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Bariatric Surgery

The circulating and central endocannabinoid system in obesity and weight loss

Abstract

Major advances have been made in obesity treatment, focusing on restoring disturbances along the gut-brain axis. The endocannabinoid system (ECS) is a neuromodulatory signaling system, present along the entire gut-brain axis, that plays a critical role in central and peripheral regulation of food intake and body weight. Evidence on the impact of weight loss on the ECS is, however, more limited. Therefore, we set out to review the existing literature for changes in central and circulating endocannabinoid levels after bariatric surgery and other weight loss strategies in humans. The PubMed, Embase and Web of Science databases were searched for relevant articles. Fifty-six human studies were identified. Most studies measuring circulating 2-arachidonoylglycerol (2-AG) found no difference between normal weight and obesity, or no correlation with BMI. In contrast, studies measuring circulating arachidonoylethanolamine (AEA) found an increase or positive correlation with BMI. Two studies found a negative correlation between BMI and cannabinoid receptor type 1 (CB1) receptor availability in the brain. Only one study investigated the effect of pharmacological weight management on circulating endocannabinoid concentrations and found no effect on AEA concentrations. So far, six studies investigated potential changes in circulating endocannabinoids after bariatric surgery and reported conflicting results. Available evidence does not univocally support that circulating endocannabinoids are upregulated in individuals with obesity, which may be explained by variability across studies in several potential confounding factors (e.g. age and sex) as well as heterogeneity within the obesity population (e.g. BMI only vs. intra-abdominal adiposity). While several studies investigated the effect of lifestyle interventions on the circulating ECS, more studies are warranted that focus on pharmacologically and surgically induced weight loss. In addition, we identified several research needs which should be fulfilled to better understand the role of the ECS in obesity and its treatments.

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Fig. 1: Schematic representation of the main results of the current literature review.

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References

  1. World Health Organisation. Obesity and overweight. 2021. Available from: https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight.

  2. Berthoud HR, Lenard NR, Shin AC. Food reward, hyperphagia, and obesity. Am J Physiol-Reg I. 2011. https://doi.org/10.1152/ajpregu.00028.2011.

  3. Ochner CN, Stice E, Hutchins E, Afifi L, Geliebter A, Hirsch J, et al. Relation between changes in neural responsivity and reductions in desire to eat high-calorie foods following gastric bypass surgery. Neuroscience. 2012;209:128–35. https://doi.org/10.1016/j.neuroscience.2012.02.030

    Article  CAS  PubMed  Google Scholar 

  4. van Son J, van Galen KA, Bruijn AM, Koopman KE, Versteeg RI, la Fleur SE, et al. Striatal dopamine transporter availability is not associated with food craving in lean and obese humans; a molecular imaging study. Brain Sci. 2021;11. https://doi.org/10.3390/brainsci11111428.

  5. Wang GJ, Volkow ND, Logan J, Pappas NR, Wong CT, Zhu W, et al. Brain dopamine and obesity. Lancet. 2001. https://doi.org/10.1016/S0140-6736(00)03643-6.

  6. De Araujo IE, Schatzker M, Small DM. Rethinking food reward. Annu Rev Psychol. 2019. https://doi.org/10.1146/annurev-psych-122216.

  7. Makaronidis JM, Batterham RL. Potential mechanisms mediating sustained weight loss following roux-en-y gastric bypass and sleeve gastrectomy. Endocrinol Metab Clin North Am. 2016 https://doi.org/10.1016/j.ecl.2016.04.006.

  8. Akalestou E, Miras AD, Rutter GA, le Roux CW. Mechanisms of weight loss after obesity surgery. Endocr Rev. 2022;43:19–34. https://doi.org/10.1210/endrev/bnab022

    Article  PubMed  Google Scholar 

  9. Casimiro I, Sam S, Brady MJ. Endocrine implications of bariatric surgery: a review on the intersection between incretins, bone, and sex hormones. Physiol Rep. 2019;7:14111. https://doi.org/10.14814/phy2.14111

    Article  Google Scholar 

  10. Mukorako P, St-Pierre DH, Flamand N, Biertho L, Lebel S, Lemoine N, et al. Hypoabsorptive surgeries cause limb-dependent changes in the gut endocannabinoidome and microbiome in association with beneficial metabolic effects. Int J Obes. 2023;47:630–41. https://doi.org/10.1038/s41366-023-01307-3

    Article  CAS  Google Scholar 

  11. Hankir MK, Seyfried F, Hintschich CA, Diep TA, Kleberg K, Kranz M, et al. Gastric bypass surgery recruits a gut PPAR-α-striatal D1R pathway to reduce fat appetite in obese rats. Cell Metab. 2017. https://doi.org/10.1016/j.cmet.2016.12.006.

  12. Guijarro A, Osei-Hyiaman D, Harvey-White J, Kunos G, Suzuki S, Nadtochiy S, et al. Sustained weight loss after Roux-en-Y gastric bypass is characterized by down regulation of endocannabinoids and mitochondrial function. Ann Surg. 2008;247:779–90. https://doi.org/10.1097/SLA.0b013e318166fd5f

    Article  PubMed  Google Scholar 

  13. Coccurello R, Maccarrone M. Hedonic eating and the “delicious circle”: From lipid-derived mediators to brain dopamine and back. Front Neurosci. 2018;12:271. https://doi.org/10.3389/fnins.2018.00271

    Article  PubMed  PubMed Central  Google Scholar 

  14. Mazier W, Saucisse N, Gatta-Cherifi B, Cota D. The endocannabinoid system: pivotal orchestrator of obesity and metabolic disease. Trends Endocrinol Metab. 2015;26:524–37. https://doi.org/10.1016/j.tem.2015.07.007

    Article  CAS  PubMed  Google Scholar 

  15. Pi-Sunyer FX, Aronne LJ, Heshmati HM, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients. JAMA. 2006;295:761–75. https://doi.org/10.1001/jama.295.7.761.

    Article  CAS  PubMed  Google Scholar 

  16. Christensen R, Kristensen K, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007. https://doi.org/10.1016/S0140-6736(07)61721-8.

  17. Chakhtoura M, Haber R, Ghezzawi M, Rhayem C, Tcheroyan R, Mantzoros CS. Pharmacotherapy of obesity: an update on the available medications and drugs under investigation. Lancet. 2023. https://doi.org/10.1016/j.eclinm.2023.101882.

  18. Chia CW, Carlson OD, Liu DD, Gonzalez-Mariscal I, Santa-Cruz Calvo S, Egan JM. Incretin secretion in humans is under the influence of cannabinoid receptors. Am J Physiol Endocrinol Metab. 2017;313:359. https://doi.org/10.1152/ajpendo.00080.2017

    Article  Google Scholar 

  19. Azar S, Sherf-Dagan S, Nemirovski A, Webb M, Raziel A, Keidar A, et al. Circulating endocannabinoids are reduced following bariatric surgery and associated with improved metabolic homeostasis in humans. Obes Surg. 2019;29:268–76. https://doi.org/10.1007/s11695-018-3517-0

    Article  PubMed  Google Scholar 

  20. Rahman SMK, Uyama T, Hussain Z, Ueda N. Roles of endocannabinoids and endocannabinoid-like molecules in energy homeostasis and metabolic regulation: a nutritional perspective. Annu Rev Nutr. 2021. https://doi.org/10.1146/annurev-nutr-043020-.

  21. Hillard CJ. Circulating endocannabinoids: from whence do they come and where are they going? Neuropsychopharmacology. 2018. https://doi.org/10.1038/npp.2017.130.

  22. Atwood BK, MacKie K. CB 2: A cannabinoid receptor with an identity crisis. Br J Pharm. 2010;160:467–79. https://doi.org/10.1111/j.1476-5381.2010.00729.x

    Article  CAS  Google Scholar 

  23. Alger BE, Kim J. Supply and demand for endocannabinoids. Trends Neurosci. 2011;34:304–15. https://doi.org/10.1016/j.tins.2011.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Behl T, Chadha S, Sachdeva M, Sehgal A, Kumar A, Dhruv, et al. Understanding the possible role of endocannabinoid system in obesity. Prostag Oth Lipid M. 2021 https://doi.org/10.1016/j.prostaglandins.2020.106520.

  25. Hawkins MN, Horvath TL. Cannabis in fat: high hopes to treat obesity. J Clin Invest. 2017;127:3918–20. https://doi.org/10.1172/JCI97042

    Article  PubMed  PubMed Central  Google Scholar 

  26. Gonthier MP, Hoareau L, Festy F, Matias I, Valenti M, Bès-Houtmann S, et al. Identification of endocannabinoids and related compounds in human fat cells. Obesity. 2007;15:837–45. https://doi.org/10.1038/OBY.2007.581

    Article  CAS  PubMed  Google Scholar 

  27. Alvheim AR, Malde MK, Osei-Hyiaman D, Lin YH, Pawlosky RJ, Madsen L, et al. Dietary linoleic acid elevates endogenous 2-AG and anandamide and induces. Obesity. 2012;20:1984–94. https://doi.org/10.1038/oby.2012.38

    Article  CAS  PubMed  Google Scholar 

  28. Watson JE, Kim JS, Das A. Emerging class of omega-3 fatty acid endocannabinoids & their derivatives. Prostag Oth Lipid M 2019;143:106337. https://doi.org/10.1016/j.prostaglandins.2019.106337

    Article  CAS  Google Scholar 

  29. Di Patrizio NV. Endocannabinoids and the gut-brain control of food intake and obesity. Nutrients. 2021;13. https://doi.org/10.3390/nu13041214.

  30. Weltens N, Zhao D, Van Oudenhove L. Where is the comfort in comfort foods? Mechanisms linking fat signaling, reward, and emotion. Neurogastroenterol Motil. 2014;26:303–15. https://doi.org/10.1111/nmo.12309

    Article  CAS  PubMed  Google Scholar 

  31. Bourdy R, Hertz A, Filliol D, Andry V, Goumon Y, Mendoza J, et al. The endocannabinoid system is modulated in reward and homeostatic brain regions following diet-induced obesity in rats: a cluster analysis approach. Eur J Nutr. 2021;60:4621–33. https://doi.org/10.1007/s00394-021-02613-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Monteleone P, Piscitelli F, Scognamiglio P, Monteleone AM, Canestrelli B, di Marzo V, et al. Hedonic eating is associated with increased peripheral levels of ghrelin and the endocannabinoid 2-arachidonoyl-glycerol in healthy humans: a pilot study. J Clin Endocr Metab. 2012. https://doi.org/10.1210/jc.2011-3018.

  33. Weltens N, Iven J, Van Oudenhove L, Kano M. The gut–brain axis in health neuroscience: implications for functional gastrointestinal disorders and appetite regulation. Ann N. Y Acad Sci. 2018;1428:129–50. https://doi.org/10.1111/nyas.13969

    Article  PubMed  Google Scholar 

  34. Avalos B, Argueta DA, Perez PA, Wiley M, Wood C, Dipatrizio NV Cannabinoid cb1 receptors in the intestinal epithelium are required for acute western-diet preferences in mice. Nutrients. 2020;12. https://doi.org/10.3390/nu12092874.

  35. Engeli S. Dysregulation of the endocannabinoid system in obesity. J Neuroendocrinol. 2008;20:110–5. 10.1111/j.1365-2826.2008.01683.x.

  36. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. 2015. https://doi.org/10.1016/j.mce.2014.11.029.

  37. Hallam J, Boswell RG, Devito EE, Kober H. Gender-related differences in food craving and obesity. Yale J Biol Med. 2016;89:161–73.

    PubMed  PubMed Central  Google Scholar 

  38. Ney LJ, Matthews A, Bruno R, Felmingham KL. Modulation of the endocannabinoid system by sex hormones: implications for posttraumatic stress disorder. Neurosci Biobehav Rev. 2018;94:302–20. https://doi.org/10.1016/j.neubiorev.2018.07.006

    Article  CAS  PubMed  Google Scholar 

  39. Laurikainen H, Tuominen L, Tikka M, Merisaari H, Armio RL, Sormunen E, et al. Sex difference in brain CB1 receptor availability in man. Neuroimage. 2019;184:834–42. https://doi.org/10.1016/j.neuroimage.2018.10.013

    Article  CAS  PubMed  Google Scholar 

  40. Normandin MD, Zheng MQ, Lin KS, Mason NS, Lin SF, Ropchan J, et al. Imaging the cannabinoid CB1 receptor in humans with [11 C] OMAR: Assessment of kinetic analysis methods, test-retest reproducibility, and gender differences. J Cereb Blood Flow Metab. 2015;35:1313–22. https://doi.org/10.1038/jcbfm.2015.46

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Van Laere K, Goffin K, Casteels C, Dupont P, Mortelmans L, de Hoon J, et al. Gender-dependent increases with healthy aging of the human cerebral cannabinoid-type 1 receptor binding using [18 F]MK-9470 PET. Neuroimage. 2008;39:1533–41. https://doi.org/10.1016/j.neuroimage.2007.10.053

    Article  PubMed  Google Scholar 

  42. Piyanova A, Lomazzo E, Bindila L, Lerner R, Albayram O, Ruhl T, et al. Age-related changes in the endocannabinoid system in the mouse hippocampus. Mech Ageing Dev. 2015. https://doi.org/10.1016/j.mad.2015.08.005.

  43. Chu L, Liu W, Deng J, Wu Y, Yang H, Wang W, et al. Age-related changes in endogenous glucocorticoids, gonadal steroids, endocannabinoids and their ratios in plasma and hair from the male C57BL/6 mice. Gen Comp Endocrinol. 2021;301:113651. https://doi.org/10.1016/j.ygcen.2020.113651

    Article  CAS  PubMed  Google Scholar 

  44. Dutta S, Sengupta P Men and mice: Relating their ages. Life Sci. 2016. https://doi.org/10.1016/j.lfs.2015.10.025.

  45. Martín-Pérez C, Contreras-Rodríguez O, Pastor A, Christensen E, Andrews ZB, de la Torre R, et al. Endocannabinoid signaling of homeostatic status modulates functional connectivity in reward and salience networks. Psychopharmacology. 2021;239:1311–9. https://doi.org/10.1007/s00213-021-05890-z

    Article  CAS  PubMed  Google Scholar 

  46. Tischmann L, Drummen M, Gatta-Cherifi B, Raben A, Fogelholm M, Hartmann B, et al. Effects of a high-protein/moderate-carbohydrate diet on appetite, gut peptides, and endocannabinoids-a preview study. Nutrients. 2019;11. https://doi.org/10.3390/nu11102269.

  47. Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, De Wit H, et al. Circadian rhythm of circulating levels of the endocannabinoid 2 arachidonoylglycerol. J Clin Endocr Metab. 2015;100:220–6. https://doi.org/10.1210/jc.2014-3455

    Article  CAS  PubMed  Google Scholar 

  48. Kratz D, Thomas D, Gurke R. Endocannabinoids as potential biomarkers: It’s all about pre-analytics. J Mass Spectrom Adv Clin Lab. 2021;22:56–63. https://doi.org/10.1016/j.jmsacl.2021.11.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kratz D, Sens A, Schäfer SMG, Hahnefeld L, Geisslinger G, Thomas D, et al. Pre-analytical challenges for the quantification of endocannabinoids in human serum. J Chromatogr B. 2022 https://doi.org/10.1016/j.jchromb.2022.123102.

  50. Hillard CJ, Weinlander KM, Stuhr KL. Contributions of endocannabinoid signaling to psychiatric disorders in humans: Genetic and biochemical evidence. Neuroscience. 2012;204:207–29. https://doi.org/10.1016/j.neuroscience.2011.11.020

    Article  CAS  PubMed  Google Scholar 

  51. Gurke R, Thomas D, Schreiber Y, Schäfer SMG, Fleck SC, Geisslinger G, et al. Determination of endocannabinoids and endocannabinoid-like substances in human K3EDTA plasma – LC-MS/MS method validation and pre-analytical characteristics. Talanta. 2019;204:386–94. https://doi.org/10.1016/j.talanta.2019.06.004

    Article  CAS  PubMed  Google Scholar 

  52. Zoerner AA, Gutzki FM, Batkai S, May M, Rakers C, Engeli S, et al. Quantification of endocannabinoids in biological systems by chromatography and mass spectrometry: A comprehensive review from an analytical and biological perspective. BBA Mol Cell Biol L. 2011. https://doi.org/10.1016/j.bbalip.2011.08.004.

  53. Di Marzo V, Verrijken A, Hakkarainen A, Petrosino S, Mertens I, Lundbom N, et al. Role of insulin as a negative regulator of plasma endocannabinoid levels in obese and nonobese subjects. Eur J Endocrinol. 2009;161:715–22. https://doi.org/10.1530/EJE-09-0643

    Article  CAS  PubMed  Google Scholar 

  54. Heinitz S, Basolo A, Piaggi P, Piomelli D, Von Schwartzenberg RJ, Krakoff J. Peripheral endocannabinoids associated with energy expenditure in native americans of southwestern heritage. J Clin Endocr Metab. 2018. https://doi.org/10.1210/jc.2017-02257.

  55. Jumpertz R, Guijarro A, Pratley RE, Piomelli D, Krakoff J. Central and peripheral endocannabinoids and cognate acylethanolamides in humans: Association with race, adiposity, and energy expenditure. J Clin Endocr Metab. 2011. https://doi.org/10.1210/jc.2010-2028.

  56. Nicholson J, Azim S, Rebecchi MJ, Galbavy W, Feng T, Reinsel R, et al. Leptin levels are negatively correlated with 2-arachidonoylglycerol in the cerebrospinal fluid of patients with osteoarthritis. PLoS One. 2015. https://doi.org/10.1371/journal.pone.0123132.

  57. Quercioli A, Pataky Z, Montecucco F, Carballo S, Thomas A, Staub C, et al. Coronary vasomotor control in obesity and morbid obesity: contrasting flow responses with endocannabinoids, leptin, and inflammation. JACC Cardiovasc Imaging. 2012. https://doi.org/10.1016/j.jcmg.2012.01.020.

  58. Quercioli A, Pataky Z, Vincenti G, Makoundou V, Di Marzo V, Montecucco F, et al. Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity. Eur Heart J. 2011. https://doi.org/10.1093/eurheartj/ehr029.

  59. Van Eyk HJ, Van Schinkel LD, Kantae V, Dronkers CEA, Westenberg JJM, De Roos A, et al. Caloric restriction lowers endocannabinoid tonus and improves cardiac function in type 2 diabetes. Nutr Diabetes. 2018;8. https://doi.org/10.1038/s41387-017-0016-7.

  60. Engeli S, Lehmann AC, Kaminski J, Haas V, Janke J, Zoerner AA, et al. Influence of dietary fat intake on the endocannabinoid system in lean and obese subjects. Obesity. 2014;22:70–6. https://doi.org/10.1002/oby.20728

    Article  CAS  Google Scholar 

  61. Fanelli F, Mezzullo M, Belluomo I, Di Lallo VD, Baccini M, Ibarra Gasparini D, et al. Plasma 2-arachidonoylglycerol is a biomarker of age and menopause related insulin resistance and dyslipidemia in lean but not in obese men and women. Mol Metab. 2017. https://doi.org/10.1016/j.molmet.2017.03.005.

  62. Little TJ, Cvijanovic N, Dipatrizio NV, Argueta DA, Rayner CK, Feinle-Bisset C, et al. Endocannabinoids and cannabinoid receptors as regulators of endocrine functions and tissue metabolism: Plasma endocannabinoid levels in lean, overweight, and obese humans: Relationships to intestinal permeability markers, inflammation, and incretin secretion. Am J Physiol Endoc M. 2018. https://doi.org/10.1152/ajpendo.00355.2017.

  63. Matias I, Gatta-Cherifi B, Tabarin A, Clark S, Leste-Lasserre T, Marsicano G, et al. Endocannabinoids measurement in human saliva as potential biomarker of obesity. PLoS One. 2012;7:42399. https://doi.org/10.1371/journal.pone.0042399

    Article  CAS  Google Scholar 

  64. Montecucco F, Lenglet S, Quercioli A, Burger F, Thomas A, Lauer E, et al. Gastric bypass in morbid obese patients is associated with reduction in adipose tissue inflammation via N-oleoylethanolamide (OEA)-mediated pathways. Thromb Haemost. 2015. https://doi.org/10.1160/TH14-06-0506.

  65. Sipe JC, Scott TM, Murray S, Harismendy O, Simon GM, Cravatt BF, et al. Biomarkers of endocannabinoid system activation in severe obesity. PLoS One. 2010;5:8792. https://doi.org/10.1371/journal.pone.0008792

    Article  CAS  Google Scholar 

  66. Rigamonti AE, Piscitelli F, Aveta T, Agosti F, De Col A, Bini S, et al. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults. Food Nutr Res. 2015. https://doi.org/10.3402/fnr.v59.29678.

  67. Fernández-Aranda F, Sauchelli S, Pastor A, Gonzalez ML, De La Torre R, Granero R, et al. Moderate-vigorous physical activity across body mass index in females: Moderating effect of endocannabinoids and temperament. PLoS One. 2014;9:104534. https://doi.org/10.1371/journal.pone.0104534

    Article  CAS  Google Scholar 

  68. Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després JP, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes. 2007;31:692–9. https://doi.org/10.1038/sj.ijo.0803539

    Article  CAS  Google Scholar 

  69. Lotfi Yagin N, Aliasgharzadeh S, Alizadeh M, Aliasgari F, Mahdavi R The association of circulating endocannabinoids with appetite regulatory substances in obese women. Obes Res Clin Pract. 2020. https://doi.org/10.1016/j.orcp.2020.05.007.

  70. Rahmanian M, Yaghin NL, Alizadeh M Blood level of 2-arachidonoyl glycerol (2-AG), neuropeptide y and omentin and their correlation with food habits in obese women. Galen Med J. 2021. https://doi.org/10.31661/gmj.v9i0.1721.

  71. Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, et al. Activation of the peripheral endocannabinoid system in human obesity. Diabetes. 2005. https://doi.org/10.2337/diabetes.54.10.2838.

  72. Pei R, DiMarco DM, Putt KK, Martin DA, Gu Q, Chitchumroonchokchai C, et al. Low-fat yogurt consumption reduces biomarkers of chronic inflammation and inhibits markers of endotoxin exposure in healthy premenopausal women: a randomised controlled trial. Br J Nutr. 2017;118:1043–51. https://doi.org/10.1017/S0007114517003038

    Article  CAS  PubMed  Google Scholar 

  73. Blüher M, Engeli S, Klöting N, Berndt J, Fasshauer M, Bátkai S, et al. Dysregulation of the peripheral and adipose tissue endocannabinoid system in human abdominal obesity. Diabetes. 2006. https://doi.org/10.2337/db06-0812.

  74. Gatta-Cherifi B, Matias I, Vallée M, Tabarin A, Marsicano G, Piazza PV, et al. Simultaneous postprandial deregulation of the orexigenic endocannabinoid anandamide and the anorexigenic peptide YY in obesity. Int J Obes. 2012;36:880–5. https://doi.org/10.1038/ijo.2011.165

    Article  CAS  Google Scholar 

  75. Pastor A, Fernández-Aranda F, Fitó M, Jiménez-Murcia S, Botella C, Fernández-Real JM, et al. A lower olfactory capacity is related to higher circulating concentrations of endocannabinoid 2-arachidonoylglycerol and higher body mass index in women. PLoS One. 2016;11:0148734. https://doi.org/10.1371/journal.pone.0148734

    Article  CAS  Google Scholar 

  76. Castonguay-Paradis S, Lacroix S, Rochefort G, Parent L, Perron J, Martin C, et al. Dietary fatty acid intake and gut microbiota determine circulating endocannabinoidome signaling beyond the effect of body fat. Sci Rep. 2020;10:15975. https://doi.org/10.1038/s41598-020-72861-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Sirigu A, et al. Krill oil significantly decreases 2-arachidonoylglycerol plasma levels in obese subjects. Nutr Metab. 2011;8:7. https://doi.org/10.1186/1743-7075-8-7

    Article  CAS  Google Scholar 

  78. Baenas I, Miranda-Olivos R, Granero R, Solé-Morata N, Sánchez I, Pastor A, et al. Association of anandamide and 2-arachidonoylglycerol concentrations with clinical features and body mass index in eating disorders and obesity. Eur Psychiatry. 2023;66:e49. https://doi.org/10.1192/j.eurpsy.2023.2411

    Article  PubMed  PubMed Central  Google Scholar 

  79. Matias I, Lehmann EW, Zizzari P, Byberg S, Cota D, Torekov SS, et al. Endocannabinoid-related molecules predict the metabolic efficacy of GLP-1 receptor agonism in humans with obesity. J Endocrinol Invest. 2023;47:1289–94. https://doi.org/10.1007/s40618-023-02228-8

    Article  CAS  PubMed  Google Scholar 

  80. Carta G, Melis M, Pintus S, Pintus P, Piras CA, Muredda L, et al. Participants with normal weight or with obesity show different relationships of 6-n-propylthiouracil (PROP) taster status with BMI and plasma endocannabinoids. Sci Rep. 2017;7:1361. https://doi.org/10.1038/s41598-017-01562-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Melis M, Carta G, Pintus S, Pintus P, Piras CA, Murru E, et al. Polymorphism rs1761667 in the CD36 gene is associated to changes in fatty acid metabolism and circulating endocannabinoid levels distinctively in normal weight and obese subjects. Front Physiol. 2017;8:1006. https://doi.org/10.3389/fphys.2017.01006

    Article  PubMed  PubMed Central  Google Scholar 

  82. De Moraes Martins CJ, Genelhu V, Pimentel MMG, Celoria BMJ, Mangia RF, Aveta T, et al. Circulating endocannabinoids and the polymorphism 385 C > A in fatty acid amide hydrolase (FAAH) gene may identify the obesity phenotype related to cardiometabolic risk: a study conducted in a Brazilian population of complex interethnic admixture. PLoS One. 2015. https://doi.org/10.1371/journal.pone.0142728.

  83. Hanlon EC, Leproult R, Stuhr KL, Doncheck EM, Hillard CJ, Van Cauter E. Circadian misalignment of the 24-hour profile of endocannabinoid 2-arachidonoylglycerol (2-AG) in obese adults. J Clin Endocrinol Metab. 2020;105:792–802. https://doi.org/10.1210/clinem/dgaa028

    Article  PubMed  PubMed Central  Google Scholar 

  84. Fanelli F, Mezzullo M, Repaci A, Belluomo I, Ibarra Gasparini D, Di Dalmazi G, et al. Profiling plasma N-Acylethanolamine levels and their ratios as a biomarker of obesity and dysmetabolism. Mol Metab. 2018;14:82–94. https://doi.org/10.1016/j.molmet.2018.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Joosten MM, Balvers MGJ, Verhoeckx KCM, Hendriks HFJ, Witkamp RF. Plasma anandamide and other N-acylethanolamines are correlated with their corresponding free fatty acid levels under both fasting and non-fasting conditions in women. Nutr Metab. 2010;7:49. https://doi.org/10.1186/1743-7075-7-49

    Article  CAS  Google Scholar 

  86. Grosshans M, Schwarz E, Bumb JM, Schaefer C, Rohleder C, Vollmert C, et al. Oleoylethanolamide and human neural responses to food stimuli in obesity. JAMA Psychiat. 2014. https://doi.org/10.1038/10.1001/jamapsychiatry.2014.1215.

  87. Abdulnour J, Yasari S, Rabasa-Lhoret R, Faraj M, Petrosino S, Piscitelli F, et al. Circulating endocannabinoids in insulin sensitive vs. Insulin resistant obese postmenopausal women. A MONET group study. Obesity. 2014. https://doi.org/10.1002/oby.20498.

  88. Grapov D, Adams SH, Pedersen TL, Garvey WT, Newman JW. Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids. PLoS One. 2012;7:48852. https://doi.org/10.1371/journal.pone.0048852

    Article  CAS  Google Scholar 

  89. Engeli S, Blüher M, Jumpertz R, Wiesner T, Wirtz H, Bosse-Henck A, et al. Circulating anandamide and blood pressure in patients with obstructive sleep apnea. J Hypertens. 2012;30:2345–51. https://doi.org/10.1097/HJH.0b013e3283591595

    Article  CAS  PubMed  Google Scholar 

  90. Hanlon EC, Tasali E, Leproult R, Stuhr KL, Doncheck E, De Wit H, et al. Sleep restriction enhances the daily rhythm of circulating levels of endocannabinoid 2-arachidonoylglycerol. Sleep. 2016. https://doi.org/10.5665/sleep.5546.

  91. Cedernaes J, Fanelli F, Fazzini A, Pagotto U, Broman JE, Vogel H, et al. Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans. Psychoneuroendocrinology. 2016. https://doi.org/10.1016/j.psyneuen.2016.09.014.

  92. Ceccarini J, Weltens N, Ly HG, Tack J, Van Oudenhove L, Van Laere K Association between cerebral cannabinoid 1 receptor availability and body mass index in patients with food intake disorders and healthy subjects: a [(18)F]MK-9470 PET study. Transl Psychiatry. 2016. https://doi.org/10.1038/tp.2016.118.

  93. Lahesmaa M, Eriksson O, Gnad T, Oikonen V, Bucci M, Hirvonen J, et al. Cannabinoid type 1 receptors are upregulated during acute activation of brown adipose tissue. Diabetes. 2018;67:1226–36. https://doi.org/10.2337/db17-1366

    Article  PubMed  Google Scholar 

  94. Kantonen T, Pekkarinen L, Karjalainen T, Bucci M, Kalliokoski K, Haaparanta-Solin M, et al. Obesity risk is associated with altered cerebral glucose metabolism and decreased μ-opioid and CB1 receptor availability. Int J Obes. 2021 https://doi.org/10.1038/s41366-021-00996-y.

  95. Fernández-Rilo AC, Forte N, Palomba L, Tunisi L, Piscitelli F, Imperatore R, et al. Orexin induces the production of an endocannabinoid-derived lysophosphatidic acid eliciting hypothalamic synaptic loss in obesity. Mol Metab. 2023;72:101713. https://doi.org/10.1016/j.molmet.2023.101713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Srivastava RK, Ruiz de Azua I, Conrad A, Purrio M, Lutz B. Cannabinoid CB1 receptor deletion from catecholaminergic neurons protects from diet-induced obesity. Int J Mol Sci. 2022 23. https://doi.org/10.3390/ijms232012635.

  97. Bracken MB. Why animal studies are often poor predictors of human reactions to exposure. J R Soc Med. 2009;102:120–2. https://doi.org/10.1258/jrsm.2008.08k033

    Article  PubMed  PubMed Central  Google Scholar 

  98. Pataky Z, Carrard I, Gay V, Thomas A, Carpentier A, Bobbioni-Harsch E, et al. Effects of a weight loss program on metabolic syndrome, eating disorders and psychological outcomes: mediation by endocannabinoids. Obes Facts. https://doi.org/10.1159/000487890. (2018).

  99. Di Marzo V, Côté M, Matias I, Lemieux I, Arsenault BJ, Cartier A, et al. Changes in plasma endocannabinoid levels in viscerally obese men following a 1 year lifestyle modification programme and waist circumference reduction: Associations with changes in metabolic risk factors. Diabetologia. 2009;52:213–7. https://doi.org/10.1007/s00125-008-1178-6

    Article  CAS  PubMed  Google Scholar 

  100. Haidari F, Aghamohammadi V, Mohammadshahi M, Ahmadi-Angali K, Asghari-Jafarabadi M Whey protein supplementation reducing fasting levels of anandamide and 2-AG without weight loss in pre-menopausal women with obesity on a weight-loss diet. Trials. 2020. https://doi.org/10.1186/s13063-020-04586-7.

  101. Grapov D, Fiehn O, Campbell C, Chandler CJ, Burnett DJ, Souza EC, et al. Impact of a weight loss and fitness intervention on exercise-associated plasma oxylipin patterns in obese, insulin-resistant, sedentary women. Physiol Rep. 2020. https://doi.org/10.14814/phy2.14547.

  102. Drummen M, Tischmann L, Gatta-Cherifi B, Cota D, Matias I, Raben A, et al. Role of endocannabinoids in energy-balance regulation in participants in the postobese state - A PREVIEW study. J Clin Endocrinol Metab. 2020. https://doi.org/10.1210/clinem/dgaa193.

  103. Tagliamonte S, Laiola M, Ferracane R, Vitale M, Gallo MA, Meslier V, et al. Mediterranean diet consumption affects the endocannabinoid system in overweight and obese subjects: possible links with gut microbiome, insulin resistance and inflammation. Eur J Nutr. 2021. https://doi.org/10.1007/s00394-021-02538-8.

  104. Soldevila-Domenech N, Pastor A, Sala-Vila A, Lázaro I, Boronat A, Muñoz D, et al. Sex differences in endocannabinoids during 3 years of Mediterranean diet intervention: Association with insulin resistance and weight loss in a population with metabolic syndrome. Front Nutr. 2022;9:1076677. https://doi.org/10.3389/fnut.2022.1076677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yagin NL, Hajjarzadeh S, Aliasgharzadeh S, Aliasgari F, Mahdavi R The association of dietary patterns with endocannabinoids levels in overweight and obese women. Lipids Health Dis. 2020. https://doi.org/10.1186/s12944-020-01341-4.

  106. Siebers M, Biedermann SV, Bindila L, Lutz B, Fuss J. Exercise-induced euphoria and anxiolysis do not depend on endogenous opioids in humans. Psychoneuroendocrinology. 2021;126:105173. https://doi.org/10.1016/j.psyneuen.2021.105173

    Article  CAS  PubMed  Google Scholar 

  107. Manca C, Pintus S, Murru E, Fantola G, Vincis M, Batetta B, et al. Fatty acid metabolism and derived-mediators distinctive of PPAR-α activation in obese subjects post bariatric surgery. Nutrients. 2021 13. https://doi.org/10.3390/nu13124340.

  108. Zoon HFA, de Bruijn SEM, Smeets PAM, de Graaf C, Janssen IMC, Schijns W, et al. Altered neural responsivity to food cues in relation to food preferences, but not appetite-related hormone concentrations after RYGB-surgery. Behav Brain Res. 2018. https://doi.org/10.1016/j.bbr.2018.07.016.

  109. Mallipedhi A, Prior SL, Dunseath G, Bracken RM, Barry J, Caplin S, et al. Changes in plasma levels of n-arachidonoyl ethanolamine and N-palmitoylethanolamine following bariatric surgery in morbidly obese females with impaired glucose homeostasis. J Diabetes Res. 2015. https://doi.org/10.1155/2015/680867.

  110. Quercioli A, Montecucco F, Pataky Z, Thomas A, Ambrosio G, Staub C, et al. Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: Relation to alterations in endocannabinoids and adipocytokines. Eur Heart J. 2013. https://doi.org/10.1093/eurheartj/eht085.

  111. Le Foll D, Lechaux D, Rascle O, Cabagno G. Weight loss and quality of life after bariatric surgery: a 2-year longitudinal study. Surg Obes Relat Dis. 2020;16:56–64. https://doi.org/10.1016/j.soard.2019.10.010

    Article  PubMed  Google Scholar 

  112. Tuero C, Valenti V, Rotellar F, Landecho MF, Cienfuegos JA, Frühbeck G. Revisiting the ghrelin changes following bariatric and metabolic surgery. Obes Surg. 2020;30:2763–80. https://doi.org/10.1007/s11695-020-04601-5

    Article  PubMed  Google Scholar 

  113. Pucci A, Batterham RL. Mechanisms underlying the weight loss effects of RYGB and SG: similar, yet different. J Endocrinol Invest. 2019;42:117–28. https://doi.org/10.1007/s40618-018-0892-2

    Article  CAS  PubMed  Google Scholar 

  114. Haghighat N, Ashtari-Larky D, Aghakhani L, Asbaghi O, Hoseinpour H, Hosseini B, et al. How does fat mass change in the first year after bariatric surgery? a systemic review and meta-analysis. Obes Surg. 2021;31:3799–821. https://doi.org/10.1007/s11695-021-05512-9

    Article  PubMed  Google Scholar 

  115. Xie S, Furjanic MA, Ferrara JJ, McAndrew NR, Ardino EL, Ngondara A, et al. The endocannabinoid system and rimonabant: a new drug with a novel mechanism of action involving cannabinoid CB 1 receptor antagonism-or inverse agonism-as potential obesity treatment and other therapeutic use. J Clin Pharm Ther. 2007;32:209–31. https://doi.org/10.1111/j.1365-2710.2007.00817.x

    Article  CAS  PubMed  Google Scholar 

  116. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-Year experience from the RIO-Europe study. Lancet. 2005. https://doi.org/10.1016/S0140-6736(05)66374-X.

  117. Cinar R, Iyer MR, Kunos G The therapeutic potential of second and third generation CB1R antagonists. Pharm Ther. 2020. https://doi.org/10.1016/j.pharmthera.2020.107477.

  118. Inversago Pharma. Novo Nordisk to acquire Inversago Pharma to develop new therapies for people living with obesity, diabetes and other serious metabolic diseases. 2023. https://inversago.com/en/2023/novo-nordisk-to-acquire-inversago-pharma-to-develop-new-therapies-for-people-living-with-obesity-diabetes-and-other-serious-metabolic-diseases/.

  119. Pete D, Narouze S. Endocannabinoids: Anandamide and 2-Arachidonoylglycerol (2-AG). In: Narouze S (ed). Cannabinoids and Pain. 1st ed. Springer Nature; 2021. 63–69

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NM, NW and RV conceptualized the study. NM was responsible for conducting the search, screening potentially eligible studies, extracting and analyzing data, interpreting results, and drafting the manuscript. NW, BVDS, LVO, RV reviewed the manuscript and provided critical feedback.

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Mattelaer, N., Van der Schueren, B., Van Oudenhove, L. et al. The circulating and central endocannabinoid system in obesity and weight loss. Int J Obes (2024). https://doi.org/10.1038/s41366-024-01553-z

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