Editors' ChoiceMetabolism

Endocannabinoids in glucocorticoid-induced metabolic syndrome

Sci. Signal.  20 Jan 2015:
Vol. 8, Issue 360, pp. ec15
DOI: 10.1126/scisignal.aaa6954

Glucocorticoids are hormones that regulate metabolism and inflammation. Because of their anti-inflammatory properties, they are used clinically. However, a major side effect of long-term glucocorticoid treatment is metabolic syndrome, which is characterized by weight gain, glucose intolerance, insulin insensitivity, and dyslipidemia. Bowles et al. used a mouse model of chronic glucocorticoid administration as a system to test the role of endocannabinoids (endogenous cannabinoids) in this drug-induced metabolic disorder. Changes associated with glucocorticoid-induced metabolic syndrome were attenuated in mice with a global knockout of the cannabinoid 1 receptor (CB1R) or mice administered a peripheral- and central-acting inhibitor of this receptor. Quantification of endocannabinoids in the circulation, white adipose tissue, liver, and brain showed that glucocorticoids induced an increase in two endocannabinoids [AEA (N-arachidonoylethanolamine) and PEA (N-palmitoylethanolamine)] specifically in the liver and circulation, but not in the brain or white adipose tissue. Consistent with this increase in endocannabinoids, in the liver glucocorticoids increased the abundance of mRNAs encoding the enzyme involved in AEA biosynthesis and the CB1R and reduced the abundance of the mRNA encoding an enzyme that metabolizes AEA. Supporting the importance of a peripheral endocannabinoid pathway, a peripherally restricted inhibitor of CB1R reduced the metabolic syndrome effects of glucocorticoids and liver-specific knockout of CB1R rescued glucocorticoid-induced dyslipidemia. Thus, peripheral endocannabinoid signaling mediates some of the metabolic effects of chronic glucocorticoid treatment.

N. P. Bowles, I. N. Karatsoreos, X. Li, V. K. Vemuri, J.-A. Wood, Z. Li, K. L. K. Tamashiro, G. J. Schwartz, A. M. Makriyannis, G. Kunos, C. J. Hillard, B. S. McEwen, M. N. Hill, A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome. Proc. Natl. Acad. Sci. U.S.A. 112, 285–290 (2015). [Abstract] [Full Text]