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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...

Systemic arterial hypertension is the most important modifiable risk factor for all-cause morbidity and mortality worldwide and is associated with an increased risk of cardiovascular disease (CVD). Fewer than half of those with hypertension are aware of their condition, and many others are aware but not treated or inadequately treated, although successful treatment of hypertension reduces the global burden of disease and mortality. The aetiology of hypertension involves the complex interplay of environmental and pathophysiological factors that affect multiple systems, as well as genetic predisposition. The evaluation of patients with hypertension includes accurate standardized blood pressure (BP) measurement, assessment of the patients' predicted risk of atherosclerotic CVD and evidence of target-organ damage, and detection of secondary causes of hypertension and presence of comorbidities (such as CVD and kidney disease). Lifestyle changes, including dietary modifications and increased physical activity, are effective in lowering BP and preventing hypertension and its CVD sequelae. Pharmacological therapy is very effective in lowering BP and in preventing CVD outcomes in most patients; first-line antihypertensive medications include angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, dihydropyridine calcium-channel blockers and thiazide diuretics.

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Background-Water drinking increases blood pressure profoundly in patients with autonomic failure and substantially in older control subjects. The mechanism that mediates this response is not known. Methods and Results-We studied the effect of drinking tap water on seated blood pressure in 47 patients with severe autonomic failure (28 multiple system atrophy [MSA], 19 pure autonomic failure patients [PAF]). Eleven older controls and 8 young controls served as control group. We also studied the mechanisms that could increase blood pressure with water drinking. Systolic blood pressure increased profoundly with water drinking, reaching a maximum of 33Ϯ5 mm Hg in MSA and 37Ϯ7 in PAF mm Hg after 30 to 35 minutes. The pressor response was greater in patients with more retained sympathetic function and was almost completely abolished by trimethaphan infusion. Systolic blood pressure increased by 11Ϯ2.4 mm Hg in elderly but not in young controls. Plasma norepinephrine increased in both groups. Plasma renin activity, vasopressin, and blood volume did not change in any group. Conclusions-Water drinking significantly and rapidly raises sympathetic activity. Indeed, it raises plasma norepinephrine as much as such classic sympathetic stimuli as caffeine and nicotine. This effect profoundly increases blood pressure in autonomic failure patients, and this effect can be exploited to improve symptoms due to orthostatic hypotension. Water drinking also acutely raises blood pressure in older normal subjects. The pressor effect of oral water is an important yet unrecognized confounding factor in clinical studies of pressor agents and antihypertensive medications.

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 (CB 1 ) 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, CB 1 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. Diabetes 55:3053-3060, 2006 E ndocannabinoids are lipid mediators derived from membrane phospholipids or triglycerides with complex effects on body weight and metabolic regulation (1,2). Several enzymes are involved in the synthesis and degradation of the two most important endocannabinoids, anandamide and 2-arachidonoyl glycerol (2-AG). At least two G-protein-coupled cannabinoid receptors (CB 1 and CB 2 ) have been identified (3,4). Activation of central CB 1 receptors clearly promotes food intake and weight gain (5-7). However, pharmacological blockade with rimonabant (SR141716) or genetic knockout of the CB 1 receptor demonstrated that weight reduction under these conditions is only partly promoted by decreased food intake (8 -10). These findings prompted the search for peripheral metabolic effects of endocannabinoids. CB 1 receptors have now been identified in rodent liver (11), skeletal muscle (12), adipocytes (9,13), and pancreas (14). The potential role of peripheral CB 1 receptors for metabolic regulation is further promoted by statistical analyses of clinical trials, suggesting that the influence of CB 1 receptor blockade on adiponectin levels, lipids, and glucose homeostasis goes beyond the effect of weight loss alone (15-17).In general, endocannabinoid formation and signaling is dependent on external stimuli such as cellular stress, tissue damage, or metabolic challenges (3,4). However, recent findings point to profound changes in the regulation of the endocannabinoid system in obesity. Experimental data suggest that the endocannabinoid sy...

Genetic or acquired deficits in norepinephrine inactivation may underlie hyperadrenergic states that lead to orthostatic intolerance.

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: