Department of Physiology, School of Medicine, University of Santiago de Compostela-Instituto de Investigación Sanitaria, S Francisco s/n, Santiago de Compostela (A Coruña), Spain
Diabetes Obes Metab. 2012 Mar;14(3):234-43. doi: 10.1111/j.1463-1326.2011.01515.x. Epub 2011 Nov 7.
Cannabinoids are known to control energy homeostasis. Atypical cannabinoids produce pharmacological effects via unidentified targets. We sought to investigate whether the atypical cannabinoid O-1602 controls food intake and body weight.
The rats were injected acutely or subchronically with O-1602, and the expression of several factors involved in adipocyte metabolism was assessed by real-time polymerase chain reaction. In vivo findings were corroborated with in vitro studies incubating 3T3-L1 adipocytes with O-1602, and measuring intracellular calcium and lipid accumulation. Finally, as some reports suggest that O-1602 is an agonist of the putative cannabinoid receptor GPR55, we tested it in mice lacking GPR55.
Central and peripheral administration of O-1602 acutely stimulates food intake, and chronically increases adiposity. The hyperphagic action of O-1602 is mediated by the downregulation of mRNA and protein levels of the anorexigenic neuropeptide cocaine- and amphetamine-regulated transcript. The effects on fat mass are independent of food intake, and involve a decrease in the expression of lipolytic enzymes such as hormone sensitive lipase and adipose triglyceride lipase in white adipose tissue. Consistently, in vitro data showed that O-1602 increased the levels of intracellular calcium and lipid accumulation in adipocytes. Finally, we injected O-1602 in GPR55 -/- mice and found that O-1602 was able to induce feeding behaviour in GPR55-deficient mice.
These findings show that O-1602 modulates food intake and adiposity independently of GPR55 receptor. Thus atypical cannabinoids may represent a novel class of molecules involved in energy balance.
大麻素已知可控制能量平衡。非典型大麻素通过未识别的靶点产生药理作用。我们试图研究非典型大麻素 O-1602 是否控制食物摄入和体重。
大鼠急性或亚慢性注射 O-1602，实时聚合酶链反应评估参与脂肪细胞代谢的几种因子的表达。体内发现与 3T3-L1 脂肪细胞孵育 O-1602 并测量细胞内钙和脂质积累的体外研究相吻合。最后，由于一些报告表明 O-1602 是假定的大麻素受体 GPR55 的激动剂，我们在缺乏 GPR55 的小鼠中测试了它。
O-1602 中枢和外周给药可急性刺激食物摄入，慢性增加肥胖。O-1602 的致肥胖作用是通过下调厌食性神经肽可卡因和安非他命调节转录物的 mRNA 和蛋白水平介导的。对脂肪量的影响与食物摄入无关，涉及白色脂肪组织中脂肪分解酶（如激素敏感脂肪酶和脂肪甘油三酯脂肪酶）表达的降低。一致地，体外数据表明 O-1602 增加了脂肪细胞内钙和脂质积累的水平。最后，我们在 GPR55 -/- 小鼠中注射 O-1602，发现 O-1602 能够在 GPR55 缺陷型小鼠中诱导摄食行为。
这些发现表明 O-1602 可独立于 GPR55 受体调节食物摄入和肥胖。因此，非典型大麻素可能代表参与能量平衡的新型分子类别。
