Elsevier

Metabolism

Volume 59, Issue 5, May 2010, Pages 734-741
Metabolism

Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans

https://doi.org/10.1016/j.metabol.2009.09.018Get rights and content

Abstract

Dysregulation of the endocannabinoid system in the visceral adipose tissue (VAT) is associated with metabolic and cardiovascular complications of obesity. We studied perirenal VAT CB1 receptor expression in relation to anthropometry, VAT area and endocannabinoid levels, kidney microvascular damage (MVDa), and the presence of the CB1 gene A3813G variant, the frequency of which was also evaluated in a large population of obese-hypertensive (OH) patients with or without the metabolic syndrome (MetS). Perirenal VAT and kidney samples were obtained from 30 patients undergoing renal surgery. Total and perirenal VAT areas were determined by computed tomography. CB1 messenger RNA expression and endocannabinoid levels in perirenal VAT were determined by quantitative reverse transcriptase polymerase chain reaction and liquid chromatography–mass spectrometry, respectively. The MVDa was evaluated in healthy portions of kidney cortex. The A3813G alleles were identified by genotyping in these patients and in 280 nondiabetic OH patients (age ≤65 years). Metabolic syndrome was defined according to the Adult Treatment Panel III criteria. Perirenal VAT CB1 expression was 40% lower in patients with the A3813G polymorphism, and correlated positively with perirenal and total VAT area and with perirenal VAT levels of the endocannabinoid anandamide. A 2-fold higher CB1 expression was associated with MVDa. The OH patients with the A3813G allele had lower prevalence of MetS in both unadjusted and adjusted models. Genetics influence perirenal VAT CB1 expression and the prevalence of MetS in OH. Increased VAT is associated with increased perirenal VAT endocannabinoid tone, which in turn correlates with increased MVDa. Endocannabinoid overactivity might be involved in human visceral obesity and its renal complications.

Introduction

Visceral obesity is strongly associated with increased risk for several chronic diseases such as the metabolic syndrome (MetS), diabetes, and hypertension [1], [2]. Indeed, increased visceral adiposity is regarded as the link between overweight and cardiometabolic complications. Obesity is also causally linked, directly and indirectly, to the development of chronic renal disease that results from microvascular damage (MVDa) [3], [4]. The understanding of the obesity-associated mechanisms that lead to complications is crucial. In this setting, the endocannabinoid system (ECS) plays an important role in the control of food intake, lipid and glucose metabolism through both central and peripheral effects, lipogenesis, and fat accumulation [5]. The 2 most widely studied endocannabinoids (ECs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), act indeed also in the periphery through the cannabinoid CB1 receptor to regulate energy balance and body fat composition. Dysregulated ECS activity is believed to contribute to the pathogenesis of human obesity and its associated cardiometabolic risk [6], [7], [8], [9], [10]. Accordingly, long-term treatment with a CB1 receptor antagonist (rimonabant) reduced food intake and improved several metabolic and cardiovascular risk factors in obese subjects [11], [12], [13], [14]. Furthermore, the Rimonabant in Obesity–Lipids trial conducted on high-risk dyslipidemic patients showed that CB1 receptor antagonism could induce substantial and not entirely weight loss–dependent increases in high-density lipoprotein (HDL) cholesterol and in the levels of adiponectin, a “protective” adipokine for the cardiovascular system [11], [15].

The relevance of the overactive adipose ECS and of adipose tissue CB1 receptor to the pathogenesis of visceral obesity and associated metabolic disorders in humans, particularly those concerned with kidney dysfunction and failure, is still not fully understood, also because multiple genes and gene-environment interactions play a crucial role in this context. Several human CB1 polymorphisms have been previously described in European American, African American, and Japanese subjects in relation to addiction vulnerability [16]. However, the effect of Cnr1 variants on obesity and related clinical parameters appears somewhat contradictory depending on the population, sex, and body mass index (BMI) of the cohorts analyzed, as well as on other factors [17], [18], [19]. Russo et al [20] showed that, in a male population with a wide range of BMI, the presence of the A3813G variant in the CB1 receptor gene (Cnr1) was associated with an increase of subscapular skinfold thickness, an index of general subcutaneous adiposity, and also with a slight increase of waist circumference that is usually considered an index of visceral fat. The 3813A/G (rs12720071) single nucleotide polymorphism (SNP) is localized in exon 4, which lies in sequences encoding the 3' untranslated region. This polymorphism is one of several tag SNPs of Cnr1 for white populations (HapMap-CEU) in the Seattle SNPs database (http://gvs.gs.washington.edu/GVS/) and was thus selected as a maximally informative site for Cnr1, according to the tag SNPs approach in the evaluation of gene candidacy for common diseases [21]. However, it is not known if and how this or other genetic variants of the Cnr1 gene affect CB1 expression and function, and hence ECS activity, in the adipose tissue.

The primary aim of the present study was to analyze EC levels and CB1 expression in human perirenal visceral adipose tissue (VAT), obtained from unselected patients with a wide range of BMI, from normal weight (BMI <25 kg/m2) to obese (BMI ≥30 kg/m2), in relation to total amount of perirenal and abdominal adipose tissue and to plasma adiponectin concentrations.

Moreover, because one of the end points of dysmetabolism is micro- and macrovascular damage, we also wanted to evaluate the association between perirenal VAT CB1 expression and the degree of MVDa in the kidney. Furthermore, to study the influence of genetics on CB1 gene expression level, we investigated whether the Cnr1 A3813G variant was associated with different levels of CB1 messenger RNA (mRNA) in perirenal VAT. Finally, the same genetic variant was also analyzed in relation to clinical and metabolic parameters in a larger population of obese-hypertensive patients (OH), with a likely overactive ECS [6], [7], [8], [9] and higher risk of developing a MetS.

Section snippets

Patients and human tissue samples

Tissue samples were obtained during elective surgery (radical nephrectomy) from 30 patients admitted to the United Hospital of Ancona for localized clear cell renal carcinoma (T1/T2, N0, M0), a population similar to the one already described [22]. Briefly, patients were 24 men and 6 women, with average age of 64.4 ± 13.3 years, BMI = 26.8 ± 3.4 kg/m2 (lowest BMI value, 21.4 kg/m2; highest BMI value, 38.1 kg/m2), waist circumference = 99.3 ± 11.6 cm, systolic blood pressure [SBP] = 139.4 ± 20.3

Results

There were no significant differences between whole population (n = 30) and subset patients (available for EC quantification and CT image analyses, n = 12) regarding clinical data and adiponectin plasma levels (Table 1).

Perirenal adipose tissue area was correlated with total VAT area (r = 0.697, P = .025) as evaluated from the analysis of the available abdominal CT scan images (n = 12), suggesting that perirenal adipose tissue expands similarly to total VAT, thus contributing to visceral

Discussion

Our findings indicate that increased total visceral adiposity in individuals within a wide range of BMI and blood pressure is related to increased CB1 gene expression in perirenal VAT, which in turn is associated with increased VAT AEA, but not 2-AG, levels. Considering that increased total visceral adiposity was also associated with increased amounts of perirenal VAT, these findings indicate that higher amounts of VAT are very likely to be accompanied by up-regulation of the ECS in perirenal

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