A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome

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

Research output: Contribution to journalArticlepeer-review

57 Scopus 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.

Original languageEnglish (US)
Pages (from-to)285-290
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number1
DOIs
StatePublished - Jan 6 2015

Keywords

  • 2-AG
  • Anandamide
  • Corticosterone
  • Liver
  • Obesity

ASJC Scopus subject areas

  • General

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