Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH)

Abstract

BACKGROUND: The brain endogenous cannabinoid system modulates reward and craving pathways and consequently may affect body weight. A naturally occurring missense polymorphism in the gene encoding fatty acid amide hydrolase (FAAH), the primary enzyme for inactivation of endocannabinoids, is associated with problem drug use. AIMS: To investigate the relationship between the FAAH cDNA 385 A/A (P129T) polymorphism and overweight disorders in subjects of multiple ethnic backgrounds attending a medical screening clinic. SUBJECTS: A total of 2667 subjects of white, black and Asian ancestry were genotyped and stratified by a standardized clinicbased assessment of body mass index (BMI, weight in kilograms/(height in meters) 2 or kg/m 2 ). METHODS: Subjects were genotyped for the FAAH cDNA 385 C-A polymorphism using allele-specific oligonucleotide hybridization methods by investigators blinded to all clinical information. BMI was calculated based on exact clinical measurements and World Health Organization ranges were used to stratify subjects. Statistical methods included the Fisher exact test, Mann-Whitney U-test and multivariable logistic regression analysis. RESULTS: The homozygous FAAH 385 A/A genotype was significantly associated with overweight and obesity in white subjects (P ¼ 0.005) and in black subjects (P ¼ 0.05) but not in a small group of Asians. The median BMI for all subjects was significantly greater in the FAAH 385 A/A genotype group compared to heterozygote and wild-type groups (P ¼ 0.0001). In white subjects, there was an increasing frequency of the FAAH 385 A/A genotype with increasing BMI categories of overweight (P ¼ 0.02) and obese (P ¼ 0.006) with the same trend in black subjects. CONCLUSIONS: These results suggest a role for the FAAH 385 A/A missense polymorphism as an endocannabinoid risk factor in overweight/obesity and may provide indirect evidence to support cannabinoid antagonist treatment strategies in overweight disorders.

Association between cannabinoid type-1 receptor polymorphism and body mass index in a southern Italian population

“…12 Moreover, a recent study has shown that overweight and obesity are associated with a potential genetic malfunction of the fatty acid amide hydrolase (FAAH), one of the endocannabinoid degrading enzymes, further substantiating the hypothesis of a hyperactive endocannabinoid system as a possible cause of obesity. 8 To date we have no evidence of mRNA CB1-receptor stability or protein expression levels in A-allele carriers but the significant association of the presence of the polymorphic variant to a lower BMI is an intriguing issue. Moreover, Ravinet et al 5 found that CB-1 gene-deficient mice were lean and resistant to diet-induced obesity and showed reduced plasma insulin and leptin levels.…”

“…A recent study has shown that overweight and obesity are associated with a potential genetic malfunction of one of the endocannabinoid degrading enzymes, further substantiating the hypothesis of a hyperactive endocannabinoid system as a possible cause of obesity. 8 A silent intragenic biallelic polymorphism (1359G/A) of the CB1 gene (CNR1, X54937 GenBank accession number), resulting in the substitution of G to A at nucleotide position 1359 in codon 435 (Thr), was reported as a common polymorphism in the German population, 9 reaching frequencies of 24-32% for the rarer allele (A).…”

Cannabinoid-1 receptor antagonists in type-2 diabetes

“…A genetic polymorphism of one of the enzymes responsible for EC breakdown (FAAH) has been linked with overweight and obesity in both white and black subjects. 61 A mutation in FAAH was also shown to influence lipid changes after a low-fat diet in obese subjects. 62 Furthermore, single-nucleotide polymorphisms of the gene encoding CB1 receptor have been shown to be associated with BMI and fat distribution in two independent samples of adult white European men.…”

Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men

“…3,5 In addition, the recent finding of a missense polymorphism in an endocannabinoid degrading enzyme, the fatty acid amide hydrolase (FAAH), associated with overweight and obesity supports the notion that the endocannabinoid system is upregulated in obesity. 2,6 On the basis of this background, the objective of the present study was to investigate the associations between the levels of AEA, 2-AG, OEA and PEA and body fat distribution assessed by computed tomography (intra-abdominal and subcutaneous adipose tissue (AT)) in a sample of nondiabetic men covering a wide range of adiposity values.…”