The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis
The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis
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DOI：
10.1172/jci200317725
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发表时间：
2003-08-01
影响因子：
15.9
通讯作者：
Pagotto, U
中科院分区：
文献类型：
--
作者：
Cota, D;Marsicano, G;Pagotto, U
大麻素受体1型（CB 1）及其内源性配体，内源性大麻素，参与调节食物摄入。在这里，我们表明，缺乏CB 1的小鼠与破坏CB 1基因导致食欲减退和精益。与WT（CB 1（+/+））同窝出生的小鼠相比，缺乏CB 1的小鼠（CB 1（-/-））表现出减少的自发热量摄入，并且由于总脂肪量减少，体重降低。在年轻的CB 1（-/-）小鼠中，瘦型主要是由热量摄入减少引起的，而在成年CB 1（-/-）小鼠中，代谢因素似乎有助于瘦型。在自发活动、体温或能量消耗方面，基因型之间没有显着差异。发现下丘脑CB 1 mRNA与已知调节食物摄入的神经肽共表达，如促肾上腺皮质激素释放激素（CRH）、可卡因-苯丙胺调节转录物（CART）、黑色素浓缩激素（MCH）和前食欲素原，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。CB 1（-/-）小鼠室旁核CRH mRNA水平显著升高，下丘脑背内侧区和外侧区CART mRNA水平显著降低。CB 1也可在正常小鼠脂肪细胞中检测到，CB 1特异性激活可增强原代脂肪细胞培养物的成脂作用。我们的研究结果表明，大麻素系统是一个必不可少的内源性调节能量稳态通过中央食欲以及外周脂肪生成机制，因此可能代表一个有前途的目标，以治疗疾病的特点是受损的能量平衡。
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 CB 1 (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 CB 1 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 prepro-orexin, 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 hpogenesis 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.