Biomarkers of Endocannabinoid System Activation in Severe Obesity

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2010 Jan 26

PMID 20098695

Citations 71

Authors

Jack C Sipe

T Michael Scott

Sarah Murray

Olivier Harismendy

Gabriel M Simon

Benjamin F Cravatt

Jill Waalen

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Methodology/principal Findings: Plasma samples were obtained from 96 severely obese subjects with body mass index (BMI) of > or = 40 kg/m(2), and 48 normal weight subjects with BMI of < or = 26 kg/m(2). 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/significance: Significantly 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.

Citing Articles

Sex Differences in Endocannabinoid and Inflammatory Markers Associated with Posttraumatic Stress Disorder.

Rajasekera T, Joseph A, Pan H, Dreyfuss J, Fida D, Wilson J medRxiv. 2025; .

PMID: 39974010 PMC: 11838936. DOI: 10.1101/2025.01.13.25320467.

Endocannabinoid dysregulation and PTSD in urban adolescents: Associations with anandamide concentrations and FAAH genotype.

Marusak H, Ely S, Zundel C, Gowatch L, Shampine M, Carpenter C Psychopharmacology (Berl). 2024; .

PMID: 39547971 DOI: 10.1007/s00213-024-06717-3.

The Role of Genetic Variations in the FAAH rs324420 Polymorphism and its Interaction with CRHR1 rs110402 and CNR1 rs2180619 in Anxiety and- Trauma Related Symptoms After Military Deployment.

Leen N, de Weijer A, Boks M, Baas J, Vermetten E, Geuze E Chronic Stress (Thousand Oaks). 2024; 8:24705470241285828.

PMID: 39484094 PMC: 11526235. DOI: 10.1177/24705470241285828.

The endocannabinoid system in appetite regulation and treatment of obesity.

Kurtov M, Rubinic I, Likic R Pharmacol Res Perspect. 2024; 12(5):e70009.

PMID: 39292202 PMC: 11409765. DOI: 10.1002/prp2.70009.

Investigating the alterations of endocannabinoidome signaling in the human small intestine in the context of obesity and type 2 diabetes.

Rakotoarivelo V, Allam-Ndoul B, Martin C, Biertho L, Di Marzo V, Flamand N Heliyon. 2024; 10(6):e26968.

PMID: 38515705 PMC: 10955212. DOI: 10.1016/j.heliyon.2024.e26968.

References

Osei-Hyiaman D, Depetrillo M, Pacher P, Liu J, Radaeva S, Batkai S . Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005; 115(5):1298-305. PMC: 1087161. DOI: 10.1172/JCI23057. View

Kaufmann I, Schelling G, Eisner C, Richter H, Krauseneck T, Vogeser M . Anandamide and neutrophil function in patients with fibromyalgia. Psychoneuroendocrinology. 2008; 33(5):676-85. DOI: 10.1016/j.psyneuen.2008.02.009. View

Jesudason D, Wittert G . Endocannabinoid system in food intake and metabolic regulation. Curr Opin Lipidol. 2008; 19(4):344-8. DOI: 10.1097/MOL.0b013e328304b62b. View

Matias I, Gonthier M, Orlando P, Martiadis V, De Petrocellis L, Cervino C . Regulation, function, and dysregulation of endocannabinoids in models of adipose and beta-pancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006; 91(8):3171-80. DOI: 10.1210/jc.2005-2679. View

Walker J, Krey J, Chu C, Huang S . Endocannabinoids and related fatty acid derivatives in pain modulation. Chem Phys Lipids. 2002; 121(1-2):159-72. DOI: 10.1016/s0009-3084(02)00152-4. View

Cravatt B, Lichtman A . Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol. 2003; 7(4):469-75. DOI: 10.1016/s1367-5931(03)00079-6. View

Sipe J, Waalen J, Gerber A, Beutler E . Overweight and obesity associated with a missense polymorphism in fatty acid amide hydrolase (FAAH). Int J Obes (Lond). 2005; 29(7):755-9. DOI: 10.1038/sj.ijo.0802954. View

Monteleone P, Tortorella A, Martiadis V, Di Filippo C, Canestrelli B, Maj M . The cDNA 385C to A missense polymorphism of the endocannabinoid degrading enzyme fatty acid amide hydrolase (FAAH) is associated with overweight/obesity but not with binge eating disorder in overweight/obese women. Psychoneuroendocrinology. 2008; 33(4):546-50. DOI: 10.1016/j.psyneuen.2008.01.004. View

Martin B, Mechoulam R, Razdan R . Discovery and characterization of endogenous cannabinoids. Life Sci. 1999; 65(6-7):573-95. DOI: 10.1016/s0024-3205(99)00281-7. View

10.

Gonthier M, Hoareau L, Festy F, Matias I, Valenti M, Bes-Houtmann S . Identification of endocannabinoids and related compounds in human fat cells. Obesity (Silver Spring). 2007; 15(4):837-45. DOI: 10.1038/oby.2007.581. View

11.

Mechoulam R . Recent advantages in cannabinoid research. Forsch Komplementarmed. 1999; 6 Suppl 3:16-20. DOI: 10.1159/000057151. View

12.

Di Marzo V, Melck D, Bisogno T, De Petrocellis L . Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1999; 21(12):521-8. DOI: 10.1016/s0166-2236(98)01283-1. View

13.

Gaetani S, Kaye W, Cuomo V, Piomelli D . Role of endocannabinoids and their analogues in obesity and eating disorders. Eat Weight Disord. 2008; 13(3):e42-8. View

14.

Chiang K, Gerber A, Sipe J, Cravatt B . Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use. Hum Mol Genet. 2004; 13(18):2113-9. DOI: 10.1093/hmg/ddh216. View

15.

Di Marzo V . The endocannabinoid system in obesity and type 2 diabetes. Diabetologia. 2008; 51(8):1356-67. DOI: 10.1007/s00125-008-1048-2. View

16.

Di Marzo V, Bisogno T, De Petrocellis L, Melck D, Martin B . Cannabimimetic fatty acid derivatives: the anandamide family and other endocannabinoids. Curr Med Chem. 1999; 6(8):721-44. View

17.

Di Marzo V, Deutsch D . Biochemistry of the endogenous ligands of cannabinoid receptors. Neurobiol Dis. 1999; 5(6 Pt B):386-404. DOI: 10.1006/nbdi.1998.0214. View

18.

Bellocchio L, Cervino C, Pasquali R, Pagotto U . The endocannabinoid system and energy metabolism. J Neuroendocrinol. 2008; 20(6):850-7. DOI: 10.1111/j.1365-2826.2008.01728.x. View

19.

Engeli S, Jordan J . The endocannabinoid system: body weight and metabolic regulation. Clin Cornerstone. 2007; 8 Suppl 4:S24-35. DOI: 10.1016/s1098-3597(06)80041-4. View

20.

Di Marzo V, Fontana A, Cadas H, Schinelli S, Cimino G, Schwartz J . Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994; 372(6507):686-91. DOI: 10.1038/372686a0. View