Unité Mixte de Recherche 866 Institut National de la Santé et de la Recherche Médicale-Université de Bourgogne, Team Physiopathology of Dyslipidemia, Faculty of Sciences Gabriel, Dijon, France.
Diabetes. 2010 Apr;59(4):926-34. doi: 10.2337/db09-1482. Epub 2010 Jan 28.
The beneficial effects of the inactivation of endocannabinoid system (ECS) by administration of antagonists of the cannabinoid receptor (CB) 1 on several pathological features associated with obesity is well demonstrated, but the relative contribution of central versus peripheral mechanisms is unclear. We examined the impact of CB1 antagonism on liver and adipose tissue lipid metabolism in a mouse model of diet-induced obesity.
Mice were fed either with a standard diet or a high-sucrose high-fat (HSHF) diet for 19 weeks and then treated with the CB1-specific antagonist SR141716 (10 mg x kg(-1) x day(-1)) for 6 weeks.
Treatment with SR141716 reduced fat mass, insulin levels, and liver triglycerides primarily increased by HSHF feeding. Serum adiponectin levels were restored after being reduced in HSHF mice. Gene expression of scavenger receptor class B type I and hepatic lipase was induced by CB1 blockade and associated with an increase in HDL-cholesteryl ether uptake. Concomitantly, the expression of CB1, which was strongly increased in the liver and adipose tissue of HSHF mice, was totally normalized by the treatment. Interestingly, in visceral but not subcutaneous fat, genes involved in transport, synthesis, oxidation, and release of fatty acids were upregulated by HSHF feeding, while this effect was counteracted by CB1 antagonism.
A reduction in the CB1-mediated ECS activity in visceral fat is associated with a normalization of adipocyte metabolism, which may be a determining factor in the reversion of liver steatosis induced by treatment with SR141716.
通过给予大麻素受体（CB）1 拮抗剂使内源性大麻素系统（ECS）失活，对与肥胖相关的几种病理特征具有有益的影响，这已得到充分证明，但中枢与外周机制的相对贡献尚不清楚。我们在饮食诱导肥胖的小鼠模型中检查了 CB1 拮抗作用对肝脏和脂肪组织脂质代谢的影响。
小鼠喂食标准饮食或高蔗糖高脂肪（HSHF）饮食 19 周，然后用 CB1 特异性拮抗剂 SR141716（10 mg·kg(-1)·d(-1)）治疗 6 周。
SR141716 治疗主要降低了 HSHF 喂养引起的脂肪量、胰岛素水平和肝甘油三酯。HSHF 小鼠的血清脂联素水平降低后得到恢复。CB1 阻断诱导了清道夫受体 B 类 I 型和肝脂肪酶的基因表达，并与 HDL-胆甾醇醚摄取增加相关。同时，CB1 的表达在 HSHF 小鼠的肝脏和脂肪组织中强烈增加，通过治疗完全恢复正常。有趣的是，在内脏脂肪中，但不在皮下脂肪中，脂肪酸的转运、合成、氧化和释放相关基因的表达被 HSHF 喂养上调，而这种效应被 CB1 拮抗作用抵消。
内脏脂肪中 CB1 介导的 ECS 活性降低与脂肪细胞代谢的正常化相关，这可能是 SR141716 治疗逆转肝脂肪变性的决定因素。
