title: Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity.
abstract: Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed melanocortin 2 receptor accessory protein 2 (MRAP2), we characterized mice with whole-body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic adenosine monophosphate, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.
authors.affiliation: Division of Endocrinology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Masato
authors.initials: M
authors.lastname: Asai
authors.forename: Shwetha
authors.initials: S
authors.lastname: Ramachandrappa
authors.forename: Maria
authors.initials: M
authors.lastname: Joachim
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shen
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Nikhil
authors.initials: N
authors.lastname: Nuthalapati
authors.forename: Visali
authors.initials: V
authors.lastname: Ramanathan
authors.forename: David E
authors.initials: DE
authors.lastname: Strochlic
authors.forename: Peter
authors.initials: P
authors.lastname: Ferket
authors.forename: Kirsten
authors.initials: K
authors.lastname: Linhart
authors.forename: Caroline
authors.initials: C
authors.lastname: Ho
authors.forename: Tatiana V
authors.initials: TV
authors.lastname: Novoselova
authors.forename: Sumedha
authors.initials: S
authors.lastname: Garg
authors.forename: Martin
authors.initials: M
authors.lastname: Ridderstråle
authors.forename: Claude
authors.initials: C
authors.lastname: Marcus
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Julia M
authors.initials: JM
authors.lastname: Keogh
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: Li F
authors.initials: LF
authors.lastname: Chan
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Clark
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Majzoub
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000818:Animals; D015992:Body Mass Index; D001835:Body Weight / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D058261:Receptor Activity-Modifying Proteins / Q000235:genetics / Q000378:metabolism*; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C574273:MC4R protein, mouse; C551627:MRAP2 protein, human; C582669:MRAP2 protein, mouse; D058261:Receptor Activity-Modifying Proteins; D044105:Receptor, Melanocortin, Type 4