Pagotto Uberto, Vicennati Valentina, Pasquali Renato
Endocrinology Unit and Center for Applied Biomedical Research, Dept. of Internal Medicine and Gastroenterology, S. Orsola-Malpighi General Hospital, Bologna, Italy.
Ann Med. 2005;37(4):270-5. doi: 10.1080/07853890510037419.
The endocannabinoids are endogenous lipids capable of binding to both cannabinoid receptors (CB) CB1 and CB2. These receptors belong to the G protein-coupled family receptors and they were discovered while investigating the mode of action of ?(9)-tetrahydrocannabinol, a component of Cannabis sativa, to which they bind with high affinity. Among many other brain sites, CB1 is present in the hypothalamic nuclei involved in the control of energy balance and body weight, as well as in neurons of the mesolimbic system which is believed to mediate the incentive value of food. At central nervous system level, CB1 activation is necessary to induce food intake after a short period of food deprivation, and when CB1 is activated by endocannabinoids produced in situ, a stimulation of the ingestion of palatable food has been described. CB1 stimulation leads to modulation of the release of some hypothalamic anorexigenic and orexigenic mediators, as well as of dopamine in the nucleus accumbens shell. Recent evidence has proved that CB1 is also present in the peripheral organs, such as the adipose tissue and gastrointestinal system, key organs in the regulation of energy metabolism. Animal models have provided solid evidence that genetically induced obesity leads to long-lasting overstimulation of endocannabinoid system synthesis resulting in permanent overactivation of CB1, which may then contribute to the maintenance of this disease. Importantly, at peripheral level, CB1 activation has been shown to stimulate lipogenesis in adipocytes. CB1 blockers increase adiponectin production in adipocytes, which leads to increased fatty acid oxidation and free fatty acid clearance. Moreover, CB1 has been shown to be up-regulated in adipocytes derived from obese rodents. These results support the role of endocannabinoids in the development and maintenance of obesity, paving the way for the development of a new class of drugs such as the CB1 blockers as a therapy for tackling obesity and the associated major cardiovascular risk factors.
内源性大麻素是一类内源性脂质，能够与大麻素受体（CB）CB1和CB2结合。这些受体属于G蛋白偶联家族受体，它们是在研究大麻（Cannabis sativa）的一种成分Δ(9)-四氢大麻酚的作用模式时被发现的，内源性大麻素能与其高亲和力结合。在许多其他脑区中，CB1存在于参与能量平衡和体重控制的下丘脑核团中，也存在于中脑边缘系统的神经元中，据信该系统介导食物的奖励价值。在中枢神经系统水平，短期禁食后诱导食物摄入需要激活CB1，并且当CB1被原位产生的内源性大麻素激活时，会出现对美味食物摄入的刺激。刺激CB1会导致一些下丘脑厌食和促食欲介质的释放以及伏隔核壳中多巴胺的释放受到调节。最近的证据表明，CB1也存在于外周器官中，如脂肪组织和胃肠道系统，这些都是能量代谢调节中的关键器官。动物模型提供了确凿的证据，表明基因诱导的肥胖会导致内源性大麻素系统合成长期过度刺激，从而导致CB1持续过度激活，这可能进而导致这种疾病的持续存在。重要的是，在外周水平，已证明激活CB1会刺激脂肪细胞中的脂肪生成。CB1阻滞剂会增加脂肪细胞中脂联素的产生，从而导致脂肪酸氧化增加和游离脂肪酸清除增加。此外，已证明在肥胖啮齿动物来源的脂肪细胞中CB1上调。这些结果支持了内源性大麻素在肥胖发生和维持中的作用，为开发一类新型药物（如CB1阻滞剂）作为治疗肥胖及相关主要心血管危险因素的疗法铺平了道路。
