供了原则性的证据，表明利莫那班和 MCH1 受体拮抗剂的联合治疗可有效降低体重，低于利莫那班和 SNAP-94847 单药治疗的体重。此外，联合治疗使利莫那班在强迫游泳试验中引起的行为变化正常化。
