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...

Abstract-The renin-angiotensin-aldosterone system has been causally implicated in obesity-associated hypertension. We studied the influence of obesity and weight reduction on the circulating and adipose tissue renin-angiotensin-aldosterone system in menopausal women. Blood samples were analyzed for angiotensinogen, renin, aldosterone, angiotensinconverting enzyme activity, and angiotensin II. In adipose tissue biopsy samples, we analyzed angiotensinogen, renin, renin-receptor, angiotensin-converting enzyme, and angiotensin II type-1 receptor gene expression. Obese women (nϭ19) had higher circulating angiotensinogen, renin, aldosterone, and angiotensin-converting enzyme than lean women (nϭ19), and lower angiotensinogen gene expression in adipose tissue. Seventeen women successfully participated in a weight reduction protocol over 13 weeks to reduce daily caloric intake by 600 kcal. Body weight was reduced by Ϫ5%, as were angiotensinogen levels by Ϫ27%, renin by Ϫ43%, aldosterone by Ϫ31%, angiotensin-converting enzyme activity by Ϫ12%, and angiotensinogen expression by Ϫ20% in adipose tissue (all PϽ0.05). The plasma angiotensinogen decrease was highly correlated with the waist circumference decline (rϭ0.74; PϽ0.001). Weight and renin-angiotensin-aldosterone system reductions were accompanied by a Ϫ7-mm Hg reduced systolic ambulatory blood pressure. These data suggest that a 5% reduction in body weight can lead to a meaningfully reduced renin-angiotensin-aldosterone system in plasma and adipose tissue, which may contribute to the reduced blood pressure. The renin-angiotensin-aldosterone system (RAAS) has been implicated by several authors. 3 In humans, increased circulating angiotensinogen (AGT), renin, aldosterone, and angiotensin-converting enzyme (ACE) activity were reported in obese subjects. 4 -10 Furthermore, increased RAAS gene expression was described in adipose tissue, especially in rodent models of obesity. 3,[11][12][13][14][15] The link between adipose tissue AGT gene expression and blood pressure was recently documented in 2 mouse models. Targeted AGT expression in adipocytes of wild-type and AGT knockout mice increased circulating AGT levels and blood pressure. 16 Targeted expression of 11␤-hydroxysteroid dehydrogenase-1 in adipocytes increased blood pressure, plasma AGT, and adipose tissue AGT gene expression in mice with a wild-type genetic background. 17,18 The relationship between blood pressure and the RAAS in obese humans comes mostly from observational and not from intervention studies. The influence of weight loss on RAAS activity, especially on AGT plasma levels and the adipose tissue RAAS, has not been explored. MethodsThe institutional review board approved both studies; all volunteers gave informed written consent. Thirty-eight white menopausal women participated in the cross-sectional study, 30 menopausal women started the weight reduction protocol, and 17 achieved the 5% body weight reduction goal. None had diabetes mellitus, liver disease, congestive heart failure, coronary heart diseas...

Studies in mice suggest that adipocytes serve as glucose sensors and regulate systemic glucose metabolism through release of serum retinol-binding protein 4 (RBP4). This model has not been validated in humans. RBP4 was highly expressed in isolated mature human adipocytes and secreted by differentiating human adipocytes. In contrast to the animal data, RBP4 mRNA was downregulated in subcutaneous adipose tissue of obese women, and circulating RBP4 concentrations were similar in normal weight, overweight, and obese women (n ‫؍‬ 74). RBP4 was positively correlated with GLUT4 expression in adipose tissue, independent of any obesity-associated variable. Five percent weight loss slightly decreased adipose RBP4 expression but did not influence circulating RBP4. In another set of experiments, we stratified patients (n ‫؍‬ 14) by low or high basal fasting interstitial glucose concentrations, as determined by the microdialysis technique. Venous glucose concentrations were similar throughout oral glucose tolerance testing, and basal RBP4 expression in adipose tissue and serum RBP4 concentrations were similar in the groups with higher and lower interstitial glucose levels. Our findings point to profound differences between rodents and humans in the regulation of adipose or circulating RBP4 and challenge the notion that glucose uptake by adipocytes has a dominant role in the regulation of RBP4. Diabetes 55: