title: A peripheral endocannabinoid mechanism contributes to glucocorticoid-mediated metabolic syndrome.
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.
authors.affiliation: Laboratories of Neuroendocrinology and nbowles@mail.rockefeller.edu mcewen@mail.rockefeller.edu mnhill@ucalgary.ca.
authors.forename: Nicole P
authors.initials: NP
authors.lastname: Bowles
authors.affiliation: Laboratories of Neuroendocrinology and Department of Integrative Physiology and Neuroscience, Washington State University, Pullman, WA 99164;
authors.forename: Ilia N
authors.initials: IN
authors.lastname: Karatsoreos
authors.affiliation: Departments of Medicine and Neuroscience, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Li
authors.affiliation: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115;
authors.forename: V Kiran
authors.initials: VK
authors.lastname: Vemuri
authors.affiliation: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115;
authors.forename: Jodi-Anne
authors.initials: JA
authors.lastname: Wood
authors.affiliation: Molecular Genetics, The Rockefeller University, New York, NY 10065;
authors.forename: Zhiying
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205;
authors.forename: Kellie L K
authors.initials: KL
authors.lastname: Tamashiro
authors.affiliation: Departments of Medicine and Neuroscience, Albert Einstein College of Medicine of Yeshiva University, Bronx, NY 10461;
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Schwartz
authors.affiliation: Center for Drug Discovery, Department of Pharmaceutical Sciences and Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115;
authors.forename: Alexandros M
authors.initials: AM
authors.lastname: Makriyannis
authors.affiliation: National Institute of Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892;
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.affiliation: Department of Pharmacology and Toxicology and Neuroscience Research Center, Medical College of Wisconsin, Milwaukee, WI 53226; and.
authors.forename: Cecilia J
authors.initials: CJ
authors.lastname: Hillard
authors.affiliation: Laboratories of Neuroendocrinology and nbowles@mail.rockefeller.edu mcewen@mail.rockefeller.edu mnhill@ucalgary.ca.
authors.forename: Bruce S
authors.initials: BS
authors.lastname: McEwen
authors.affiliation: Laboratories of Neuroendocrinology and Departments of Cell Biology and Anatomy and Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada T2N 4N1 nbowles@mail.rockefeller.edu mcewen@mail.rockefeller.edu mnhill@ucalgary.ca.
authors.forename: Matthew N
authors.initials: MN
authors.lastname: Hill
mesh_terms: D000818:Animals; D003345:Corticosterone / Q000494:pharmacology; D050171:Dyslipidemias / Q000378:metabolism; D063388:Endocannabinoids / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D005938:Glucocorticoids / Q000009:adverse effects*; D008099:Liver / Q000378:metabolism; D024821:Metabolic Syndrome / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D063388:Endocannabinoids; D005938:Glucocorticoids; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D003345:Corticosterone
keywords: 2-AG; anandamide; corticosterone; liver; obesity