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A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome
Tuesday, 2015/01/13 | 08:34:23

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, and Matthew N. Hill




Obesity and associated metabolic disorders (e.g., cardiovascular disease and type 2 diabetes) are major public health concerns. These disorders result, in part, from hormonal dysregulation, particularly of glucocorticoids (GCs; central regulators of metabolism and adipogenesis). The specific mechanisms by which GCs modulate these processes remain largely unknown, but GCs increase production of endocannabinoids—potent central and peripheral regulators of appetite, energy balance, and metabolism. Our results show that sustained exposure to GCs produces obesity and metabolic syndrome through a peripheral endocannabinoid mechanism. These data further our understanding of the role of endocannabinoid signaling to promote not only diet-induced, but also, hormonal-mediated obesity and support the argument that peripheral blockade of endocannabinoid signaling could be a potential treatment for obese conditions.




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.


See: http://www.pnas.org/content/112/1/285.abstract.html?etoc

PNAS January 6, 2014; Vol.112; no.1:  285–290

Fig. 1. CB1R signaling is required for GC-mediated metabolic abnormalities. Graphs show that CORT-treated CB1R−/− mice have reduced (A) weight, (B) adiposity, and (C) adipocyte size. Similarly, (D) plasma insulin and (E) plasma leptin as measured by ELISA show a blunted CORT-induced increase compared with WT. (F) The CORT-induced increase in food consumption is reduced in CB1R−/− mice as shown in week 4 of food intake; however, pair-feeding studies show that this hyperphagia does not mediate the development of obesity (Fig. S2). CB1R−/− mice are also protected against the CORT-induced increase in (G) liver weight, (H) plasma cholesterol, (I) alanine aminotransferase (ALT), (J) triglycerides, and (K) hepatic triglycerides. (L) CB1R−/− mice are also protected against the development of hepatic steatosis as noted by the decreased accumulation of lipid droplets in the liver as measured by Oil Red O staining as well as decreased macrovesicular steatosis as measured by H&E staining (Fig. S1B). Data are expressed as means ± SEMs (n = 4–5 per group). Asterisks indicate the significant effects of CORT treatment relative to vehicle treatment in mice. Pound signs indicate statistically significant differences between CORT-treated WT and CB1R−/− mice. VEH, vehicle. *P < 0.05; **P < 0.01; ***P < 0.001; #P < 0.05; ##P < 0.01; ###P < 0.001. (Scale bar, 100 µm.)

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