Research Article: Biomarkers of Endocannabinoid System Activation in Severe Obesity

Date Published: January 20, 2010

Publisher: Public Library of Science

Author(s): Jack C. Sipe, T. Michael Scott, Sarah Murray, Olivier Harismendy, Gabriel M. Simon, Benjamin F. Cravatt, Jill Waalen, Adrian Vella. http://doi.org/10.1371/journal.pone.0008792

Abstract: Obesity is a worldwide epidemic, and severe obesity is a risk factor for many diseases, including diabetes, heart disease, stroke, and some cancers. Endocannabinoid system (ECS) signaling in the brain and peripheral tissues is activated in obesity and plays a role in the regulation of body weight. The main research question here was whether quantitative measurement of plasma endocannabinoids, anandamide, and related N-acylethanolamines (NAEs), combined with genotyping for mutations in fatty acid amide hydrolase (FAAH) would identify circulating biomarkers of ECS activation in severe obesity.

Partial Text: Endocannabinoids (ECs) are a family of polyunsaturated fatty acid derivatives that function as lipid signaling molecules by acting as endogenous ligands at the two known cannabinoid receptors (CBRs), CB1 and CB2, present in the nervous system and peripheral organs of many living species [1]–[4]. The endocannabinoid system (ECS) is highly developed in mammals, especially in humans, and the physiology and pharmacology of the ECS have been the subject of several comprehensive reviews in recent years [5]–[7]. The most well-studied of the ECs are the fatty acid amides (FAAs) represented by N-arachidonyl ethanolamine (AEA) or anandamide, N-palmitoyl ethanolamine (PEA), N-oleoyl ethanolamine (OEA) and related N-acylethanolamine (NAE) derivatives together with the esters of arachidonic acid including 2-arachidonyl glycerol (2-AG) as well as other lipid signaling molecules acting at CBRs [2], [7]–[10]. Some of these ECs are known to modulate a variety of physiological functions including synaptic transmission, immune function, nociception, fertility, and cardiovascular function, in addition to nervous system development, and are involved in many pathophysiological disease processes [5], [7], [11].

The principal new findings of this study were that subjects with the FAAH 385 A mutant alleles controlling for BMI had modest but significant elevation (p = 0.04) of AEA and related NAEs (Table 3; Figure 1) There was also modest but significantly elevated (p<0.05) circulating mean plasma levels of anandamide (AEA) in severely obese carriers of the FAAH 385 mutant A alleles compared to normal BMI subjects with the wild-type FAAH genotype Table 4; Figure 1). In Figure 1, there is the appearance of elevated AEA levels in several groups but only the comparison of the control FAAH-WT normal weight subjects with the FAAH 385 A carrier obese was statistically significant (p<0.05). Because plasma levels of N-acylethanolamine analogues related to AEA, including PEA, OEA and LEA, are significantly elevated in severely obese carriers of the mutant FAAH 385 A alleles, this supports the concept of a functional FAAH enzyme mutation in subjects with FAAH 385 C→A SNPs. Taken together, these findings provide further evidence of activation of the ECS in severely obese subjects with the FAAH 385 C→A mutation. Despite the relatively small subject cohort, tight plasma ranges and statistical significance (Figure 1) was achieved by using highly sensitive triple quadrupole mass spectroscopy methods. All statistical methods using both the original dataset and log-transformed dataset confirmed the internal and external validity of this study. These findings are statistically robust with significant two-sided p values ranging from p = 0.04 to p<0.05 in the case of AEA to p = 0.003 in the case of OEA (Tables 4 and Figure 1). Although there is a modest 1.14 fold elevation of mean plasma AEA levels in severely obese mutant FAAH carriers, the findings are nevertheless statistically significant in this careful case-controlled study. Source: http://doi.org/10.1371/journal.pone.0008792

 

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