BackgroundHeterozygous mutations in melanocortin-4 receptor (MC4R) are the most frequent genetic cause of obesity. Bariatric surgery is a successful treatment for severe obesity. The mechanisms of weight loss after bariatric surgery are not well understood.MethodsNinety-two patients who had Roux-en-Y gastric bypass (RYGB) surgery were screened for MC4R mutations. We compared percent excess weight loss (%EWL) in the four MC4R mutation carriers with that of two control groups: 8 matched controls and with the remaining 80 patients who underwent RYGB.ResultsFour patients were heterozygous for functionally significant MC4R mutations. In patients with MC4R mutations, the %EWL after RYGB (66% EWL) was not significantly different compared to matched controls (70% EWL) and non-matched controls (60% EWL) after 1 year of follow-up.ConclusionsThis study suggests that patients with heterozygous MC4R mutations also benefit from RYGB and that weight loss may be independent of the presence of such mutations

Aslan, Ivy R

Calton, Melissa A

Campos, Guilherme M

Evans, Daniel S

Merriman, Raphael B

Vaisse, Christian

eScholarship - University of California

UCSFUC San Francisco Previously Published WorksTitleWeight Loss after Roux-en-Y Gastric Bypass in Obese Patients Heterozygous for MC4R MutationsPermalinkhttps://escholarship.org/uc/item/6mz9c8c7JournalObesity Surgery, 21(7)ISSN0960-8923AuthorsAslan, Ivy RCampos, Guilherme MCalton, Melissa Aet al.Publication Date2011-07-01DOI10.1007/s11695-010-0295-8 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaCLINICAL RESEARCHWeight Loss after Roux-en-Y Gastric Bypass in ObesePatients Heterozygous for MC4R MutationsIvy R. Aslan & Guilherme M. Campos &Melissa A. Calton & Daniel S. Evans &Raphael B. Merriman & Christian VaissePublished online: 19 October 2010# The Author(s) 2010. This article is published with open access at Springerlink.comAbstractBackground Heterozygous mutations in melanocortin-4receptor (MC4R) are the most frequent genetic cause ofobesity. Bariatric surgery is a successful treatment forsevere obesity. The mechanisms of weight loss afterbariatric surgery are not well understood.Methods Ninety-two patients who had Roux-en-Y gastricbypass (RYGB) surgery were screened for MC4R mutations.We compared percent excess weight loss (%EWL) in the fourMC4R mutation carriers with that of two control groups:8 matched controls and with the remaining 80 patients whounderwent RYGB.Results Four patients were heterozygous for functionallysignificant MC4R mutations. In patients with MC4Rmutations, the %EWL after RYGB (66% EWL) was notsignificantly different compared to matched controls (70%EWL) and non-matched controls (60% EWL) after 1 yearof follow-up.Conclusions This study suggests that patients with hetero-zygous MC4R mutations also benefit from RYGB and thatweight loss may be independent of the presence of suchmutations.Keywords Melanocortin-4 receptor . Roux-en-Y gastricbypass . ObesityIntroductionLifestyle modification, such as diet and exercise, is noteffective in maintaining long-term weight loss in patientswith class III (BMI>40 kg/m2) obesity. Bariatric surgery iscurrently the most effective therapy for these patients.Outcomes after different types of bariatric surgery arevariable and the mechanisms of resultant weight loss arepoorly understood [1]. It has been suggested that theoutcome of these procedures could be influenced by geneticvariations implicated in the predisposition to obesity [2].Genetic factors account for 40% to 70% of an individual’spredisposition to obesity [3]. Several known obesity-associated mutations involve genes of the hypothalamicleptin–melanocortin system. These include mutations inleptin, the leptin receptor, proopiomelanocortin, prohormoneconvertase 1/3, and melanocortin-4 receptor (MC4R) [3–5].Specifically, heterozygous MC4R mutations are the mostcommon genetic form of obesity, and mutations in thisgene account for approximately 2.5% of severely obeseindividuals [6, 7].MC4R is expressed at low levels and is found inhypothalamic nuclei involved in the regulation of foodintake and in particular neurons of the paraventricularnucleus [8]. The physiological role of MC4R in food intakeand body weight regulation is best demonstrated by theI. R. AslanDepartment of Pediatrics, Division of Endocrinology,University of California San Francisco,San Francisco, CA 94143, USAM. A. Calton :D. S. Evans :C. Vaisse (*)Diabetes Center and Department of Medicine,University of California San Francisco,513 Parnassus Avenue, Room HSW1113,San Francisco, CA 94143-0573, USAe-mail: vaisse@medicine.ucsf.eduG. M. CamposDepartment of Surgery, University of Wisconsin,Madison, WI, USAR. B. MerrimanDivision of Gastroenterology, California Pacific Medical Center,San Francisco, CA 94115, USAOBES SURG (2011) 21:930–934DOI 10.1007/s11695-010-0295-8phenotype of the MC4R knockout mice [9]. Mice lackingboth alleles of MC4R (MC4R−/− mice) develop a maturity-onset hyperphagic obesity syndrome by 10 weeks of age.Mice heterozygous for an MC4R deletion (MC4R+/− mice)show an average weight that is intermediate between that ofwild-type and MC4R−/− mice. This suggests that haplo-insufficiency at the MC4R locus is sufficient to cause analteration in the regulation of body weight in rodents.MC4R regulates food intake and maintains long-termenergy homeostasis by integrating signals provided by itsagonist α-melanocyte stimulating hormone and antagonistagouti-related peptide from leptin-sensitive neurons in thearcuate nucleus [10]. An important argument for showingthat non-synonymous mutations are responsible for adisease is the demonstration of the functional relevance ofthese mutations (i.e., the demonstration that the mutatedproduct behaves differently in a functional assay). Func-tional studies of MC4R mutations associated with obesityindicate that multiple functional alterations contribute totheir pathogenicity and that more severely impairedreceptor function in vitro correlates with earlier age ofobesity onset and higher BMI [6].Lifestyle interventions based on exercise, behavior, andnutrition therapy in children with MC4R mutations are noteffective in providing long-term weight loss in contrast tochildren without MC4R mutations [11]. In addition, acontroversial report suggested that carriers of non-obesity-associated genetic variations at the MC4R locus mighthave poorer weight loss outcomes after gastric banding[2, 12].Here, we compare the weight loss outcome after Roux-en-Y gastric bypass (RYGB) in patients who are heterozy-gous carriers of rare functionally relevant obesity-associatedMC4R mutations with that of control patients who do notcarry such mutations.Patients and MethodsPatientsNinety-two patients who were considered appropriatecandidates for RYGB were screened for MC4R mutations.Criteria used at the University of California San FranciscoBariatric Surgery Program for the selection of patients for aRYGB has been described in detail previously [13]. Briefly,all patients met the 1991 NIH Consensus DevelopmentConference guidelines, including: BMI (weight in kilo-grams divided by height in meters squared) >40 or BMIbetween 35 and 40 with obesity-related comorbidities for atleast 5 years and a documented attempt of medicallysupervised therapy for weight loss for at least 6 months[14]. All patients also underwent preoperative psycholog-ical, nutritional, and medical evaluations. Active bingeeating disorder is considered a contraindication for bariatricsurgery at the UCSF Bariatric Program. Procedure selectionwas determined by patient preference and occurred afterparticipation in a 1-h educational and screening sessionwith a dietician and a bariatric surgeon and after medicaland psychological clearances.Surgical Technique for RYGBThe technique for RYGB has been described previously[15]. In brief, it was performed laparoscopically usingstaplers (US Surgical Corporation, Norwalk, CT) to createa 15- to 30-mL gastric pouch, the antecolic gastro-jejunostomy, the100-cm Roux limb, and the side-to-sidejejunojejunostomy.Postoperative CarePatients were given clear liquids on the first postoperativeday and then advanced to a full liquid diet on the secondpostoperative day. Patients were seen in clinic 2 weekspostoperatively, then every 3 months for the first year. Afterthe operation, patients received prenatal vitamins, calciumsupplements, vitamin D, and acid suppression medication.Nutritional supplements were prescribed as needed fordocumented deficiencies. All weight measurements wereobtained at the UCSF Bariatric Surgery Center. Calculationof excess weight loss was based on Metropolitan LifeInsurance height and weight tables to determine ideal bodyweight (IBW) [16]. We defined excess weight as the weightabove the patient’s IBW. We calculated the total weight loss(kg) on each follow-up time and the percent excess weightloss (%EWL) after surgery, which was weight loss dividedby excess weight multiplied by 100 on each follow-uppoint.Control Group MatchingControls were matched for gender and the presence ofdiabetes. In addition, controls were matched within onestandard deviation for baseline BMI before surgery and forage. The UCSF Committee on Human Research approvedthe protocols, and informed written consent was obtainedfrom all patients.Gene AnalysisGenomic DNA was extracted from white blood cells usingstandard methods. Our group previously described DNAsequencing and in vitro analysis of blood samples frompatients with MC4R mutations [7].OBES SURG (2011) 21:930–934 931Statistical Analyses and Power CalculationThe comparison of %EWL at each follow-up time point (1,3, 6, 9, and 12 months) between cases (n=4) and matchedcontrols (n=8) was performed using a paired, two-tailed ttest. Additionally, the comparison between the four casesand the 88 controls (8 matched controls and 80 non-matched controls) was performed using linear regressionwhile adjusting for age, gender, self-reported race, andbaseline BMI.ResultsIdentification of MC4R MutationsNinety-two patients were screened for MC4R mutations.The mean ± SD of BMI and age prior to surgery was 55±8.5 kg/m2 and 45±10.4 years, respectively.Four patients carried heterozygous MC4R mutations.One patient carried the Cys271Phe (812G>T) mutation, onepatient carried the nonsense mutation Gln307stop(919C>T), and two patients carried the Arg236Cys(706C>T) mutation. All these mutations cause functionalalteration in vitro [7].Weight Loss After RYGBSubjects who were heterozygous for known MC4R non-synonymous mutations, defined as cases, were matched tosubjects who lacked any non-synonymous MC4R muta-tions, defined as controls, based on age, sex, BMI, and type2 diabetes mellitus (see “Patients and Methods”). Fourcases were matched to eight controls (Table 1). Wecompared %EWL between MC4R mutation carriers andthe entire cohort of 88 patients without MC4R mutations (4matched controls and 80 non-matched controls) with astarting BMI>40 kg/m2 at all time points (1, 3, 6, 9, and12 months). There was no statistically significant differencein %EWL between cases and controls at any time point(Fig. 1).Linear regression controlling for age, sex, self-reportedrace, and baseline BMI was used to compare %EWLbetween cases and all 88 controls patients (8 matchedcontrols and 80 non-matched controls) without MC4Rmutations in the cohort at the 9- and 12-month follow-uptime points. After controlling for all the above variables,MC4R mutation carriers did not have a significantlydifferent %EWL at 9 or 12 months. At 9 months offollow-up, the mutation carriers had less %EWL comparedto controls; however, at 12 months, the mutation carriershad more %EWL compared to controls. Thus, neither therate nor the absolute amount of weight loss was relatedto the presence of MC4R variants. In fact, the onlypredictor that was significant was baseline BMI. Forevery 10 points greater in BMI, patients lost 10% lessEWL at a follow-up time of 9 months (effect size ± SE,1±0.38, p=0.006) and 7% less EWL at a follow-up timeof 12 months (effect size ± SE, −0.7±0.3, p=0.026). Thecombination of analysis of matched pairs and linearTable 1 Clinical data from patients heterozygous for MC4R mutations and eight matched non-carrier for MC4R mutations controlsPair MC4R mutation Gender Age (years) BMI (kg/m2) Dyslipidemia DM HTN PerioperativecomplicationsPair 1Carrier Cys271Phe Female 55 53.8 − + + NoneControl Female 65 55.7 + + + NoneControl Female 55 51.2 + + − NoneControl Female 55 68.8 − + + NonePair 2Carrier Glu307Stop Male 43 54.3 + − − NoneControl Male 42 57.9 − − − NoneControl Male 49 47.5 − − + NonePair 3Carrier Arg236Cys Female 47 63.9 − − − NoneControl Female 55 57.3 − − − NoneControl Female 49 65.7 − − + NonePair 4Carrier Arg236Cys Male 37 43.5 − − − PneumoniaControl Male 36 40.5 − − + NoneDM diabetes mellitus, HTN hypertension, + presence of comorbidity, − absence of comorbidity932 OBES SURG (2011) 21:930–934regression analysis provides better statistical analyses withthe available cohort.Perioperative (30 Days) ComplicationsAmong the MC4R mutation carriers, one patient hadaspiration pneumonia and was admitted to the ICU. Hewas discharged home on postoperative day 8. Out ofeight matched control patients, none had perioperativecomplications.DiscussionBariatric surgery is an effective weight loss tool for selectedseverely obese patients for whom conventional medical andbehavioral therapy for obesity has failed. With risingobesity rates, bariatric surgery has become a more commontool to achieve weight control and resolution of comorbid-ities [17]. Heterozygous MC4R mutations are the mostcommon genetic form of obesity, and mutations in this geneaccount for approximately 2.5% of severely obese individ-uals [6, 7]. Our study is the first one to document weightloss after RYGB in patients with heterozygous MC4Rmutations, and the results, although preliminary, suggestthat patients with these mutations were able to lose as muchweight as patients without MC4R mutations after RYGB. Itis well established that obese patients can achieve a %EWLof approximately 60% after RYGB [18], and previousstudies suggests that the %EWL after RYGB is superiorthan that obtained with gastric banding [19].A previous report suggested that carriers of geneticvariations at the MC4R locus have poorer outcomes aftergastric banding [2]. This study, however, grouped manydisparate mutations and polymorphisms together. A largemajority of patients in the study carried MC4R variants thatwere not associated with obesity (i.e., found also in non-obese controls) and with no demonstrated functional effecton the MC4R protein. In addition, patients with bingeeating disorders were included, which has been implicatedin poorer outcomes after bariatric surgery, making theindependent effect of MC4R gene variants in the previousstudy unclear [12].Other studies have demonstrated resolution of or markedimprovement in type 2 diabetes mellitus (DM) afterbariatric surgery [20]. Only one out of the four patientswith MC4R mutations had type 2 DM prior to RYGB,which did not resolve after surgery. Due to the smallsample size of MC4R mutation carriers, we could notdraw conclusions about the benefits of bariatric surgeryfor the resolution of diabetes in patients with heterozygousMC4R mutations. In a previous cohort of 769 obese adultpatients, there was no significant difference in theprevalence of type 2 DM between carriers and non-carriers of MC4R patients. Nineteen patients were foundto be MC4R carriers, and the prevalence of type 2 DMwas 20% among these patients, similar to our patients withMC4R mutations [6].The limitations of our study are mostly due to therarity of patients with MC4R mutations and the lack ofpower to drawn definitive conclusions. Further researchto understand the pathogenic mechanisms underlyingobesity caused by MC4R mutations is required for thedevelopment of rational and effective treatments. Thisresearch is challenging because in addition to the relativesmall number of patients with MC4R mutations, there isgreat genetic heterogeneity of the disorder. However, ourstudy is the first one to document weight loss afterRYGB in patients with heterozygous MC4R mutationsand provide preliminary information of outcomes afterRYGB.In conclusion, and in view of the limitations describedabove, our study shows that patients with heterozygousMC4R mutations had a similar rate of weight loss and %EWL after RYGB as patients without MC4R mutations.This suggests that heterozygous MC4R mutation statusshould not influence the decision to perform RYGB as atreatment for severe obesity.Fig. 1 %EWL curves of MC4Rmutation carriers (n=4),matched controls for gender,age, race, BMI, and presence ofdiabetes (n=8) and non-matchedcontrols (n=80) from 1 to12 months post-RYGBOBES SURG (2011) 21:930–934 933Acknowledgments This publication was supported by NIH/NCRRUCSF-CTSI UL1 RR024131. IA was supported by American HeartAssociation post-doctoral fellowship and Genentech clinical fellow-ship. DSE is supported by National Institutes of Health training grantT32 DK007418. CV is supported by NIH RO1 DK DK60540 andDK068152 as well as an established investigator award from theAmerican Heart Association: AHA#0740041N. GMC was supportedby Grant Number KL2 RR024130 from the National Center forResearch Resources (NCRR).Disclosure Statement The authors have nothing to disclose.Open Access This article is distributed under the terms of the CreativeCommons Attribution Noncommercial License which permits anynoncommercial use, distribution, and reproduction in any medium,provided the original author(s) and source are credited.References1. Tadross JA, le Roux CW. The mechanisms of weight loss afterbariatric surgery. Int J Obes (Lond). 2009;33 Suppl 1:S28–32.2. Potoczna N, Branson R, Kral JG, et al. Gene variants and bingeeating as predictors of comorbidity and outcome of treatment insevere obesity. J Gastrointest Surg. 2004;8(8):971–81. discussion81–2.3. Ranadive SA, Vaisse C. Lessons from extreme human obesity:monogenic disorders. Endocrinol Metab Clin North Am. 2008;37(3):733–51. x.4. Farooqi S, O’Rahilly S. Genetics of obesity in humans. EndocrRev. 2006;27(7):710–18.5. Farooqi IS. Genetic and hereditary aspects of childhood obesity.Best Pract Res Clin Endocrinol Metab. 2005;19(3):359–74.6. Lubrano-Berthelier C, Dubern B, Lacorte JM, et al. Melanocortin4 receptor mutations in a large cohort of severely obese adults:prevalence, functional classification, genotype–phenotype relation-ship, and lack of association with binge eating. J Clin EndocrinolMetab. 2006;91(5):1811–8.7. Calton MA, Ersoy BA, Zhang S, et al. Association of functionallysignificant melanocortin-4 but not melanocortin-3 receptor mutationswith severe adult obesity in a large North American case–controlstudy. Hum Mol Genet. 2009;18:1140–7.8. Mountjoy KG, Mortrud MT, Low MJ, et al. Localization of themelanocortin-4 receptor (MC4-R) in neuroendocrine and auto-nomic control circuits in the brain. Mol Endocrinol. 1994;8(10):1298–308.9. Huszar D, Lynch CA, Fairchild-Huntress V, et al. Targeteddisruption of the melanocortin-4 receptor results in obesity inmice. Cell. 1997;88(1):131–41.10. Schwartz MW, Woods SC, Porte Jr D, et al. Central nervoussystem control of food intake. Nature. 2000;404(6778):661–71.11. Reinehr T, Hebebrand J, Friedel S, et al. Lifestyle intervention inobese children with variations in the melanocortin 4 receptor gene.Obesity (Silver Spring). 2009;17(2):382–9.12. List JF, Habener JF. Defective melanocortin 4 receptors inhyperphagia and morbid obesity. N Engl J Med. 2003;348(12):1160–3.13. Campos GM, Ciovica R, Rogers SJ, et al. Spectrum and riskfactors of complications after gastric bypass. Arch Surg. 2007;142(10):969–75. discussion 76.14. National Institutes of Health. Gastrointestinal surgery for severeobesity: National Institutes of Health Consensus DevelopmentConference Statement. Am J Clin Nutr. 1992 Feb;55(2 Suppl):615S–9S.15. Campos GM, Rabl C, Mulligan K, et al. Factors associated withweight loss after gastric bypass. Arch Surg. 2008;143(9):877–83.discussion 84.16. Deitel M, Gawdat K, Melissas J. Reporting weight loss 2007.Obes Surg. 2007;17(5):565–8.17. Pories WJ. Bariatric surgery: risks and rewards. J Clin EndocrinolMetab. 2008;93(11 Suppl 1):S89–96.18. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: asystematic review and meta-analysis. Jama. 2004;292(14):1724–37.19. Nguyen NT, Slone JA, Nguyen XM, et al. A prospective randomizedtrial of laparoscopic gastric bypass versus laparoscopic adjustablegastric banding for the treatment of morbid obesity: outcomes,quality of life, and costs. Ann Surg. 2009;250:631–41.20. Buchwald H, Estok R, Fahrbach K, et al. Weight and type 2diabetes after bariatric surgery: systematic review and meta-analysis. Am J Med. 2009;122(3):248–56. e5.934 OBES SURG (2011) 21:930–934

English

Weight Loss after Roux-en-Y Gastric Bypass in Obese Patients Heterozygous for MC4R Mutations

Weight loss after Roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations.

Weight loss after Roux-en-Y gastric bypass in obese patients heterozygous for MC4R mutations.

Abstract

Similar works

Full text

Available Versions

eScholarship - University of California