Activation of the Peripheral Endocannabinoid System in Human Obesity

Stefan Engeli

Jana Böhnke

Mareike Feldpausch

Kerstin Gorzelniak

Friedrich Luft+2 authors

^{Franz Volhard Clinical Research Center, Charité Campus Buch, and HELIOS Klinikum Berlin, Berlin, Germany}

^{Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, Maryland}

^{Cardiovascular Obesity Research & Management, Department of Medicine, McMaster University, Hamilton, Ontario, Canada}

Address correspondence and reprint requests to Stefan Engeli, MD, Franz Volhard Clinical Research Center (Haus 129), Charité Campus Buch, Wiltbergstr. 50, 13125, Berlin, Germany. E-mail: ed.hcub-etirahc.kvf@ilegne

Abstract

Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by −34% for CB-1 and −59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.

Abstract

Obesity is one of the main risk factors for the development of type 2 diabetes, and weight loss may be a successful means of reducing the number of patients affected by type 2 diabetes (1–4). Exogenous cannabinoids and endocannabinoids increase food intake and promote weight gain in animals by activating central endocannabinoid receptors (5–8). This phenomenon has been exploited in the treatment of cachexia using tetrahydrocannabinol (9). Endocannabinoids are derived from membrane phospholipids (anandamide [AEA]) or triglycerides (2-arachidonoylglycerol [2-AG]) (10). Endocannabinoids bind to the G-protein–coupled cannabinoid (CB) type 1 and type 2 receptors. In animals, CB-1 is expressed in the brain, gastrointestinal organs, and adipose tissue, whereas CB-2 is predominantly expressed on peripheral immune cells (11). Intracellular degradation by the enzyme fatty acid amide hydrolase (FAAH) limits endocannabinoid action (10).

In genetic animal models of obesity, brain endocannabinoid levels are increased and CB-1 is downregulated (12,13). CB-1 gene–deficient mice are lean and resistant to diet-induced obesity (14). Similarly, pharmacological CB-1 blockade with SR141716 (rimonabant) reduces food intake and body weight (8,12,15). Central and peripheral mechanisms may contribute to this weight loss (16). Indeed, CB-1 activation in isolated mouse adipocytes increases the activity of the lipogenic enzyme lipoprotein lipase (16). Moreover, CB-1 blockade increases adiponectin gene expression in adipose tissue and elevates circulating adiponectin levels in the obese Zucker rat (17). Recently, the activation of CB-1 receptors in the liver was shown to increase de novo synthesis of fatty acids by activating the transcription factor sterol regulatory element–binding protein 1c (SREBP-1c) in mice (18).

Rimonabant has been tested successfully in phase III trials as an adjunctive obesity treatment (19,20). The role of the endocannabinoid system, especially the balance between central and peripheral effects, for human obesity is now becoming clearer. We studied the peripheral endocannabinoid system, namely CB-1 and FAAH expression, in human tissues, including subcutaneous adipose tissue. CB-1 and FAAH gene expression as well as circulating endocannabinoid levels were compared in lean and obese women. These studies were repeated in obese women after a 5% weight loss.

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