Wei L W, Yuan Z Q, Zhao M D, Gu C W, Han J H, Fu L
Laboratory Animal Center, Southwest Medical University, Luzhou, Sichuan, 646000, China.
Department of Orthopaedics, The First Affiliated Hospital, Orthopaedic Institute, Soochow University, Suzhou, Jiangsu, 215006, China.
Biochemistry (Mosc). 2018 Oct;83(10):1279-1287. doi: 10.1134/S0006297918100127.
A growing number of evidences accumulated about critical metabolic role of cannabinoid type 1 receptor (CB1), carnitine palmitoyltransferase-1 (CPT1) and peroxisome proliferator-activated receptors (PPARs) in some peripheral tissues, including adipose tissue, liver, skeletal muscle and heart. To better understand the interactions of CB1, CPT1 and PPARs in these tissues, 30 diet-induced obese (DIO) C57BL/6J male mice were obtained, weight-matched and divided into two groups (15 in each group): (i) DIO/vehicle mice (D-Veh) and (ii) DIO/SR141716 mice (D-SR) treated with SR141716 (or rimonabant, a selective CB1 receptor blocker) administered orally (10 mg/kg daily). Another 15 mice fed standard diet (STD) formed the STD/vehicle group (S-Veh). At the end of 3-week treatment, mean body weight was 28.4 ± 0.5, 36.5 ± 0.8, and 30.3 ± 1.2 g for the S-Veh, D-Veh, and D-SR group, respectively (p < 0.05; D-Veh vs. D-SR). Liver weight in the D-SR group was also decreased significantly compared to the D-Veh group (p < 0.05). Serum levels of total cholesterol, high-density lipoprotein cholesterol, leptin and adiponectin in the D-SR group were ameliorated compared to the D-Veh group (p < 0.05). Both qRT-PCR and Western blot assay revealed that CB1 expression levels were efficiently blocked by SR141716 in subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), skeletal muscles and liver (D-SR vs. D-Veh; p < 0.05), whereas there was no significant difference between S-Veh and D-Veh mice (p > 0.05). Simultaneously with the reduction of CB1 expression in the D-SR group, the expression levels of CPT1A isoform (protein) in the liver and heart and CPT1B isoform (protein) in the SAT, VAT, liver and skeletal muscles were significantly increased (p < 0.05; D-SR vs. D-Veh). Interestingly, the CPT1A and CPT1B expression levels in heart were detected slightly. The expression levels of PPARα in the SAT, VAT, liver and skeletal muscles and PPARγ in the SAT and skeletal muscles in the D-SR group were significantly increased compared to the D-Veh mice (p < 0.05). However, the PPARβ expression level differed from that of PPARα and PPARγ. Taken together, these data indicate that the inhibition of CB1 could ameliorate lipid metabolism via the stimulation of the CPT1A and CPT1B expression in vivo. Simultaneously, the PPARα and PPARγ expression levels significantly differed compared to that of PPARβ in obesity and lipid metabolism-related disorders under blockade of CB1. Both the mechanism of the influence of CB1 inhibition on lipid metabolism in the examined tissues and the specific mechanism of PPARα, PPARγ and PPARβ involvement in lipid exchange under these conditions remain to be further elucidated.
越来越多的证据表明，1型大麻素受体（CB1）、肉碱棕榈酰转移酶-1（CPT1）和过氧化物酶体增殖物激活受体（PPARs）在包括脂肪组织、肝脏、骨骼肌和心脏在内的一些外周组织中发挥着关键的代谢作用。为了更好地理解CB1、CPT1和PPARs在这些组织中的相互作用，我们获取了30只饮食诱导肥胖（DIO）的C57BL/6J雄性小鼠，将体重匹配的小鼠分为两组（每组15只）：（i）DIO/载体小鼠（D-Veh）和（ii）用SR141716（或利莫那班，一种选择性CB1受体阻滞剂）口服给药（每日10 mg/kg）处理的DIO/SR141716小鼠（D-SR）。另外15只喂食标准饮食（STD）的小鼠组成STD/载体组（S-Veh）。在3周治疗结束时，S-Veh、D-Veh和D-SR组的平均体重分别为28.4±0.5、36.5±0.8和30.3±1.2 g（p<0.05；D-Veh与D-SR相比）。与D-Veh组相比，D-SR组的肝脏重量也显著降低（p<0.05）。与D-Veh组相比，D-SR组的血清总胆固醇、高密度脂蛋白胆固醇、瘦素和脂联素水平有所改善（p<0.05）。qRT-PCR和蛋白质印迹分析均显示，SR141716可有效阻断皮下脂肪组织（SAT）、内脏脂肪组织（VAT）、骨骼肌和肝脏中CB1的表达水平（D-SR与D-Veh相比；p<0.05），而S-Veh和D-Veh小鼠之间无显著差异（p>0.05）。在D-SR组中，随着CB1表达的降低，肝脏和心脏中CPT1A亚型（蛋白质）以及SAT、VAT、肝脏和骨骼肌中CPT1B亚型（蛋白质）的表达水平显著升高（p<0.05；D-SR与D-Veh相比）。有趣的是，心脏中CPT1A和CPT1B的表达水平检测结果较低。与D-Veh小鼠相比，D-SR组中SAT、VAT、肝脏和骨骼肌中PPARα以及SAT和骨骼肌中PPARγ的表达水平显著升高（p<0.05）。然而，PPARβ的表达水平与PPARα和PPARγ不同。综上所述，这些数据表明，抑制CB1可通过刺激体内CPT1A和CPT1B的表达来改善脂质代谢。同时，在CB1阻断的情况下，肥胖和脂质代谢相关疾病中PPARα和PPARγ的表达水平与PPARβ相比有显著差异。CB1抑制对所检测组织中脂质代谢的影响机制以及在这些条件下PPARα、PPARγ和PPARβ参与脂质交换的具体机制仍有待进一步阐明。
