Bowles Nicole P, Karatsoreos Ilia N, Li Xiaosong, Vemuri V Kiran, Wood Jodi-Anne, Li Zhiying, Tamashiro Kellie L K, Schwartz Gary J, Makriyannis Alexandros M, Kunos George, Hillard Cecilia J, McEwen Bruce S, Hill Matthew N
Laboratories of Neuroendocrinology and
Laboratories of Neuroendocrinology and Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164;
Proc Natl Acad Sci U S A. 2015 Jan 6;112(1):285-90. doi: 10.1073/pnas.1421420112. Epub 2014 Dec 22.
Glucocorticoids are known to promote the development of metabolic syndrome through the modulation of both feeding pathways and metabolic processes; however, the precise mechanisms of these effects are not well-understood. Recent evidence shows that glucocorticoids possess the ability to increase endocannabinoid signaling, which is known to regulate appetite, energy balance, and metabolic processes through both central and peripheral pathways. The aim of this study was to determine the role of endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. Using a mouse model of excess corticosterone exposure, we found that the ability of glucocorticoids to increase adiposity, weight gain, hormonal dysregulation, hepatic steatosis, and dyslipidemia was reduced or reversed in mice lacking the cannabinoid CB1 receptor as well as mice treated with the global CB1 receptor antagonist AM251. Similarly, a neutral, peripherally restricted CB1 receptor antagonist (AM6545) was able to attenuate the metabolic phenotype caused by chronic corticosterone, suggesting a peripheral mechanism for these effects. Biochemical analyses showed that chronic excess glucocorticoid exposure produced a significant increase in hepatic and circulating levels of the endocannabinoid anandamide, whereas no effect was observed in the hypothalamus. To test the role of the liver, specific and exclusive deletion of hepatic CB1 receptor resulted in a rescue of the dyslipidemic effects of glucocorticoid exposure, while not affecting the obesity phenotype or the elevations in insulin and leptin. Together, these data indicate that glucocorticoids recruit peripheral endocannabinoid signaling to promote metabolic dysregulation, with hepatic endocannabinoid signaling being especially important for changes in lipid metabolism.
已知糖皮质激素通过调节进食途径和代谢过程来促进代谢综合征的发展；然而，这些作用的确切机制尚未完全明确。最近的证据表明，糖皮质激素具有增强内源性大麻素信号传导的能力，而内源性大麻素信号传导已知可通过中枢和外周途径调节食欲、能量平衡和代谢过程。本研究的目的是确定内源性大麻素信号传导在糖皮质激素介导的肥胖和代谢综合征中的作用。使用过量皮质酮暴露的小鼠模型，我们发现，在缺乏大麻素CB1受体的小鼠以及用全球CB1受体拮抗剂AM251治疗的小鼠中，糖皮质激素增加肥胖、体重增加、激素失调、肝脂肪变性和血脂异常的能力降低或逆转。同样，一种中性的、外周受限的CB1受体拮抗剂（AM6545）能够减轻慢性皮质酮引起的代谢表型，表明这些作用存在外周机制。生化分析表明，慢性过量糖皮质激素暴露导致肝脏和循环中内源性大麻素花生四烯乙醇胺水平显著升高，而下丘脑未观察到影响。为了测试肝脏的作用，特异性和排他性地删除肝脏CB1受体可挽救糖皮质激素暴露引起的血脂异常作用，同时不影响肥胖表型或胰岛素和瘦素的升高。总之，这些数据表明，糖皮质激素通过募集外周内源性大麻素信号传导来促进代谢失调，其中肝脏内源性大麻素信号传导对脂质代谢变化尤为重要。
