OR03-1 Glucocorticoids Promote Obesity and Metabolic Syndrome Through a Hepatic Endocannabinoid Mechanism

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR03-Glucocorticoids & Glucocorticoid Actions
Basic/Translational
Saturday, June 15, 2013: 11:30 AM-1:00 PM
Presentation Start Time: 11:30 AM
Room 130 (Moscone Center)
Matthew Hill*1, Nicole P. Bowles2, Ilia Nicholas Karatsoreos3, Cecilia J Hillard4 and Bruce S McEwen5
1Univ of Calgary, Calgary, AB, Canada, 2The Rockefeller University, New York, NY, 3Washington State University, Pullman, WA, 4Medical College of Wisconsin, Milwaukee, WI, 5Rockefeller Univ, New York, NY
Glucocorticoids are known to promote the development of metabolic syndrome through a multitude of pathways including the regulation of both feeding pathways and metabolic processes. Recent evidence has demonstrated that glucocorticoids possess the ability to increase the production and release of endocannabinoid molecules. Endocannabinoids are potent regulators of appetite, energy balance and metabolic processes through both central and peripheral regulation of feeding and metabolism. The aim of the current study was to determine the role of the endocannabinoid signaling in glucocorticoid-mediated obesity and metabolic syndrome. In our model, male mice are given free access to 100 µg/ml corticosterone, or vehicle solution, for 4 weeks, at the end of which markers of obesity and metabolic markers were examined. In wild-type or vehicle treated mice, glucocorticoid administration resulted in an increase in total body weight, the weight of the abdominal/gonadal fat pads, fatty liver (as indicated by elevated Oil Red O staining, elevated ALT and hepatic triglyceride content), adipocyte expansion and dramatic elevations in the circulating levels of triglycerides, insulin, leptin, and glucose. Glucocorticoid administration also increased feeding behaviour, nearly tripling food intake over vehicle exposed animals; however, food restriction did not attenuate the effects of glucocorticoid exposure on obesity, indicating that while feeding behaviour is increased the ability of glucocorticoids to promote obesity is through a more direct effect on metabolic processes. With respect to the endocannabinoid system, corticosterone treatment surprisingly resulted in a reduction in the tissue levels of the endocannabinoid 2-AG within the hypothalamus, with no effects on the other endocannabinoid anandamide. Conversely, within the liver and the circulation, anandamide levels were dramatically increased by glucocorticoids, while 2-AG levels were found to decrease. Interestingly, we found that CB1 receptor deficient mice were protected from the effects of glucocorticoids on obesity and metabolic processes. Similarly, global pharmacological blockade of the CB1 receptor throughout the corticosterone treatment regimen also attenuated the effects on obesity. More so, administration of a peripherally restricted CB1 receptor antagonist also blocked glucocorticoid-induced obesity and metabolic changes. Taken together, these data indicate that glucocorticoids increase hepatic production of anandamide, which in turn contributes to the development of obesity and metabolic syndrome. In support of this hypothesis, recent work has highlighted the hepatic endocannabinoid system as a necessary component of diet-induced obesity, demonstrating that this system may be a critical player in the development of obesity, through both diet and hormonal pathways.

Nothing to Disclose: MH, NPB, INK, CJH, BSM

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: NIH grant MH41256 awarded to BSM; NIH grant DA026996 awarded to CJH; Canadian Insitutes of Health Research grant awarded to MNH
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