1Márta Korbonits, Dept. of Endocrinology, Barts and the London School of Medicine and Dentistry, Charterhouse Sq., London EC1M 6BQ, UK.
FASEB J. 2013 Dec;27(12):5112-21. doi: 10.1096/fj.13-232918. Epub 2013 Aug 27.
This study aimed to investigate whether the growth hormone release and metabolic effects of ghrelin on AMPK activity of peripheral tissues are mediated by cannabinoid receptor type 1 (CB1) and the central nervous system. CB1-knockout (KO) and/or wild-type mice were injected peripherally or intracerebroventricularly with ghrelin and CB1 antagonist rimonabant to study tissue AMPK activity and gene expression (transcription factors SREBP1c, transmembrane protein FAS, enzyme PEPCK, and protein HSL). Growth hormone levels were studied both in vivo and in vitro. Peripherally administered ghrelin in liver, heart, and adipose tissue AMPK activity cannot be observed in CB1-KO or CB1 antagonist-treated mice. Intracerebroventricular ghrelin treatment can influence peripheral AMPK activity. This effect is abolished in CB1-KO mice and by intracerebroventricular rimonabant treatment, suggesting that central CB1 receptors also participate in the signaling pathway that mediates the effects of ghrelin on peripheral tissues. Interestingly, in vivo or in vitro growth hormone release is intact in response to ghrelin in CB1-KO animals. Our data suggest that the metabolic effects of ghrelin on AMPK in peripheral tissues are abolished by the lack of functional CB1 receptor via direct peripheral effect and partially through the central nervous system, thus supporting the existence of a possible ghrelin-cannabinoid-CB1-AMPK pathway.
本研究旨在探讨生长激素释放和 ghrelin 对 AMPK 活性的代谢作用是否通过大麻素受体 1（CB1）和中枢神经系统介导。通过外周或脑室内注射 ghrelin 和 CB1 拮抗剂 rimonabant 研究组织 AMPK 活性和基因表达（转录因子 SREBP1c、跨膜蛋白 FAS、酶 PEPCK 和蛋白 HSL），研究 CB1-KO 和野生型小鼠。同时在体内和体外研究生长激素水平。在外周给予 CB1-KO 或 CB1 拮抗剂处理的小鼠中，不能观察到 ghrelin 在肝脏、心脏和脂肪组织中对 AMPK 活性的影响。脑室内给予 ghrelin 可以影响外周 AMPK 活性。这种效应在 CB1-KO 小鼠中被消除，并且通过脑室内给予 rimonabant 处理也被消除，表明中枢 CB1 受体也参与了介导 ghrelin 对周围组织作用的信号通路。有趣的是，在 CB1-KO 动物中，生长激素的释放对 ghrelin 的反应在体内或体外都是完整的。我们的数据表明，缺乏功能性 CB1 受体通过直接外周作用和部分通过中枢神经系统，使 ghrelin 对周围组织中 AMPK 的代谢作用被消除，从而支持可能存在 ghrelin-大麻素-CB1-AMPK 途径的存在。
