Activation of the peripheral endocannabinoid system in human obesity - PubMed (original) (raw)

Activation of the peripheral endocannabinoid system in human obesity

Stefan Engeli et al. Diabetes. 2005 Oct.

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.

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Figures

FIG. 1

FIG. 1

Expression of CB-1 and FAAH genes in human tissues. Real-time RT-PCR of a multiple tissue human RNA panel, normalized by 18S rRNA expression. Data are given in arbitrary units (AUs) relative to CB-1 or FAAH gene expression in adipose tissue.

FIG. 2

FIG. 2

Expression of CB-1 and FAAH by human adipose cells. A: CB-1 and FAAH mRNA was detected by real-time PCR in isolated human adipocytes. B: Confocal microscopy revealed localization of the CB-1 receptor in the adipocyte membrane. The negative control (left; only second antibody added) confirms the specificity of fluorescence signals seen in the right confocal image. C: Increased expression of CB-1 and FAAH genes in isolated mature human adipocytes (AC) compared with isolated human preadipocytes (PAC). CB-1 gene expression data were confirmed by Western blotting (insert). Data are means ± SE from seven pairs and are given as arbitrary units (AUs), normalized by 18S rRNA expression. Group comparison by Student’s t test. *P < 0.05.

FIG. 3

FIG. 3

Influence of obesity and weight loss on the peripheral endocannabinoid system. Subcutaneous adipose tissue biopsies and blood samples were obtained from 20 lean and 20 obese postmenopausal women in a cross-sectional study (A) and from 17 obese postmenopausal women before and after a 5% body weight loss by a dietary protocol (B). Circulating levels of AEA and AGs (1/2-AG) were increased in the obese women by 35 and 52%, respectively. In contrast, adipose tissue CB-1 mRNA was decreased by −34% and FAAH mRNA by −59% in the obese subjects. Neither circulating levels of AEA and 1/2-AG nor adipose tissue, CB-1, or FAAH mRNA were influenced by the weight loss protocol. Gene expression is given in arbitrary units (AUs), normalized by GAPDH expression. Group comparison was performed with Student’s t test for independent samples (cross-sectional study) or the t test for paired samples (weight loss study). *P < 0.05 vs. lean.

FIG. 4

FIG. 4

Relation of FAAH expression in adipose tissue and circulating endocannabinoids. Both circulating AEA and Ags (1/2-AG) were negatively correlated with the expression of the FAAH gene in 40 human adipose tissue samples. Gene expression is given in arbitrary units (AUs), normalized by GAPDH expression.

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