Faculty Collaboration Database

A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc Natl Acad Sci U S A 2015 Jan 06;112(1):285-90

Date

12/24/2014

Pubmed ID

25535367

Pubmed Central ID

PMC4291642

DOI

10.1073/pnas.1421420112

Scopus ID

2-s2.0-84920450557 (requires institutional sign-in at Scopus site)   92 Citations

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.

Author List

Bowles NP, Karatsoreos IN, Li X, Vemuri VK, Wood JA, Li Z, Tamashiro KL, Schwartz GJ, Makriyannis AM, Kunos G, Hillard CJ, McEwen BS, Hill MN

Author

Cecilia J. Hillard PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Corticosterone
Dyslipidemias
Endocannabinoids
Glucocorticoids
Liver
Metabolic Syndrome
Mice, Inbred C57BL
Obesity
Organ Specificity
RNA, Messenger
Receptor, Cannabinoid, CB1
Signal Transduction