Di Marzo V, Goparaju S K, Wang L, Liu J, Bátkai S, Járai Z, Fezza F, Miura G I, Palmiter R D, Sugiura T, Kunos G
Endocannabinoid Research Group, Istituto per la Chimica di Molecole di Interesse Biologico, CNR, 80072, Arco Felice, Naples, Italy.
Nature. 2001 Apr 12;410(6830):822-5. doi: 10.1038/35071088.
Leptin is the primary signal through which the hypothalamus senses nutritional state and modulates food intake and energy balance. Leptin reduces food intake by upregulating anorexigenic (appetite-reducing) neuropeptides, such as alpha-melanocyte-stimulating hormone, and downregulating orexigenic (appetite-stimulating) factors, primarily neuropeptide Y. Genetic defects in anorexigenic signalling, such as mutations in the melanocortin-4 (ref. 5) or leptin receptors, cause obesity. However, alternative orexigenic pathways maintain food intake in mice deficient in neuropeptide Y. CB1 cannabinoid receptors and the endocannabinoids anandamide and 2-arachidonoyl glycerol are present in the hypothalamus, and marijuana and anandamide stimulate food intake. Here we show that following temporary food restriction, CB1 receptor knockout mice eat less than their wild-type littermates, and the CB1 antagonist SR141716A reduces food intake in wild-type but not knockout mice. Furthermore, defective leptin signalling is associated with elevated hypothalamic, but not cerebellar, levels of endocannabinoids in obese db/db and ob/ob mice and Zucker rats. Acute leptin treatment of normal rats and ob/ob mice reduces anandamide and 2-arachidonoyl glycerol in the hypothalamus. These findings indicate that endocannabinoids in the hypothalamus may tonically activate CB1 receptors to maintain food intake and form part of the neural circuitry regulated by leptin.
瘦素是下丘脑感知营养状态并调节食物摄入和能量平衡的主要信号。瘦素通过上调促厌食（减少食欲）的神经肽，如α-黑素细胞刺激素，并下调促食欲（刺激食欲）的因子，主要是神经肽Y，来减少食物摄入。促厌食信号传导中的基因缺陷，如黑皮质素-4（参考文献5）或瘦素受体的突变，会导致肥胖。然而，替代的促食欲途径维持了缺乏神经肽Y的小鼠的食物摄入。CB1大麻素受体以及内源性大麻素花生四烯乙醇胺和2-花生四烯酸甘油存在于下丘脑中，大麻和花生四烯乙醇胺会刺激食物摄入。在此我们表明，在短期食物限制后，CB1受体基因敲除小鼠比其野生型同窝小鼠吃得少，并且CB1拮抗剂SR141716A可减少野生型小鼠而非基因敲除小鼠的食物摄入。此外，在肥胖的db/db和ob/ob小鼠以及 Zucker大鼠中，瘦素信号传导缺陷与下丘脑而非小脑中内源性大麻素水平升高有关。对正常大鼠和ob/ob小鼠进行急性瘦素治疗可降低下丘脑中的花生四烯乙醇胺和2-花生四烯酸甘油。这些发现表明，下丘脑中的内源性大麻素可能持续激活CB1受体以维持食物摄入，并构成受瘦素调节的神经回路的一部分。
