Metabolic Diseases Institute, University of Cincinnati, 2140 East Galbraith Road, Building B, Room 332, Cincinnati, OH 45237-1625, USA.
Diabetologia. 2011 Dec;54(12):3121-31. doi: 10.1007/s00125-011-2302-6. Epub 2011 Oct 11.
AIMS/HYPOTHESIS: We examined the physiological mechanisms by which cannabinoid receptor 1 (CB1) antagonism improves glucose metabolism and insulin sensitivity independent of its anorectic and weight-reducing effects, as well as the effects of CB1 antagonism on brown adipose tissue (BAT) function.
Three groups of diet-induced obese mice received for 1 month: vehicle; the selective CB1 antagonist SR141716; or vehicle/pair-feeding. After measurements of body composition and energy expenditure, mice underwent euglycaemic-hyperinsulinaemic clamp studies to assess in vivo insulin action. In separate cohorts, we assessed insulin action in weight-reduced mice with diet-induced obesity (DIO), and the effect of CB1 antagonism on BAT thermogenesis. Surgical denervation of interscapular BAT (iBAT) was carried out in order to study the requirement for the sympathetic nervous system in mediating the effects of CB1 antagonism on BAT function.
Weight loss associated with chronic CB1 antagonism was accompanied by increased energy expenditure, enhanced insulin-stimulated glucose utilisation, and marked activation of BAT thermogenesis. Insulin-dependent glucose uptake was significantly increased in white adipose tissue and BAT, whereas glycogen synthesis was increased in liver, fat and muscle. Despite marked weight loss in the mice, SR141716 treatment did not improve insulin-mediated suppression of hepatic glucose production nor increase skeletal muscle glucose uptake. Denervation of iBAT blunted the effect of SR141716 on iBAT differentiation and insulin-mediated glucose uptake.
CONCLUSIONS/INTERPRETATION: Chronic CB1 antagonism markedly enhances insulin-mediated glucose utilisation in DIO mice, independent of its anorectic and weight-reducing effects. The potent effect on insulin-stimulated BAT glucose uptake reveals a novel role for CB1 receptors as regulators of glucose metabolism.
目的/假设：我们研究了大麻素受体 1 (CB1) 拮抗剂改善葡萄糖代谢和胰岛素敏感性的生理机制，这些作用独立于其厌食和减重作用，以及 CB1 拮抗剂对棕色脂肪组织 (BAT) 功能的影响。
三组饮食诱导肥胖的小鼠接受了为期 1 个月的治疗：载体；选择性 CB1 拮抗剂 SR141716；或载体/配对喂养。在测量身体成分和能量消耗后，小鼠进行了正常血糖高胰岛素钳夹研究，以评估体内胰岛素作用。在另一组实验中，我们评估了饮食诱导肥胖（DIO）小鼠体重减轻后的胰岛素作用，以及 CB1 拮抗剂对 BAT 产热的影响。对肩胛间 BAT（iBAT）进行了外科去神经支配，以研究交感神经系统在介导 CB1 拮抗剂对 BAT 功能的影响中的作用。
慢性 CB1 拮抗剂治疗伴随的体重减轻伴随着能量消耗增加、胰岛素刺激的葡萄糖利用增强和 BAT 产热的显著激活。胰岛素依赖性葡萄糖摄取在白色脂肪组织和 BAT 中显著增加，而糖原合成在肝脏、脂肪和肌肉中增加。尽管小鼠体重明显减轻，但 SR141716 治疗并没有改善胰岛素介导的肝葡萄糖产生抑制，也没有增加骨骼肌葡萄糖摄取。iBAT 去神经支配削弱了 SR141716 对 iBAT 分化和胰岛素介导的葡萄糖摄取的影响。
结论/解释：慢性 CB1 拮抗剂显著增强了 DIO 小鼠中胰岛素介导的葡萄糖利用，独立于其厌食和减重作用。对胰岛素刺激的 BAT 葡萄糖摄取的强烈影响揭示了 CB1 受体作为葡萄糖代谢调节剂的新作用。
