Cota Daniela, Marsicano Giovanni, Tschöp Matthias, Grübler Yvonne, Flachskamm Cornelia, Schubert Mirjam, Auer Dorothee, Yassouridis Alexander, Thöne-Reineke Christa, Ortmann Sylvia, Tomassoni Federica, Cervino Cristina, Nisoli Enzo, Linthorst Astrid C E, Pasquali Renato, Lutz Beat, Stalla Günter K, Pagotto Uberto
Clinical Neuroendocrinology Group, Max-Planck-Institute of Psychiatry, Munich, Germany.
J Clin Invest. 2003 Aug;112(3):423-31. doi: 10.1172/JCI17725.
The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.
1型大麻素受体（CB1）及其内源性配体——内源性大麻素，参与食物摄入的调节。在此我们表明，CB1基因敲除小鼠中CB1的缺失导致摄食减少和体型消瘦。与野生型（CB1+/+）同窝小鼠相比，缺乏CB1的小鼠（CB1-/-）自发热量摄入减少，由于总脂肪量减少，体重下降。在年轻的CB1-/-小鼠中，消瘦表型主要由热量摄入减少引起，而在成年CB1-/-小鼠中，代谢因素似乎导致了消瘦表型。在运动活性、体温或能量消耗方面，未检测到不同基因型之间的显著差异。发现下丘脑CB1 mRNA与已知调节食物摄入的神经肽共同表达，如促肾上腺皮质激素释放激素（CRH）、可卡因-安非他明调节转录物（CART）、促黑素细胞激素（MCH）和前阿黑皮素原，这表明内源性大麻素受体在控制食欲的中枢网络中可能发挥作用。CB1-/-小鼠室旁核中CRH mRNA水平显著升高，下丘脑背内侧和外侧区域CART mRNA水平降低。在附睾小鼠脂肪细胞中也检测到CB1，CB1特异性激活增强了原代脂肪细胞培养中的脂肪生成。我们的结果表明，大麻素系统是能量稳态的重要内源性调节因子，通过中枢食欲调节机制以及外周脂肪生成机制发挥作用，因此可能是治疗以能量平衡受损为特征的疾病的一个有前景的靶点。
