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Activation of the Peripheral Endocannabinoid System in Human Obesity
Open accessAbstract
Obesity is the main risk factor for the development of type 2 diabetes. Activation of the central endocannabinoid system increases food intake and promotes weight gain. Blockade of the cannabinoid type 1 (CB-1) receptor reduces body weight in animals by central and peripheral actions; the role of the peripheral endocannabinoid system in human obesity is now being extensively investigated. We measured circulating endocannabinoid concentrations and studied the expression of CB-1 and the main degrading enzyme, fatty acid amide hydrolase (FAAH), in adipose tissue of lean (n = 20) and obese (n = 20) women and after a 5% weight loss in a second group of women (n = 17). Circulating levels of anandamide and 1/2-arachidonoylglycerol were increased by 35 and 52% in obese compared with lean women (P < 0.05). Adipose tissue mRNA levels were reduced by -34% for CB-1 and -59% for FAAH in obese subjects (P < 0.05). A strong negative correlation was found between FAAH expression in adipose tissue and circulating endocannabinoids. Circulating endocannabinoids and CB-1 or FAAH expression were not affected by 5% weight loss. The expression of CB-1 and FAAH was increased in mature human adipocytes compared with in preadipocytes and was found in several human tissues. Our findings support the presence of a peripheral endocannabinoid system that is upregulated in human obesity.
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“and this effect is likely to result from downregulation of FAAH gene expression, an effect which has also been observed in adipocytes sampled from obese women.110”
From Cannabinoids as Pharmacotherapies for Neuropathic Pain: From the Bench to the Bedside (2009) · cites this paper as [110]
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“Indeed, the gene expression of fatty acid amide hydrolase (FAAH), an enzyme participating in endocannabinoid synthesis and implicated in adipocyte dysfunction (19), is higher in the abdominal than gluteal adipose tissue and WL by hypocaloric feeding decreases the gene expression of gluteal, but not abdominal, cannabin…”
BackgroundInvolvement of adipokines in rimonabant-mediated insulin sensitivity in ob/ob mice
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Serefko, A., Lachowicz-Radulska, J., Jach, M. E., Świąder, K., & Szopa, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26199549 · Cited by 12
“…correlate with obesity markers [42,45], including body mass index, waist circumference, insulin resistance, and visceral fat mass [19,46–52], as well as with some genetic causes of obesity [53]; in a study carried out by Fanelli and colleagues (2018) [54] AEA hypertone was…”
Muller, T., Demizieux, L., Troy-Fioramonti, S., Buch, C., Leemput, J., Belloir, C., de Barros, J.-P. P., Jourdan, T., Passilly‐Degrace, P., Fioramonti, X., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23062923 · Cited by 11
“The current literature strongly supports the notion that obesity induces overactivation of the ECS in adipose tissue in both animals and humans [4,6,33,50,51].”
Backgroundde ten Ryen, S. V. D., Dalle, S., Terrasi, R., Koppo, K., Muccioli, G. G., & Deldicque, L. (2023) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00645.2022 · Cited by 11
Fonseca, B. M., Moreira-Pinto, B., Costa, L., Felgueira, E., Oliveira, P., & Rebelo, I. (2021) · Reproduction Fertility and Development · doi:10.1071/rd20247 · Cited by 11
Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors
Piper, N. B. C., Whitfield, E. A., Stewart, G. D., Xu, X., & Furness, S. G. B. (2022) · Biochemical Pharmacology · doi:10.1016/j.bcp.2022.115115 · Cited by 11
Renal Endocannabinoid Dysregulation in Obesity-Induced Chronic Kidney Disease in Humans
Permyakova, A., Rothner, A., Knapp, S., Nemirovski, A., Ben‐Zvi, D., & Tam, J. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241713636 · Cited by 12
Serrano, A., Decara, J. M., Fernández‐González, R., López‐Cardona, A. P., Pavón, F. J., Orío, L., Alén, F., Gutiérrez‐Adán, A., & de Fonseca, F. R. (2014) · Biology of Reproduction · doi:10.1095/biolreprod.114.117879 · Cited by 11
“These results are in agreement with previous reports that described a reduction in CB 1 mRNA in the adipose tissue of obese women [53].”
ResultBrito, L. F., Gontijo, D. C., Toledo, R. C. L., Barcelos, R. M., de Oliveira, A. B., Brandão, G. C., Sousa, L. P., Ribeiro, S. M. R., Leite, J. P. V., Fietto, L. G., et al. (2019) · Journal of Functional Foods · doi:10.1016/j.jff.2019.03.003 · Cited by 11
Racial and sex differences in the polymorphisms of the endocannabinoid receptor genes in obesity
Thethi, T. K., Sigel, A., Japa, S., Katalenich, B., Liu, S., Nguyen, T. M., Larrazolo, J., Syu, S., Carefoot, E., McDuffie, R. H., et al. (2020) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2020.107682 · Cited by 11
Dow, R. L., Hadcock, J. R., Scott, D. O., Schneider, S. R., Paight, E. S., Iredale, P. A., Carpino, P. A., Griffith, D. A., Hammond, M., & DaSilva-Jardine, P. A. (2009) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2009.07.130 · Cited by 11
de Luis, D. A., Pacheco, D., Aller, R., Sagrado, M. G., Conde, R., Izaola, O., Cuéllar, L., Mc, T., Martin, T., & Ventosa, M. (2010) · PubMed · Cited by 11
Circulating Endocannabinoids and Mortality in Hemodialysis Patients
Moradi, H., Park, C., Streja, E., Argueta, D. A., DiPatrizio, N. V., You, A. S., Rhee, C. M., Vaziri, N. D., Kalantar‐Zadeh, K., & Piomelli, D. (2020) · American Journal of Nephrology · doi:10.1159/000505444 · Cited by 11
Chen, G., & Pang, Z. (2013) · Vitamins and hormones · doi:10.1016/b978-0-12-407766-9.00014-6 · Cited by 11
“Its level is lower in obese than in lean subjects, is unchanged with 5% BW reduction, and is negatively associated with the plasma 2-AG and anandamide levels (Engeli et al., 2005).”
BackgroundEffect of blockage of the endocannabinoid system by CB1 antagonism on cardiovascular risk
Mach, F., Montecucco, F., & Steffens, S. (2009) · Pharmacological Reports · doi:10.1016/s1734-1140(09)70003-9 · Cited by 11
“The overactivity of the endocannabinoid system promotes excessive food intake and fat accumulation in animal models and humans [11, 21].”
BackgroundEndocannabinoid System and Cardiometabolic Risk
Saavedra, L. (2007) · Clinical Pharmacology & Therapeutics · doi:10.1038/sj.clpt.6100373 · Cited by 11
Complex Cardiometabolic Risk Factors: Impact, Assessment, and Emerging Therapies
Tangalos, E. G., Cota, D., & Fujioka, K. (2006) · Journal of the American Medical Directors Association · doi:10.1016/j.jamda.2006.06.003 · Cited by 11
Rimonabant: New data and emerging experience
Wright, S. M., Dikkers, C., & Aronne, L. J. (2008) · Current Atherosclerosis Reports · doi:10.1007/s11883-008-0011-5 · Cited by 11
Silvério, R., Barth, R., Heimann, A. S., Reckziegel, P., dos Santos, G. J., Romero‐Zerbo, S., Bermúdez‐Silva, F. J., Rafacho, A., & Ferro, E. S. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084082 · Cited by 10
“Accordingly, people with obesity may exhibit an overactivity of the endocannabinoid system [7,8].”
BackgroundBeyond the Scale: Exploring the Endocannabinoid System’s Impact on Obesity
Akurati, S., & Hanlon, E. C. (2024) · Current Diabetes Reports · doi:10.1007/s11892-024-01562-2 · Cited by 13
“Additionally, elevated levels of anandamide and 2-AG were also found in individuals with obesity and diabetes, suggesting that both endocannabinoids collectively contribute to metabolic dysregulation, exacerbating insulin resistance, and promoting weight gain [47].”
Hargreaves, J., & Ney, L. J. (2025) · Targets · doi:10.3390/targets3010011 · Cited by 10
“Amir Hamzah et al. [51] discovered that basal AEA and 2-AG concentrations were significantly higher in older age groups, and Engeli et al. [54] found that peripheral endocannabinoids were significantly increased in women with obesity.”
Cannabinoid Receptor 1 and 2 Signaling Pathways Involved in Sepsis
Leite-Avalca, M. C. G., Zampronio, A., & Lehmann, C. (2021) · Shock · doi:10.1097/shk.0000000000001763 · Cited by 10
“Moreover, CB1 is also present at much lower, yet functionally relevant, levels in various peripheral tissues, including myocardium (22), postganglionic autonomic nerve terminals (10), vascular endothelial and smooth muscle cells (23) as well as the adipose tissue, (24), liver (25), and skeletal muscle (26) and regulat…”
BackgroundNahon, K. J., Kantae, V., den Haan, R., Hanssen, M. J. W., Harms, A. C., van der Stelt, M., Hankemeier, T., Jazet, I. M., Lichtenbelt, W. D. V. M., Rensen, P. C. N., et al. (2018) · Obesity · doi:10.1002/oby.22245 · Cited by 10
“In addition, individuals with obesity have reduced gene expression of endocannabinoid degradation enzymes and CB1 receptor in adipose tissue (16,17).”
BackgroundMüller, G. A., Herling, A. W., Wied, S., & Müller, T. D. (2020) · Molecules · doi:10.3390/molecules25040896 · Cited by 10
Activation of the endocannabinoid system mediates cardiac hypertrophy induced by rosiglitazone
Liu, Y.-H., Liu, Y., Zhang, X., Li, F., Zhao, B., & Wang, N. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-00858-x · Cited by 10
Obesity and the Endocannabinoid System: Is There Still a Future for CB1 Antagonists in Obesity?
Serrano, A., Pavón, F. J., Suárez, J., Cuevas, M. R., Baixerás, E., Goya, P., & de Fonseca, F. R. (2012) · Current Obesity Reports · doi:10.1007/s13679-012-0031-x · Cited by 10
“However, other studies reported no changes in CB1 gene expression in visceral and subcutaneous adipose tissue, or even reduced CB1 expression with obesity [33, 41].”
BackgroundThe Endocannabinoid System: Potential for Reducing Cardiometabolic Risk
Ginsberg, H. N., & Woods, S. C. (2009) · Obesity · doi:10.1038/oby.2009.107 · Cited by 10
“Weight-loss pharmacotherapy is recommended when BMI is ≥27 in the presence of obesity-related risk factors and when BMI is ≥30 in the absence of associated risk factors (1,9).”
BackgroundInfluentialVilches‐Flores, A., Franklin, Z. J., Hauge-Evans, A. C., Liu, B., Huang, G. C., Choudhary, P., Jones, P. M., & Persaud, S. J. (2016) · BBA Clinical · doi:10.1016/j.bbacli.2016.03.009 · Cited by 10
“Sustained elevations in endocannabinoid levels in the circulation that occur following ECS over-activation in obese and diabetic patients are reported to have detrimental effects in peripheral organs, leading to impaired insulin sensitivity, glucose intolerance and dyslipidaemia [3,4, 7,9,10].”
BackgroundInfluentialDi, X., Martínez‐Téllez, B., Krekels, E. H. J., Jurado‐Fasoli, L., Osuna‐Prieto, F. J., Ortiz-Alvarez, L., Hankemeier, T., Rensen, P. C. N., Ruiz, J. R., & Köhler, I. (2023) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgad668 · Cited by 9
Dissecting the role of cannabinoids in vascular health and disease
Guo, Y., Wei, X., Pei, J., Yang, H., & Zheng, X. (2024) · Journal of Cellular Physiology · doi:10.1002/jcp.31373 · Cited by 10
“Patients with obesity or type 2 diabetes ‐ related hyperglycemia exhibit higher concentrations of endocannabinoids in visceral fat or serum (Engeli et al., 2005; Matias et al., 2006), indicating that the ECS is upregulated in patients with obesity and those with multiple cardiovascular risk factors.”
Soares, P. N., Miranda, R. A., Peixoto, T. C., Caramez, F. A. H., Guarda, D. S., Manhães, A. C., Oliveira, E., de Moura, E. G., & Lisboa, P. C. (2019) · Life Sciences · doi:10.1016/j.lfs.2019.116575 · Cited by 9
Alkylresorcinols as New Modulators of the Metabolic Activity of the Gut Microbiota
Zabolotneva, A. A., Михайлович, Г. А., Roumiantsev, S. A., Vasiliev, I. Y., Grigoryeva, T. V., Kit, O. I., Zlatnik, E. Y., Maksimov, A. Y., Гончарова, А. С., Novikova, I. A., et al. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241814206 · Cited by 9
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Metadata
- Authors
- Engeli, S., Böhnke, J., Feldpausch, M., Gorzelniak, K., Janke, J., Bátkai, S., Pacher, P., Harvey-White, J., Luft, F. C., Sharma, A. M., & Jordan, J.
- Affiliations
- Helios Hospital Berlin-Buch (DE)
- Franz Volhard Clinical Research Center, Charité Campus Buch, and HELIOS Klinikum Berlin, Berlin, Germany
- Laboratory of Physiologic Studies, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, Bethesda, Maryland
- National Institutes of Health (US)
- McMaster University (CA)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-10-01
- Volume
- 54
- Issue
- 10
- Pages
- 2838-2843
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2228268
- OpenAlex
- W2162112945
- Cited by
- 686
- References
- 37
- Citations by year
- 2026: 11 · 2025: 14 · 2024: 20 · 2023: 19 · 2022: 20 · 2021: 30 · 2020: 29 · 2019: 24 · 2018: 30 · 2017: 30 · 2016: 15 · 2015: 31 · 2014: 29 · 2013: 29 · 2012: 33
- FWCI
- 38.06
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Sanofi
- Bundesministerium für Bildung und Forschung
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism (Z01AA000375)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Cannabis and Cannabinoid Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Keywords
- obesity, cannabinoid type 1 receptor, fatty acid amide hydrolase, anandamide, 2-arachidonoylglycerol, adipose tissue, weight loss, human adipocytes, type 2 diabetes risk
- MeSH terms
- Fatty Acid Amide Hydrolases, Adipose Tissue, Amidohydrolases, Arachidonic Acids, Body Composition, Female, Glycerides, Humans, Middle Aged, Obesity, RNA, Messenger, Weight Loss, Gene Expression, Body Mass Index, Linear Models, Postmenopause, Reverse Transcriptase Polymerase Chain Reaction, Receptor, Cannabinoid, CB1, Polyunsaturated Alkamides, Cannabinoid Receptor Modulators, Endocannabinoids
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