Matias Isabel, Vergoni Anna Valeria, Petrosino Stefania, Ottani Alessandra, Pocai Alessandro, Bertolini Alfio, Di Marzo Vincenzo
Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, 80078 Pozzuoli (NA), Italy.
Neuropharmacology. 2008 Jan;54(1):206-12. doi: 10.1016/j.neuropharm.2007.06.011. Epub 2007 Jun 29.
Endocannabinoids are paracrine/autocrine lipid mediators with several biological functions. One of these, i.e. the capability to stimulate food intake via cannabinoid CB(1) receptors, has been particularly studied, thus leading to the development of the first CB(1) receptor blocker, rimonabant, as a therapeutic tool against obesity and related metabolic disorders. Hypothalamic endocannabinoids stimulate appetite by regulating the expression and release of anorexic and orexigenic neuropeptides via CB(1) receptors. In turn, the tone of the latter receptors is regulated by hormones, including leptin, glucocorticoids and possibly ghrelin and neuropeptide Y, by modulating the biosynthesis of the endocannabinoids in various areas of the hypothalamus. CB(1) receptor stimulation is also known to increase blood glucose during an oral glucose tolerance test in rats. Here we investigated in the rat if insulin, which is known to exert fundamental actions at the level of the mediobasal hypothalamus (MBH), and the melanocortin system, namely alpha-melanocyte stimulating hormone (alpha-MSH) and melanocortin receptor-4 (MCR-4), also regulate hypothalamic endocannabinoid levels, measured by isotope-dilution liquid chromatography coupled to mass spectrometry. No effect on anandamide and 2-arachidonoylglycerol levels was observed after 2h infusion of insulin in the MBH, i.e. under conditions in which the hormone reduces blood glucose, nor with intra-cerebroventricular injection of alpha-MSH, under conditions in which the neuropeptide reduces food intake. Conversely, blockade of MCR-4 receptors with HS014 produced a late (6h after systemic administration) stimulatory effect on endocannabinoid levels as opposed to a rapid and prolonged stimulation of food-intake (observable 2 and 6h after administration). These data suggest that inhibition of endocannabinoid levels does not mediate the effect of insulin on hepatic glucose production nor the food intake-inhibitory effect of alpha-MSH, although stimulation of endocannabinoid levels might underlie part of the late stimulatory effects of MCR-4 blockade on food intake.
内源性大麻素是具有多种生物学功能的旁分泌/自分泌脂质介质。其中之一，即通过大麻素CB(1)受体刺激食物摄入的能力，已得到特别研究，从而促使首个CB(1)受体阻滞剂利莫那班的研发，作为治疗肥胖及相关代谢紊乱的工具。下丘脑内源性大麻素通过CB(1)受体调节厌食和促食欲神经肽的表达与释放来刺激食欲。反过来，后者受体的活性受激素调节，包括瘦素、糖皮质激素，可能还有胃饥饿素和神经肽Y，它们通过调节下丘脑各区域内源性大麻素的生物合成来实现。已知在大鼠口服葡萄糖耐量试验中，刺激CB(1)受体也会使血糖升高。在此，我们研究了在大鼠中，已知在中基底下丘脑(MBH)水平发挥重要作用的胰岛素以及黑皮质素系统，即α-黑素细胞刺激素(α-MSH)和黑皮质素受体-4(MCR-4)，是否也调节下丘脑内源性大麻素水平，该水平通过同位素稀释液相色谱-质谱联用进行测定。在MBH中输注胰岛素2小时后，即在该激素降低血糖的条件下，未观察到对花生四烯乙醇胺和2-花生四烯酸甘油水平有影响；在脑室内注射α-MSH后，即在该神经肽减少食物摄入的条件下，也未观察到影响。相反，用HS014阻断MCR-4受体对内源性大麻素水平产生了延迟（全身给药后6小时）的刺激作用，与之相对的是对食物摄入的快速且持久的刺激作用（给药后2小时和6小时可观察到）。这些数据表明，抑制内源性大麻素水平并不介导胰岛素对肝脏葡萄糖生成的作用，也不介导α-MSH对食物摄入的抑制作用，尽管内源性大麻素水平的刺激可能是MCR-4阻断对食物摄入的部分延迟刺激作用的基础。
