Abstract
BackgroundObesity 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.Methodology/Principal FindingsPlasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of ≥40 kg/m2, and 48 normal weight subjects with BMI of ≤26 kg/m2. Triple-quadrupole mass spectroscopy methods were used to measure plasma ECS analogs. Subjects were genotyped for human FAAH gene mutations. The principal analysis focused on the FAAH 385 C→A (P129T) mutation by comparing plasma ECS metabolite levels in the FAAH 385 minor A allele carriers versus wild-type C/C carriers in both groups. The main finding was significantly elevated mean plasma levels of anandamide (15.1±1.4 pmol/ml) and related NAEs in study subjects that carried the FAAH 385 A mutant alleles versus normal subjects (13.3±1.0 pmol/ml) with wild-type FAAH genotype (p = 0.04), and significance was maintained after controlling for BMI.Conclusions/SignificanceSignificantly increased levels of the endocannabinoid anandamide and related NAEs were found in carriers of the FAAH 385 A mutant alleles compared with wild-type FAAH controls. This evidence supports endocannabinoid system activation due to the effect of FAAH 385 mutant A genotype on plasma AEA and related NAE analogs. This is the first study to document that FAAH 385 A mutant alleles have a direct effect on elevated plasma levels of anandamide and related NAEs in humans. These biomarkers may indicate risk for severe obesity and may suggest novel ECS obesity treatment strategies.
Highlights
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 [1,2,3,4]
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 [2,7,8,9,10]
The principal new findings of this study were that subjects with the fatty acid amide hydrolase (FAAH) 385 A mutant alleles controlling for body mass index (BMI) had modest but significant elevation (p = 0.04) of AEA and related NAEs (Table 3; Figure 1) There was 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)
Summary
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 [1,2,3,4]. 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 [2,7,8,9,10] 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 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
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