期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：285-290
DOI：10.1073/pnas.1421420112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceObesity and associated metabolic disorders (e.g., cardiovascular disease and type 2 diabetes) are major public health concerns. These disorders result, in part, from hormonal dysregulation, particularly of glucocorticoids (GCs; central regulators of metabolism and adipogenesis). The specific mechanisms by which GCs modulate these processes remain largely unknown, but GCs increase production of endocannabinoids--potent central and peripheral regulators of appetite, energy balance, and metabolism. Our results show that sustained exposure to GCs produces obesity and metabolic syndrome through a peripheral endocannabinoid mechanism. These data further our understanding of the role of endocannabinoid signaling to promote not only diet-induced, but also, hormonal-mediated obesity and support the argument that peripheral blockade of endocannabinoid signaling could be a potential treatment for obese conditions. 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.
