title: Melanocortin-4 receptor signaling is required for weight loss after gastric bypass surgery.
abstract: BACKGROUND
  Roux-en-Y gastric bypass (RYGB) is one of the most effective long-term therapies for the treatment of severe obesity. Recent evidence indicates that RYGB effects weight loss through multiple physiological mechanisms, including changes in energy expenditure, food intake, food preference, and reward pathways.
  
  
  OBJECTIVE
  Because central melanocortin signaling plays an important role in the regulation of energy homeostasis, we investigated whether genetic disruption of the melanocortin-4 receptor (MC4R) in rodents and humans affects weight loss after RYGB.
  
  
  RESULTS
  Here we report that MC4R(-/-) mice lost substantially less weight after surgery than wild-type animals, indicating that MC4R signaling is necessary for the weight loss effects of RYGB in this model. Mice heterozygous for MC4R remain fully responsive to gastric bypass. To determine whether mutations affect surgically induced weight loss in humans, we sequenced the MC4R gene in 972 patients undergoing RYGB. Patients heterozygous for MC4R mutations exhibited the same magnitude and distribution of postoperative weight loss as patients without such mutations, suggesting that although two normal copies of the MC4R gene are necessary for normal weight regulation, a single normal copy of the MC4R gene is sufficient to mediate the weight loss effects of RYGB.
  
  
  CONCLUSIONS
  MC4R is the first gene identified that is required for the sustained effects of bariatric surgery. The need for MC4R signaling for the weight loss effects of RYGB in mice underscores the physiological mechanisms of action of this procedure and demonstrates that RYGB both influences and is dependent on the normal pathways that regulate energy balance.
authors.affiliation: Massachusetts General Hospital, 149 13th Street, Room 8219, Charlestown, Massachusetts 02129, USA.
authors.forename: Ida J
authors.initials: IJ
authors.lastname: Hatoum
authors.forename: Nicholas
authors.initials: N
authors.lastname: Stylopoulos
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Vanhoose
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Boyd
authors.forename: Deng Ping
authors.initials: DP
authors.lastname: Yin
authors.forename: Kate L J
authors.initials: KL
authors.lastname: Ellacott
authors.forename: Lian Li
authors.initials: LL
authors.lastname: Ma
authors.forename: Kasia
authors.initials: K
authors.lastname: Blaszczyk
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Roger D
authors.initials: RD
authors.lastname: Cone
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Lee M
authors.initials: LM
authors.lastname: Kaplan
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D004435:Eating / Q000502:physiology; D004734:Energy Metabolism / Q000502:physiology; D005260:Female; D015390:Gastric Bypass; D006579:Heterozygote; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D015431:Weight Loss / Q000502:physiology*
chemical_list: C470072:MC4R protein, human; C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4