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Dysregulation of the Peripheral and Adipose Tissue Endocannabinoid System in Human Abdominal Obesity

¹ Department of Internal Medicine III, University of Leipzig, Leipzig, Germany
² Franz-Volhard Clinical Research Center, Charité Campus Buch, HELIOS Klinikum Berlin, and Max-Delbrück Center for Molecular Medicine, Berlin, Germany
³ Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
⁴ Department of Surgery, University of Leipzig, Leipzig, Germany

Address correspondence and reprint requests to Michael Stumvoll, MD, University of Leipzig, Medical Department III, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany. E-mail: michael.stumvoll{at}medizin.uni-leipzig.de

Abbreviations: 2-AG, 2-arachidonoyl glycerol; OGTT, oral glucose tolerance test; SREBP-1c, sterol regulatory element–binding protein 1c

The endocannabinoid system has been suspected to contribute to the association of visceral fat accumulation with metabolic diseases. We determined whether circulating endocannabinoids are related to visceral adipose tissue mass in lean, subcutaneous obese, and visceral obese subjects (10 men and 10 women in each group). We further measured expression of the cannabinoid type 1 (CB₁) receptor and fatty acid amide hydrolase (FAAH) genes in paired samples of subcutaneous and visceral adipose tissue in all 60 subjects. Circulating 2-arachidonoyl glycerol (2-AG) was significantly correlated with body fat (r = 0.45, P = 0.03), visceral fat mass (r = 0.44, P = 0.003), and fasting plasma insulin concentrations (r = 0.41, P = 0.001) but negatively correlated to glucose infusion rate during clamp (r = 0.39, P = 0.009). In visceral adipose tissue, CB₁ mRNA expression was negatively correlated with visceral fat mass (r = 0.32, P = 0.01), fasting insulin (r = 0.48, P < 0.001), and circulating 2-AG (r = 0.5, P < 0.001), whereas FAAH gene expression was negatively correlated with visceral fat mass (r = 0.39, P = 0.01) and circulating 2-AG (r = 0.77, P < 0.001). Our findings suggest that abdominal fat accumulation is a critical correlate of the dysregulation of the peripheral endocannabinoid system in human obesity. Thus, the endocannabinoid system may represent a primary target for the treatment of abdominal obesity and associated metabolic changes.

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