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. Diabetes 54: 2838 -2843, 2005 O besity 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-proteincoupled 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...

Low plasma levels of the anti-inflammatory factor adiponectin characterize obesity and insulin resistance. To elucidate the relationship between plasma levels of adiponectin, adiponectin gene expression in adipose tissue, and markers of inflammation, we obtained blood samples, anthropometric measures, and subcutaneous adipose tissue samples from 65 postmenopausal healthy women. Adiponectin plasma levels and adipose-tissue gene expression were significantly lower in obese subjects and inversely correlated with obesity-associated variables, including high-sensitive C-reactive protein (hs-CRP) and interleukin-6 (IL-6). Despite adjustment for obesity-associated variables, plasma levels of adiponectin were significantly correlated to adiponectin gene expression (partial r ‫؍‬ 0.38, P < 0.05). Furthermore, the inverse correlation between plasma levels of hs-CRP and plasma adiponectin remained significant despite correction for obesity-associated variables (partial r ‫؍‬ ؊0.32, P < 0.05), whereas the inverse correlation between adiponectin plasma levels or adiponectin gene expression in adipose tissue with plasma IL-6 were largely dependent on the clustering of obesity-associated variables. In conclusion, our data suggest a transcriptional mechanism leading to decreased adiponectin plasma levels in obese women and demonstrate that low levels of adiponectin are associated with higher levels of hs-CRP and IL-6, two inflammatory mediators and markers of increased cardiovascular risk. Diabetes 52:942-947, 2003

Res. 2004;12:9 -17. Objectives: The activity of adipose 11␤-hydroxysteroid dehydrogenase (11␤-HSD) 1 is increased in obese subjects, and animal data suggest that increased cortisol formation in adipose tissue contributes to the development of the metabolic syndrome. The aim of this study was to determine whether up-regulation of human adipose 11␤-HSD1 in obesity can also be found at the gene expression level. Research Methods and Procedures: 11␤-HSD gene expression in subcutaneous adipose tissue biopsies of 70 postmenopausal women was studied by real-time reverse-transcription polymerase chain reaction. The influence of weight reduction and in vitro effects of several modulators of adipocyte gene expression on 11␤-HSD genes in human adipocytes were also studied. Results: The 11␤-HSD1 gene was highly expressed in human adipose tissue. 11␤-HSD2 mRNA was also detectable at lower levels. Adipose 11␤-HSD1 gene expression was increased by two-fold and was positively correlated with waist circumference and homeostasis model assessment index of insulin resistance. 11␤-HSD2 gene expression was reduced by half in obese women. Weight reduction did not change gene expression levels of 11␤-HSD1 or 11␤-HSD2.Cortisol increased 11␤-HSD1 gene expression in isolated human adipocytes in vitro, whereas estradiol, triiodothyronine, angiotensin II, and pioglitazone had no influence. Discussion: Our data suggest that increased expression of the 11␤-HSD1 gene is associated with metabolic abnormalities in obese women and that increased expression of this gene may contribute to the previously reported increased local conversion of cortisone to cortisol in adipose tissue of obese individuals.