Circulating endocannabinoids and brain anatomy: unraveling the weight loss connection through lifestyle and surgery approaches

Abstract

Obesity is a multifactorial disease linked to many comorbidities and has an impact on brain health. It is also known that obesity disrupts the endocannabinoid (eCB) system in the central nervous system and in the periphery, which complicates the underlying mechanisms behind obesity. However, weight loss through lifestyle interventions or bariatric surgery may alleviate obesity-related comorbidities, as well as restore eCB tone. Several studies have reported a decrease in circulating eCBs following weight loss, likely due to the positive association of these mediators with fat mass. However, further research is needed to clarify whether this reduction is a consequence of weight loss or plays a role in facilitating it. This review explores changes in circulating eCBs following weight loss and their potential roles in cerebral homeostasis and the reward system. It examines how lifestyle modifications and bariatric surgery may influence central eCB signalling and contribute to long-term weight loss success. Understanding the mechanisms behind improved brain function after weight loss could provide insights into optimizing obesity treatments.

Keywords

Endocannabinoids / obesity / bariatric surgery / lifestyle interventions / brain

References

[1] Uranga RM, Keller JN. The Complex Interactions Between Obesity, Metabolism and the Brain. Front Neurosci. 2019; 13: 513.

[2] Rubino F, Cummings DE, Eckel RH, Cohen RV, Wilding JPH, Brown WA, et al. Definition and diagnostic criteria of clinical obesity. Lancet Diabetes Endocrinol. 2025; 13: 221-62.

[3] McCuen-Wurst C, Ruggieri M, Allison KC. Disordered eating and obesity: associations between binge-eating disorder, night-eating syndrome, and weight-related comorbidities. Ann N Y Acad Sci. 2018; 1411: 96-105.

[4] Agarwal A, Agarwal M, Garg K, Dalal PK, Trivedi JK, Srivastava JS, et al. Metabolic syndrome and central obesity in depression: A cross-sectional study. Indian J Psychiatry. 2016; 58: 281-6.

[5] Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late-life as a risk factor for dementia: a meta-analysis of prospective studies. Obes Rev. 2011; 12: e426-37.

[6] Onyike CU, Crum RM, Lee HB, Lyketsos CG, Eaton WW. Is Obesity Associated with Major Depression? Results from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 2003; 158: 1139-47.

[7] Matias I, Marzo VD. Endocannabinoids and the control of energy balance. Trends Endocrinol Metab. 2007; 18: 27-37.

[8] Jager G, Witkamp RF. The endocannabinoid system and appetite: relevance for food reward. Nutr Res Rev. 2014; 27: 172-85.

[9] Pagotto U, Marsicano G, Cota D, Lutz B, Pasquali R. The Emerging Role of the Endocannabinoid System in Endocrine Regulation and Energy Balance. Endocr Rev. 2006; 27: 73-100.

[10] De Petrocellis L, Di Marzo V. An introduction to the endocannabinoid system: from the early to the latest concepts. Best Pract Res Clin Endocrinol Metab. 2009; 23: 1-15.

[11] Johnston E, Johnson S, McLeod P, Johnston M. The Relation of Body Mass Index to Depressive Symptoms. Can J Public Health. 2004; 95: 179-83.

[12] Dong C, Sanchez LE, Price RA. Relationship of obesity to depression: a family-based study. Int J Obes Relat Metab Disord. 2004; 28: 790-5.

[13] Jones-Corneille LR, Wadden TA, Sarwer DB, Faulconbridge LF, Fabricatore AN, Stack RM, et al. Axis I Psychopathology in Bariatric Surgery Candidates with and without Binge Eating Disorder: Results of Structured Clinical Interviews. Obes Surg. 2012; 22: 389-97.

[14] Deckers K, van Boxtel MPJ, Verhey FRJ, Köhler S. Obesity and cognitive decline in adults: Effect of methodological choices and confounding by age in a longitudinal study. J Nutr Health Aging. 2017; 21: 546-53.

[15] Gurvits TV, Shenton ME, Hokama H, Ohta H, Lasko NB, Gilbertson MW, et al. Magnetic resonance imaging study of hippocampal volume in chronic, combat-related posttraumatic stress disorder. Biol Psychiatry. 1996; 40: 1091-9.

[16] SCOVILLE WB, MILNER B. Loss of recent memory after bilateral hippocampal lesions. J Neurol Neurosurg Psychiatry. 1957; 20: 11-21.

[17] Raji CA, Ho AJ, Parikshak NN, Becker JT, Lopez OL, Kuller LH, et al. Brain Structure and Obesity. Hum Brain Mapp. 2010; 31: 353-64.

[18] Zapparoli L, Devoto F, Giannini G, Zonca S, Gallo F, Paulesu E. Neural structural abnormalities behind altered brain activation in obesity: Evidence from meta-analyses of brain activation and morphometric data. Neuroimage Clin. 2022; 36: 103179.

[19] Samara A, Murphy T, Strain J, Rutlin J, Sun P, Neyman O, et al. Neuroinflammation and White Matter Alterations in Obesity Assessed by Diffusion Basis Spectrum Imaging. Front Hum Neurosci. 2020; 13: 464.

[20] García-García I, Michaud A, Jurado MÁ, Dagher A, Morys F. Mechanisms linking obesity and its metabolic comorbidities with cerebral grey and white matter changes. Rev Endocr Metab Disord. 2022; 23: 833-43.

[21] Daoust J, Schaffer J, Zeighami Y, Dagher A, García-García I, Michaud A, et al. White matter integrity differences in obesity: A meta-analysis of diffusion tensor imaging studies. Neuroscience & Biobehavioral Reviews. 2021; 129: 133-41.

[22] García-García I, Michaud A, Dadar M, Zeighami Y, Neseliler S, Collins DL, et al. Neuroanatomical differences in obesity: meta-analytic findings and their validation in an independent dataset. Int J Obes (Lond). 2019; 43: 943-51.

[23] Ward MA, Carlsson CM, Trivedi MA, Sager MA, Johnson SC. The effect of body mass index on global brain volume in middle-aged adults: a cross sectional study. BMC Neurol. 2005; 5: 23.

[24] Ma Y, Ajnakina O, Steptoe A, Cadar D. Higher risk of dementia in English older individuals who are overweight or obese. Int J Epidemiol. 2020; 49: 1353-65.

[25] D’Addario C, Micioni Di Bonaventura MV, Pucci M, Romano A, Gaetani S, Ciccocioppo R, et al. Endocannabinoid signaling and food addiction. Neurosci Biobehav Rev. 2014; 47: 203-24.

[26] Muller T, Demizieux L, Troy-Fioramonti S, Gresti J, Pais de Barros JP, Berger H, et al. Overactivation of the endocannabinoid system alters the antilipolytic action of insulin in mouse adipose tissue. Am J Physiol Endocrinol Metab. 2017; 313: E26-36.

[27] 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; 55: 3053-60.

[28] Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Bátkai S, et al. Endocannabinoid activation at hepatic CB₁ receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005; 115: 1298-305.

[29] Côté M, Matias I, Lemieux I, Petrosino S, Alméras N, Després J, et al. Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond). 2007; 31: 692-9.

[30] 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.

[31] Spoto B, Fezza F, Parlongo G, Battista N, Sgro' E, Gasperi V, et al. Human adipose tissue binds and metabolizes the endocannabinoids anandamide and 2-arachidonoylglycerol. Biochimie. 2006; 88: 1889-97.

[32] Kuipers EN, Kantae V, Maarse BCE, van den Berg SM, van Eenige R, Nahon KJ, et al. High Fat Diet Increases Circulating Endocannabinoids Accompanied by Increased Synthesis Enzymes in Adipose Tissue. Front Physiol. 2019; 9: 1913.

[33] Buch C, Muller T, Leemput J, Passilly-Degrace P, Ortega-Deballon P, Pais de Barros JP, et al. Endocannabinoids Produced by White Adipose Tissue Modulate Lipolysis in Lean but Not in Obese Rodent and Human. Front Endocrinol (Lausanne). 2021; 12: 716431.

[34] Berridge KC, Ho CY, Richard JM, DiFeliceantonio AG. The tempted brain eats: pleasure and desire circuits in obesity and eating disorders. Brain Res. 2010; 1350: 43-64.

[35] Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003; 112: 423-31.

[36] Di Marzo V, Ligresti A, Cristino L. The endocannabinoid system as a link between homoeostatic and hedonic pathways involved in energy balance regulation. Int J Obes (Lond). 2009; 33: S18-24.

[37] Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002; 136: 550-7.

[38] Cristino L, Busetto G, Imperatore R, Ferrandino I, Palomba L, Silvestri C, et al. Obesity-driven synaptic remodeling affects endocannabinoid control of orexinergic neurons. Proc Natl Acad Sci U S A. 2013; 110: E2229-38.

[39] Massa F, Mancini G, Schmidt H, Steindel F, Mackie K, Angioni C, et al. Alterations in the Hippocampal Endocannabinoid System in Diet-Induced Obese Mice. J Neurosci. 2010; 30: 6273-81.

[40] Forte N, Boccella S, Tunisi L, Fernández-Rilo AC, Imperatore R, Iannotti FA, et al. Orexin-A and endocannabinoids are involved in obesity-associated alteration of hippocampal neurogenesis, plasticity, and episodic memory in mice. Nat Commun. 2021; 12: 6137.

[41] Engeli S. Dysregulation of the Endocannabinoid System in Obesity. J Neuroendocrinol. 2008; 20: 110-5.

[42] Scherma M, Fattore L, Castelli MP, Fratta W, Fadda P. The Role of the Endocannabinoid System in Eating Disorders: Neurochemical and Behavioural Preclinical Evidence. Curr Pharm Des. 2014; 20: 2089-99.

[43] 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.

[44] Verty AN, Stefanidis A, McAinch AJ, Hryciw DH, Oldfield B. Anti-Obesity Effect of the CB2 Receptor Agonist JWH-015 in Diet-Induced Obese Mice. PLoS One. 2015; 10: e0140592.

[45] Hruby A, Hu FB. The Epidemiology of Obesity: A Big Picture. Pharmacoeconomics. 2015; 33: 673-89.

[46] Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rössner S ; RIO-Europe Study Group. 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; 365: 1389-97.

[47] Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF ; RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006; 368: 1660-72.

[48] Van Gaal LF, Scheen AJ, Rissanen AM, Rössner S, Hanotin C, Ziegler O, et al.; RIO-Europe Study Group. Long-term effect of CB₁ blockade with rimonabant on cardiometabolic risk factors: two year results from the RIO-Europe Study. Eur Heart J. 2008; 29: 1761-71.

[49] Boyd ST, Fremming BA. Rimonabant--A Selective CB1 Antagonist. Ann Pharmacother. 2005; 39: 684-90.

[50] Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials. Lancet. 2007; 370: 1706-13.

[51] Ugur T, Bartels M, Kis B, Scherbaum N. Psychosis Following Anti-Obesity Treatment With Rimonabant. Obes Facts. 2008; 1: 103-5.

[52] Bambico FR, Duranti A, Tontini A, Tarzia G, Gobbi G. Endocannabinoids in the Treatment of Mood Disorders: Evidence from Animal Models. Curr Pharm Des. 2009; 15: 1623-46.

[53] Tambaro S, Tomasi ML, Bortolato M. Long-term CB₁ receptor blockade enhances vulnerability to anxiogenic-like effects of cannabinoids. Neuropharmacology. 2013; 70: 268-77.

[54] Meye FJ, Trezza V, Vanderschuren LJ, Ramakers GM, Adan RA. Neutral antagonism at the cannabinoid 1 receptor: a safer treatment for obesity. Mol Psychiatry. 2013; 18: 1294-301.

[55] Di Marzo V, Després JP. CB1 antagonists for obesity-what lessons have we learned from rimonabant? Nat Rev Endocrinol. 2009; 5: 633-8.

[56] Khan N, Laudermilk L, Ware J, Rosa T, Mathews K, Gay E, et al. Peripherally Selective CB1 Receptor Antagonist Improves Symptoms of Metabolic Syndrome in Mice. ACS Pharmacol Transl Sci. 2021; 4: 757-64.

[57] An D, Peigneur S, Hendrickx LA, Tytgat J. Targeting Cannabinoid Receptors: Current Status and Prospects of Natural Products. Int J Mol Sci. 2020; 21: 5064.

[58] Freitas HR, Isaac AR, Malcher-Lopes R, Diaz BL, Trevenzoli IH, De Melo Reis RA. Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr Neurosci. 2018; 21: 695-714.

[59] Rochefort G, Provencher V, Castonguay-Paradis S, Perron J, Lacroix S, Martin C, et al. Intuitive eating is associated with elevated levels of circulating omega-3-polyunsaturated fatty acid-derived endocannabinoidome mediators. Appetite. 2021; 156: 104973.

[60] Perdomo CM, Cohen RV, Sumithran P, Clément K, Frühbeck G. Contemporary medical, device, and surgical therapies for obesity in adults. Lancet. 2023; 401: 1116-30.

[61] Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity in adults. Am Psychol. 2020; 75: 235-51.

[62] Müller MJ, Geisler C, Heymsfield SB, Bosy-Westphal A. Recent advances in understanding body weight homeostasis in humans. F1000Res. 2018; 7: F1000 Faculty Rev-1025.

[63] Goldenberg RM, Gilbert JD, Manjoo P, Pedersen SD, Woo VC, Lovshin JA. Management of type 2 diabetes, obesity, or nonalcoholic steatohepatitis with high-dose GLP-1 receptor agonists and GLP-1 receptor-based co-agonists. Obes Rev. 2024; 25: e13663.

[64] Holmes D. Diabetes: Concerns about long-term use of GLP-1 analogues. Nat Rev Endocrinol. 2016; 12: 186.

[65] Alexander JT, Staab EM, Wan W, Franco M, Knitter A, Skandari MR, et al. The Longer-Term Benefits and Harms of Glucagon-Like Peptide-1 Receptor Agonists: a Systematic Review and Meta-Analysis. J Gen Intern Med. 2022; 37: 415-38.

[66] Bariatric surgery: surgical options and outcomes [Internet]. Edmonton: Obesity Canada; c2020 [cited 2025 Mar 4]. Available from: https://pesquisa.bvsalud.org/portal/resource/pt/biblio-1509773

[67] Gould JC, Garren MJ, Gutowski KA. Bariatric surgery. Clin Obstet Gynecol. 2006; 49: 375-88.

[68] Kissler HJ, Settmacher U. Bariatric Surgery to Treat Obesity. Semin Nephrol. 2013; 33: 75-89.

[69] 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.

[70] 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.

[71] 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. 2024; 47: 1289-94.

[72] Justinova Z, Solinas M, Tanda G, Redhi GH, Goldberg SR. The Endogenous Cannabinoid Anandamide and Its Synthetic Analog R(+)-Methanandamide Are Intravenously Self-Administered by Squirrel Monkeys. J Neurosci. 2005; 25: 5645-50.

[73] Justinová Z, Yasar S, Redhi GH, Goldberg SR. The Endogenous Cannabinoid 2-Arachidonoylglycerol Is Intravenously Self-Administered by Squirrel Monkeys. J Neurosci. 2011; 31: 7043-8.

[74] Muller T, Demizieux L, Troy-Fioramonti S, Buch C, Leemput J, Belloir C, et al. Chemical Synthesis, Pharmacokinetic Properties and Biological Effects of JM-00266, a Putative Non-Brain Penetrant Cannabinoid Receptor 1 Inverse Agonist. Int J Mol Sci. 2022; 23: 2923.

[75] Caraceni P, Viola A, Piscitelli F, Giannone F, Berzigotti A, Cescon M, et al. Circulating and hepatic endocannabinoids and endocannabinoid-related molecules in patients with cirrhosis. Liver Int. 2010; 30: 816-25.

[76] Galdino G, Romero TR, Silva JF, Aguiar DC, de Paula AM, Cruz JS, et al. The endocannabinoid system mediates aerobic exercise-induced antinociception in rats. Neuropharmacology. 2014; 77: 313-24.

[77] Galdino G, Romero T, da Silva JF, Aguiar D, de Paula AM, Cruz J, et al. Acute Resistance Exercise Induces Antinociception by Activation of the Endocannabinoid System in Rats. Anesth Analg. 2014; 119: 702-15.

[78] Raichlen DA, Foster AD, Seillier A, Giuffrida A, Gerdeman GL. Exercise-induced endocannabinoid signaling is modulated by intensity. Eur J Appl Physiol. 2013; 113: 869-75.

[79] Heyman E, Gamelin FX, Goekint M, Piscitelli F, Roelands B, Leclair E, et al. Intense exercise increases circulating endocannabinoid and BDNF levels in humans-Possible implications for reward and depression. Psychoneuroendocrinology. 2012; 37: 844-51.

[80] Forteza F, Bourdeau-Julien I, Nguyen GQ, Guevara Agudelo FA, Rochefort G, Parent L, et al. Influence of diet on acute endocannabinoidome mediator levels post exercise in active women, a crossover randomized study. Sci Rep. 2022; 12: 8568.

[81] 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; 74: 258-68.

[82] Koltyn KF, Brellenthin AG, Cook DB, Sehgal N, Hillard C. Mechanisms of Exercise-Induced Hypoalgesia. J Pain. 2014; 15: 1294-304.

[83] Crombie KM, Brellenthin AG, Hillard CJ, Koltyn KF. Endocannabinoid and Opioid System Interactions in Exercise-Induced Hypoalgesia. Pain Med. 2018; 19: 118-23.

[84] 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; 8: e14547.

[85] Gamelin FX, Aucouturier J, Iannotti FA, Piscitelli F, Mazzarella E, Aveta T, et al. Effects of chronic exercise on the endocannabinoid system in Wistar rats with high-fat diet-induced obesity. J Physiol Biochem. 2016; 72: 183-99.

[86] 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: e104534.

[87] Sadhasivam S, Alankar S, Maturi R, Vishnubhotla RV, Mudigonda M, Pawale D, et al. Inner Engineering Practices and Advanced 4-day Isha Yoga Retreat Are Associated with Cannabimimetic Effects with Increased Endocannabinoids and Short-Term and Sustained Improvement in Mental Health: A Prospective Observational Study of Meditators. Evid Based Complement Alternat Med. 2020; 2020: 8438272.

[88] Koay YC, Stanton K, Kienzle V, Li M, Yang J, Celermajer DS, et al. Effect of chronic exercise in healthy young male adults: a metabolomic analysis. Cardiovascular Research. 2021; 117: 613-22.

[89] Belitardo de Oliveira A, de Mello MT, Tufik S, Peres MFP. Weight loss and improved mood after aerobic exercise training are linked to lower plasma anandamide in healthy people. Physiol Behav. 2019; 201: 191-7.

[90] Desai S, Borg B, Cuttler C, Crombie KM, Rabinak CA, Hill MN, et al. A Systematic Review and Meta-Analysis on the Effects of Exercise on the Endocannabinoid System. Cannabis Cannabinoid Res. 2022; 7: 388-408.

[91] Bristot V, Poletto G, Pereira DMR, Hauck M, Schneider IJC, Aguiar AS Jr. The effects of exercise on circulating endocannabinoid levels-a protocol for a systematic review and meta-analysis. Syst Rev. 2022; 11: 98.

[92] 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: 6.

[93] 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; 54: 2838-43.

[94] 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; 60: 3703-16.

[95] 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 Endocrinol Metab. 2012; 97: E917-24.

[96] 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. 2018; 11: 144-56.

[97] 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.

[98] 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; 2015: 680867.

[99] 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: 4340.

[100] 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; 353: 194-202.

[101] 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. European Heart Journal. 2013; 34: 2063-73.

[102] 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; 113: 838-50.

[103] 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 (Lond). 2023; 47: 630-41.

[104] Thaler JP, Yi CX, Schur EA, Guyenet SJ, Hwang BH, Dietrich MO, et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest. 2012; 122: 153-62.

[105] Park JH, Yoo Y, Han J, Park YJ. Altered expression of inflammation-associated genes in the hypothalamus of obesity mouse models. Nutr Res. 2019; 70: 40-9.

[106] Miller AA, Spencer SJ. Obesity and neuroinflammation: A pathway to cognitive impairment. Brain Behav Immun. 2014; 42: 10-21.

[107] Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis. 2010; 37: 13-25.

[108] Sun Y, Koyama Y, Shimada S. Inflammation From Peripheral Organs to the Brain: How Does Systemic Inflammation Cause Neuroinflammation? Front Aging Neurosci. 2022; 14: 903455.

[109] Sewaybricker LE, Huang A, Chandrasekaran S, Melhorn SJ, Schur EA. The Significance of Hypothalamic Inflammation and Gliosis for the Pathogenesis of Obesity in Humans. Endocr Rev. 2023; 44: 281-96.

[110] Tuulari JJ, Karlsson HK, Antikainen O, Hirvonen J, Pham T, Salminen P, et al. Bariatric Surgery Induces White and Grey Matter Density Recovery in the Morbidly Obese: A Voxel-Based Morphometric Study. Hum Brain Mapp. 2016; 37: 3745-56.

[111] Li G, Hu Y, Zhang W, Wang J, Ji W, Manza P, et al. Brain functional and structural magnetic resonance imaging of obesity and weight loss interventions. Mol Psychiatry. 2023; 28: 1466-79.

[112] Ravinet Trillou C, Arnone M, Delgorge C, Gonalons N, Keane P, Maffrand J, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003; 284: R345-53.

[113] Cluny NL, Chambers AP, Vemuri VK, Wood JT, Eller LK, Freni C, et al. The neutral cannabinoid CB₁ receptor antagonist AM4113 regulates body weight through changes in energy intake in the rat. Pharmacol Biochem Behav. 2011; 97: 537-43.

[114] de Ceglia M, Di Bonaventura M, Romano MV, Friuli A, Micioni Di Bonaventura M, Gavito E, et al. Anxiety associated with palatable food withdrawal is reversed by the selective FAAH inhibitor PF-3845: A regional analysis of the contribution of endocannabinoid signaling machinery. International Journal of Eating Disorders. 2023; 56: 1098-113.

[115] Mock ED, Mustafa M, Gunduz-Cinar O, Cinar R, Petrie GN, Kantae V, et al. Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice. Nat Chem Biol. 2020; 16: 667-75.

[116] Moeller K, Willmes K, Klein E. A review on functional and structural brain connectivity in numerical cognition. Front Hum Neurosci. 2015; 9: 227.

[117] Lepping RJ, Bruce AS, Francisco A, Yeh HW, Martin LE, Powell JN, et al. Resting-state brain connectivity after surgical and behavioral weight loss. Obesity (Silver Spring). 2015; 23: 1422-8.

[118] Bruce AS, Bruce JM, Ness AR, Lepping RJ, Malley S, Hancock L, et al. A comparison of functional brain changes associated with surgical versus behavioral weight loss. Obesity (Silver Spring). 2014; 22: 337-43.

[119] Van Opstal AM, Wijngaarden MA, van der Grond J, Pijl H. Changes in brain activity after weight loss. Obes Sci Pract. 2019; 5: 459-67.

[120] Mueller K, Möller HE, Horstmann A, Busse F, Lepsien J, Blüher M, et al. Physical exercise in overweight to obese individuals induces metabolic- and neurotrophic-related structural brain plasticity. Front Hum Neurosci. 2015; 9: 372.

[121] Miranda M, Morici JF, Zanoni MB, Bekinschtein P. Brain-Derived Neurotrophic Factor: A Key Molecule for Memory in the Healthy and the Pathological Brain. Front Cell Neurosci. 2019; 13: 363.

[122] Hu Y, Ji G, Li G, Manza P, Zhang W, Wang J, et al. Brain Connectivity, and Hormonal and Behavioral Correlates of Sustained Weight Loss in Obese Patients after Laparoscopic Sleeve Gastrectomy. Cereb Cortex. 2021; 31: 1284-95.

[123] Duan S, Ji G, Li G, Hu Y, Zhang W, Wang J, et al. Bariatric surgery induces alterations in effective connectivity between the orbitofrontal cortex and limbic regions in obese patients. Sci China Inf Sci. 2020; 63: 170104.

[124] Liu L, Ji G, Li G, Hu Y, Jin Q, Hu C, et al. Structural changes in brain regions involved in executive-control and self-referential processing after sleeve gastrectomy in obese patients. Brain Imaging Behav. 2019; 13: 830-40.

[125] Zeighami Y, Iceta S, Dadar M, Pelletier M, Nadeau M, Biertho L, et al. Spontaneous neural activity changes after bariatric surgery: A resting-state fMRI study. Neuroimage. 2021; 241: 118419.

[126] Bohon C, Geliebter A. Change in brain volume and cortical thickness after behavioral and surgical weight loss intervention. Neuroimage Clin. 2019; 21: 101640.

[127] Prehn K, Profitlich T, Rangus I, Heßler S, Witte AV, Grittner U, et al. Bariatric Surgery and Brain Health-A Longitudinal Observational Study Investigating the Effect of Surgery on Cognitive Function and Gray Matter Volume. Nutrients. 2020; 12: 127.

[128] Rullmann M, Preusser S, Poppitz S, Heba S, Hoyer J, Schütz T, et al. Gastric-bypass surgery induced widespread neural plasticity of the obese human brain. NeuroImage. 2018; 172: 853-63.

[129] Morales I, Berridge KC. ‘Liking’ and ‘wanting’ in eating and food reward: Brain mechanisms and clinical implications. Physiol Behav. 2020; 227: 113152.

[130] Richard D, Guesdon B, Timofeeva E. The brain endocannabinoid system in the regulation of energy balance. Best Pract Res Clin Endocrinol Metab. 2009; 23: 17-32.

[131] Stoeckel LE, Weller RE, Cook EW 3rd, Twieg DB, Knowlton RC, Cox JE. Widespread reward-system activation in obese women in response to pictures of high-calorie foods. Neuroimage. 2008; 41: 636-47.

[132] Nummenmaa L, Hirvonen J, Hannukainen JC, Immonen H, Lindroos MM, Salminen P, et al. Dorsal Striatum and Its Limbic Connectivity Mediate Abnormal Anticipatory Reward Processing in Obesity. PLoS One. 2012; 7: e31089.

[133] Wenzel JM, Cheer JF. Endocannabinoid Regulation of Reward and Reinforcement through Interaction with Dopamine and Endogenous Opioid Signaling. Neuropsychopharmacology. 2018; 43: 103-15.

[134] Wang H, Lupica CR. Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes. Prog Neuropsychopharmacol Biol Psychiatry. 2014; 52: 24-7.

[135] Méndez-Díaz M, Rueda-Orozco PE, Ruiz-Contreras AE, Prospéro-García O. The endocannabinoid system modulates the valence of the emotion associated to food ingestion. Addict Biol. 2012; 17: 725-35.

[136] Monteleone AM, Di Marzo V, Monteleone P, Dalle Grave R, Aveta T, Ghoch ME, et al. Responses of peripheral endocannabinoids and endocannabinoid-related compounds to hedonic eating in obesity. Eur J Nutr. 2016; 55: 1799-805.

[137] Rigamonti AE, Bini S, Piscitelli F, Lauritano A, Di Marzo V, Vanetti C, et al. Hedonic eating in Prader-Willi syndrome is associated with blunted PYY secretion. Food Nutr Res. 2017; 61: 1297553.

[138] 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. 2022; 239: 1311-9.

[139] Redlich C, Dlugos A, Hill MN, Patel S, Korn D, Enneking V, et al. The endocannabinoid system in humans: significant associations between anandamide, brain function during reward feedback and a personality measure of reward dependence. Neuropsychopharmacology. 2021; 46: 1020-7.

[140] Salem V, Demetriou L, Behary P, Alexiadou K, Scholtz S, Tharakan G, et al. Weight Loss by Low-Calorie Diet Versus Gastric Bypass Surgery in People With Diabetes Results in Divergent Brain Activation Patterns: A Functional MRI Study. Diabetes Care. 2021; 44: 1842-51.

[141] Agarwal K, Maki KA, Vizioli C, Carnell S, Goodman E, Hurley M, et al. The Neuro-Endo-Microbio-Ome Study: A Pilot Study of Neurobiological Alterations Pre- Versus Post-Bariatric Surgery. Biol Res Nurs. 2022; 24: 362-78.

[142] Behary P, Miras AD. Food preferences and underlying mechanisms after bariatric surgery. Proc Nutr Soc. 2015; 74: 419-25.

[143] Tarragon E, Moreno JJ. Role of Endocannabinoids on Sweet Taste Perception, Food Preference, and Obesity-related Disorders. Chem Senses. 2017; 43: 3-16.

[144] Goldstone AP, Miras AD, Scholtz S, Jackson S, Neff KJ, Pénicaud L, et al. Link Between Increased Satiety Gut Hormones and Reduced Food Reward After Gastric Bypass Surgery for Obesity. J Clin Endocrinol Metab. 2016; 101: 599-609.

[145] Bermudez-Silva FJ, Cardinal P, Cota D. The role of the endocannabinoid system in the neuroendocrine regulation of energy balance. J Psychopharmacol. 2012; 26: 114-24.