A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome.

Abstract

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.

• Authors: Nicole P Bowles, Ilia N Karatsoreos, Xiaosong Li, V Kiran Vemuri, Jodi-Anne Wood, Zhiying Li, Kellie L K Tamashiro, Gary J Schwartz, Alexandros M Makriyannis, George Kunos, Cecilia J Hillard, Bruce S McEwen, Matthew N Hill
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 112 Issue 1 Pg. 285-90 (Jan 06 2015) ISSN: 1091-6490 [Electronic] United States
• PMID: 25535367 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Endocannabinoids
• Glucocorticoids
• RNA, Messenger
• Receptor, Cannabinoid, CB1
• Corticosterone

Topics

• Animals
• Corticosterone (pharmacology)
• Dyslipidemias (metabolism)
• Endocannabinoids (administration & dosage, metabolism, pharmacology)
• Glucocorticoids (adverse effects)
• Liver (metabolism)
• Metabolic Syndrome (chemically induced, metabolism, pathology)
• Mice, Inbred C57BL
• Obesity (metabolism)
• Organ Specificity (drug effects)
• RNA, Messenger (genetics, metabolism)
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)