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

Abstract

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...

Cannabinoid-1 receptor antagonists in type-2 diabetes

“…58 Furthermore, circulating 2-AG was significantly correlated with body fat, visceral fat mass, and fasting plasma insulin concentrations, but negatively correlated with glucose infusion rate during clamp in a group of ten men and ten women. 59 Obese subjects had a reduction in adipose tissue FAAH gene expression compared with lean individuals 58,59 , and FAAH gene expression was negatively correlated with visceral fat mass and with circulating 2-AG. 59 Another group also showed higher levels of 2-AG in the serum and visceral, but not subcutaneous, fat of obese subjects.…”

“…59 Obese subjects had a reduction in adipose tissue FAAH gene expression compared with lean individuals 58,59 , and FAAH gene expression was negatively correlated with visceral fat mass and with circulating 2-AG. 59 Another group also showed higher levels of 2-AG in the serum and visceral, but not subcutaneous, fat of obese subjects. In a further study in untreated asymptomatic men, plasma 2-AG levels correlated positively with body mass index (BMI), waist girth, intra-abdominal adiposity, fasting triglycerides and insulin levels, and correlated negatively with HDL-C and adiponectin levels.…”

Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: associations with changes in metabolic risk factors

“…Therefore, it is not known if interventioninduced changes in EC levels correlate with changes in metabolic dysfunctions associated with VAT. Such an observation would establish a relationship between the overactive endocannabinoid system and some metabolic risk factors that is stronger than that implied by crosssectional studies [3,4]. In the present study, we aimed to obtain this information by investigating, in a sample of viscerally obese patients, the effect of a 1 year lifestyle modification programme, consisting of healthy eating and regular physical activity/exercise, on EC levels, VAT accumulation and metabolic cardiovascular risk factors.…”

“…In obese patients, higher levels of the EC, 2-arachidonoylglycerol (2-AG), but not of another EC, anandamide, are found in VAT, but not subcutaneous adipose tissue (SAT), as compared with lean volunteers [2]. In two independent cross-sectional studies, increased plasma levels of 2-AG, but not anandamide, were shown to correlate with high levels of VAT, but not SAT, as well as with several of the aforementioned metabolic alterations [3,4]. In view of the proposed pro-lipogenic and glucose intolerance-inducing actions of CB 1 receptor stimulation in rodents [1], an upregulated EC system in the VAT of obese patients might lead to an increased VAT accumulation and contribute to ectopic fat accumulation and insulin resistance.…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…For example, genetic and diet‐induced obese animal models display elevated endocannabinoid levels in the hypothalamus and peripheral tissues (Di Marzo et al ., 2001; Osei‐Hyiaman et al ., 2005; Matias et al ., 2006). Furthermore, increased circulating levels of AEA and 2‐AG, as well as elevated levels of 2‐AG within visceral adipose tissue, have been reported in obese and/or hyperglycaemic type 2 diabetic patients (Bluher et al ., 2006; Matias et al ., 2006). In accord with this, hyperactivation of CB1R‐induced signalling has been implicated in numerous metabolic abnormalities including hyperphagia, insulin resistance, glucose intolerance and impaired lipid homeostasis (Engeli et al ., 2005; Jbilo et al ., 2005; Osei‐Hyiaman et al ., 2005).…”