The effects of cannabinnoids on thebrain Prog Neurobiol 1999 58 315 - PDF document

The effects of cannabinnoids on thebrain. Prog Neurobiol 1999; 58: 315-348.Endocannabinoids in the central nervoussystem an overview. Prostaglandins Leukotr Es-sent Fatty Acids 2002; 66: 221-233.theirendogenous agonists. Ann Rev PharmacolToxicol 1998: 38: 179-200.K, Squent polymorphism in the coding exon of the hu-man cannabinoid receptor (CNR1) gene. Mol CellProbes 1999; 13: 321-323.UART. Validation of ainsulin model for the reactions in RIA. Clin ChemLab Med 2002; 40: 1161-1167.UMMARYOFTHEEPORTOFTHEDUCATIONPERTANELONVALUATIONANDREATMENTHOLESTEROLINDULTSDULTREAT. JAMA 2001; 285: 2486-2487.TANDARDSOFDIABETESMELLITUSSSOCIATION. Diabetes Care 2007; 30: s4-s41.V, GOPARAJUL, LJ, BATKAIF, MGI, P. Leptin-regulated endocannabinoids areinvolved in maintaining food intake. Nature 2001;410: 822-825.S, JF, K. Activation of the peripheral endo-cannabinoid system in human obesity. Diabetes2005; 54: 2838-2843.P, COTARNICOLAM, MG, GV, L. Association be-tween cannabinoid type 1 receptor polymorphismand body mass index in a southern Italian popu-lation. Int J Obes 2007; 31: 908-912.P, U. Genetic variation may influ-ence obesity only under conditions of diet: analy-sis of three candidate genes. Mol Genet Metab2008; 95: 188-191.ATTEVIV, CCannabinoid type 1 receptor gene polymor-phisms are associated with central obesity in aSouthern Brazilian population. Dis Markers 2008;25: 67-74.P, SP, CFP, TF, LM, BG, VM, SGenetic variations at the endocannabinoid type 1receptor gene (CNR1) are associated with obesi-ty phenotypes in men. J Clin Endocrinol Metab2007; 92: 2382-2389.S, MERTENSW, V. The G1422A variant of the endocannabi-noid receptor gene is associated with abdominaladiposity in obese men. Endocrine 2007: 31: 138-JG, BR, PMelanocortin-4 re-ceptor gene variants affect results of gastricbanding. J Gastrointest Surg 2004; 126(Suppl2): A774.JG, LKU, HFF.Binge eating as aphenotype of melanocortin 4 receptor gene muta-tions. N Engl J Med 2003; 349: 606-609.G, PL, CM, AF, RC, VP, GV, MM, PG, P. Impact ofcommon polymorphisms in candidate genes forinsulin resistance and obesity on weight loss ofmorbidly obese subjects after laparoscopic ad-justable gastric banding and hypocaloric diet. JClin Endocrinol Metab 2005; 90: 5064-5069.R, GM, IZL, CARTINT, PInfluence of -55CTpolymorphism of UCP3 gene on surgical resultsof biliopancreatic diversion. Obes Surg 2009 (inpress). R, GM, IL, CR, MInfluence of G308A polymorphism of TumorNecrosis Factor Alpha gene on surgical results ofbiliopancreatic diversion. Obes Surg 2010: 20: G1359A polymorphism of cannabinoid receptor gene and bariatric surgery pose tissue, suggesting that adipose tissue maybe an important contributor to endocannabinoidIn our study the prevalence of GA genotypewas (59.1%), higher thanprevious studies:. Perhaps, our sam-ple with a high average BMI than previous stud-ies could explain this difference. A second find-ing is the lack of association between BMI andgenotypes of this polymorphism. This fact is incontrast with the association detected by Gazzer-ro et alwith SNP G1359A of CB1 receptor, andother polymorphisms of this receptor such asA3813A and A4895A SNPsSNP of CB1 receptor. The inconsistencies be-tween associatio

n studies may reflect the com-plex interactions between multiple population-specific genetic and environmental factors.The effects of different polymorphisms afterbariatric surgery are an interesting area of inves-tigation. Some Authors have demonstrated, thatmelanocortin-4 receptor gene variant determinethe outcome of bariatric treatment of severe obe-. In other study, Sesti et al) have demon-strated that after laparoscopic adjustable gastricbanding, carriers of G-174G IL-6 genotype hadlost more weight than G-174C or C-174C andcarriers of A866A uncoupling protein 2 geno-types have lost more weight as compared withOnly one interventional study with this poly-morphism has been published. Aberle et alhaveshown that carriers of at least one A allele inCB1 lost more weight and reduced LDL choles-terol than wild type patients.Perhaps, these dis-crepancies with our results could be explained bydifferent inclusion criteria of subjects in this pre-vious work. First, the average BMI was differentin our bariatric surgery study than previoushypocaloric diet study. Second, weight loss andthe maintenance are different. Therefore, thequestion arises of whether weight loss achievedby a BPD in our research overrides the subtlepolymorphism-dependent effects seen in Aber-le’s study. However, this topic area is an inter-esting area of investigation with unclear thera-In conclusion, the present study demonstratesthat polymorphism G1359A in the CB1 receptordid not have a significant effect on biochemicaland anthropometric improvements after bariatricsurgery. ReferencesR, IR, PEffects of lifestylemodification on adipocytokine levels in obese pa-tients. Eur Rev Med Pharmacol Sci 2008; 12: 33-DELUISR, IEarlyclinical and surgical results of biliopancreatic di-version. Obes Surg 2005; 15: 799-802.N, AGF, Mcreatic diversion. World J Surg 1998; 22: 936-D. A de Luis, D. Pacheco, R. Aller, M. González Sagrado, R. Conde, O. Izaola, et al. IEWL%: initial excess weight percent loss. WC: Waist circumference. SBP (systolic blood pressure). DBP (diastolic bloodalue in each group. Table III. ParametersBasal time 3 months9 months12 monthsWild group (G1539G)Glucose (mg/dl)103.1 ± 2093.1 ± 8* 84.1 ± 18*85.9 ± 6.7*Total ch. (mg/dl)189.1 ± 38136.4 ± 38*123.8 ± 31*135 ± 39*LDL ch. (mg/dl)84.5 ± 3055.3 ± 34*73 ± 25*62.6 ± 30*HDL ch. (mg/dl)57.3 ± 1641.5 ± 948 ± 1652.5 ± 8TG (mg/dl)145.6 ± 67133.4 ± 4799 ± 51*100 ± 42*Mutant group (G1539G andGlucose (mg/dl)112.1 ± 1893.8 ± 11* 90.5 ± 5.6*87.1 ± 5.9*Total ch. (mg/dl)188.6 ± 30130.7 ± 24*127.4 ± 21*138 ± 23*LDL ch. (mg/dl)111 ± 3596.5 ± 36*74.3 ± 22*68.2 ± 21*HDL ch. (mg/dl)64.4 ± 7.150.0 ± 1046.8 ± 1347.8 ± 11TG (mg/dl)131.4 ± 42118 ± 46*107 ± 52*106 ± 58* Table II presents anthropometric parametersand blood pressure levels. In the wild typegroup, BMI, weight, waist circumference andsystolic blood pressure decreased. In the mu-tant type group, the same parameters improved,without statistical differences between groups.No differences were detected between mutantand wild genotypes in all anthropometric para-meters. Initial weight percent loss at 1 year offollow up was similar in both groups (33.1% vsTable III shows the biochemical parameters. I

nthe wild type group, glucose, total cholesterol,LDL cholesterol and triacylglycerol concentra-tions decreased. In the mutant type group, thesame parameters improved. No differences weredetected between mutant and wild genotypes inA decrease in the percentage of cardiovascularrisk factors was detected in both groups. Afterone year, hypertension frequency decreased in G1359A polymorphism of cannabinoid receptor gene and bariatric surgery wild-type patients from 35.8% to 7.7% and from37.1% to 7.4%, in mutant-type patients. Diabetesmellitus disappeared in all patients (wild and mu-tant genotypes). Oral drugs or subcutaneous in-sulin were discontinued in all patients aftersurgery. After one year, dyslipemia frequency de-creased in wild-type patients from 10.3% to2.6% and from 11.1% to 3.7%, in mutant-typeThe finding of this study is the lack of associa-tion of the G1359A and A1359A CB1 genotypeswith clinical and biochemical outcomes afterbariatric surgery. Weight, waist circumference,systolic blood pressure, glycemia, plasma lipidlevels improved during follow up after BPD incarriers of the homozygous wild-type or het-erozygous variant genotype.The literature supports the notion that endo-cannabinoid system is positioned for regula-tion of endocannabinoid levels that could in-fluence craving and reward behaviors throughthe relevant neuronal circuitry and metabolic pa-. Also, the CB1 receptor is expressedin some peripheral human tissue studied in rela-tion to the pathogenesis of obesity and obesity-associated metabolic disorders. A marked down-regulation of the fatty acid amide hydrolase(FAAH) gene expression was found in the adi- Morbid obese51Obese15Gender (men/women)15/51Age (years)42.9 ± 13.3)48.8 ± 7.6Hypertension (%)36.6%Diabetes mellitus (%)7.6%Dyslipemia (%)10.6%Table I.Preoperative characteristics of the patients.IEWL%: initial excess weight percent loss. WC: Waist circumference. SBP (systolic blood pressure). DBP (diastolic bloodalue in each group. Table II. ParametersBasal time 3 months9 months12 monthsWild group (G1359G))48.3 ± 6.540.7 ± 6.8*36.2 ± 6.2*33.2 ± 7.7*Weight (kg)126.1 ± 20.1104.1 ± 18.3*95.3 ± 15*87.5 ± 18*IEWL%–15.825.333.1SBP mmHg151± 35136.1 ± 18*131 ± 16*129.1 ± 20*DBP mmHg90 ± 1878.8 ± 1781.3 ± 1181.2 ± 7.6WC127 ± 18114.4 ± 15*100.8 ± 16*101.6 ± 20*Mutant group (G1359A))48.9 ± 7.641.1 ± 8.4*37.4 ± 5.1*33.7 ± 5.7*Weight (kg)126.3 ± 20107.9 ± 18*93.5 ± 13*84.3 ± 13*IEWL (%)–14.526.233.6SBP mmHg135 ± 16132.5 ± 20*135.1 ± 14131.4 ± 9.2*DBP mmHg85.1 ± 6.982.2 ± 983.1 ± 6.386.2 ± 10.2WC126 ± 17112.8 ± 14*101.6 ± 12*102.9 ± 16* A sample of 66 morbidly obese patients (BMI�40) was operated on from December 2004 toDecember 2008 (Table I). We analyzed a consec-utive series of patients who underwent open BPDThe BPD consisted of an average of 200-cmalimentary limb and 80-cm common limb.Gastric volume was measured after staplingwith sterile water. Intestinal limbs were mea-sured during the surgery with a sterile tapemeasure. Follow-up visits were carried out atintervals (3, 9, and 12 months). The followingvariables were specifically recorded: age,weight, BMI, waist circumference, and associ-The frequency of patients with diabetes me

l-litus, hypertension and hyperlipidemia wasrecorded at each visit (3, 9, and 12 mo aftersurgery).Hypertension and hyperlipemia were diag-nosed in patients taking hypotensive and hy-polipemic drugs, respectively. Hypertension orhyperlipidemia according to National CholesterolEducation Program standards also was. Diabetes mellitus was diagnosed inpatients taking hypoglycemic drugs or insulin oraccording to the American Diabetes AssociationWeight, BMI, fat mass, blood pressure, basalglucose, triacylglycerols, total cholesterol, LDLcholesterol, HDL cholesterol were measured atbasal visit (before surgery) and at each visit (3, 9,Blood pressure was measured twice after a 10minutes rest with a sphygmomanometer OM-RON Mx3 (Omron Matsusaka Co. Ld, TokioJapan), and averaged.Body weight was measured to an accuracy of0.1Kg and body mass index computed as bodyPlasma glucose levels were determined by us-ing an automated glucose oxidase method (Glu-cose analyser 2, Beckman Instruments, Fullerton,CA, USA). Serum total cholesterol, HDL-choles-terol and triacylglycerol concentrations were de-termined by enzymatic colorimetric assay(Roche Diagnostics, Mannheim, Germany).signed with the Beacon Designer 4.0 (Premiermerase chain reaction (PCR) was carried outwith 50 ng of genomic DNA, 0.5 µL of eacholigonucleotide primer (primer forward:5’-TTCACA GGG CCG CAG AAA G-3’ and reverse 5’-GAG GCA TCA GGC TCA CAG AG-3’), and0.25 uL of each probes (wild probe:5’-Fam-ATCAAG AGC ACG GTC AAG ATT GCC-BHQ-1-3’)and (mutant probe:5’-Texas red- ATC AAGAGC ACA GTC AAG ATT GCC -BHQ-1-3’) ina 25 µL final volume (Termociclador iCycler IQ), Hercules, CA, USA). DNA was de-naturated at 95ºC for 3 min; this was followed by50 cycles of denaturation at 95ºC for 15 s, anda 25 µL final volume containing 12.5 uL ofIQTM Supermix (Bio-RadUSA) with hot start Taq DNA polymerase. HardyWeimberger equilibrium was assessed.The results were expressed as means The normal distribution of variables was ana-lyzed with Kolmogorov-Smirnov test. Non-para-metric variables were analyzed with the Mann-Whitney test and Wilcoxon test. Qualita tive vari-ables were analyzed with the chi-square test,with Yates correction as necessary, and Fisher’stest. Sample size estimation was performedbased on the effects on weight loss using poly-morphism frequency (30%) in morbid obese sub-jects. A p-value under 0.05 was considered statis-tically significant. The statistical analysis wasperformed for the combined as a group and wild type G1359G assecond group, with a dominant model. A -valueas considered statistically significant.(wild type group) and 27 (40.9%) pa-tients had genotype group). In the wild type group, mean age was41.6±14.6 years and there were 9 men and 30women. In the mutant type group, mean agewas 43.3±10.4 years and there were 6 men and21 women, without statistical differences.The preoperative characteristics of the patientsare shown in Table I.D.A de Luis, D. Pacheco, R. Aller, M. González Sagrado, R. Conde, O. Izaola, et al. Background:Bariatric surgeryis the most effective long-term treatment for mor-bid obesity, reducing obesity-associated co-mor-bidities. We decide to investigate the role of thepolymorphism (G

1359A) of the cannabinoid (CB)1receptor gene on clinical outcomes 1 year after bil-iopancreatic diversion in morbidly obese patients.A sample of 66 morbidly obese pa-�tients (BMI 40 kg/m) were operated. Weight,fat mass, blood pressure, basal glucose, triacyl-glycerols, total cholesterol, low-density lipopro-tein cholesterol, high-density lipoprotein choles-terol were measured at basal visit and at eachvisit. The frequency of metabolic comorbiditieswas recorded at each visit.Thirty-nine patients (59.1%) hadgenotype G1359G (wild type group) and 27(40.9%) patients had genotype G1359A (mutanttype group). In wild and mutant type groups,body mass index, weight, waist circumference,systolic blood pressure, glucose, total choles-terol, low-density lipoprotein cholesterol and tri-acylglycerols concentrations decreased, withoutstatistical between genotype groups. Initialweight percent loss at 1 year of follow up wassimilar in both genotypes (33.1% vs 33.6%; ns).The present study demonstratesthat polymorphism G1359A in the CB1 receptordid not have a significant effect on biochemicaland anthropometric improvements after bil-iopancreatic diversion surgery.Bariatric surgery, Cannabinoid receptor gene, IntroductionObesity and type 2 diabetes mellitus arespreading rapidly worldwide. Weight reduction isReview for 2010; 14: 197-201receptor gene (CNR1) and clinical results ofbiliopancreatic diversion D.A. DE LUIS, D. PACHECO, R. ALLER, M. GONZÁLEZ SAGRADO, R. CONDE,O. IZAOLA, L. CUELLAR, M.C. TERROBA, T. MARTIN, M. VENTOSA Hospital Rio Hortega, University of Valladolid, Valladolid (Spain) RETICEF RD O56/0013 : Daniel A. de Luis, MD; e-mail: dadluis@yahoo.es known to be an effective treatment for over-weight-obese patients with risk factors of meta-. Bariatric surgery is the most ef-fective long-term treatment for morbid obesity,Biliopancreatic diversion (BPD) of Scopinarois a mixed operation that has shown goodresults regarding weight loss. Nevertheless, long-term follow up is known to be heterogeneous insome surgery studies. Perhaps the genetic back-ground of these patients could influence in fol-low up and outcomes.known to have many psychoactive effects in hu-mans including increases in body weightendogenous cannabinoid system mediates andit’s positioned both functionally and anatomical-to be an important modulator of normal hu-man brain behavior. This system consists of en-dogenous ligands 2-arachidonoylglycerol (2-AG)and anandamide (ADA) and two types of G-pro-tein-coupled cannabinoid receptors: cannabinoidtype-1 receptor (CB1), located in several brainareas and in a variety of peripheral tissues in-cluding adipose tissue, and cannabinoid type-2receptor (CB2), present in the immune systemA silent intragenic biallelic polymorphism (1359G/A) of the CB1 gene resulting in the substitu-tion of the G to A at nucleotide position 1359(Thr), was reported as a common polymorphismin the German populationConsidering the evidence that endogenouscannabinoid system plays a role in metabolic as-pects of body weight and feeding behaviordecide to investigate the role of missense poly-morphism (G1359A) of CB1 receptor gene onoutcomes 1 year after biliopancreatic diversion